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Review Article

Organotypic liver culture models: Meeting current challenges in toxicity testing

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Pages 501-548 | Received 15 Oct 2011, Accepted 30 Mar 2012, Published online: 15 May 2012

References

  • Abdelmegeed MA, Carruthers NJ, Woodcroft KJ, Kim SK, Novak RF. (2005). Acetoacetate induces CYP2E1 protein and suppresses CYP2E1 mRNA in primary cultured rat hepatocytes. J Pharmacol Exp Ther 315:203–213.
  • Adams DH, Afford SC. (2002). The role of cholangiocytes in the development of chronic inflammatory liver disease. Front Biosci 7:e276–e285.
  • Agarwal S, Holton KL, Lanza R. (2008). Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells 26:1117–1127.
  • Akrawi M, Rogiers V, Vandenberghe Y, Palmer CN, Vercruysse A, Shephard EA, Phillips IR. (1993). Maintenance and induction in co-cultured rat hepatocytes of components of the cytochrome P450-mediated mono-oxygenase. Biochem Pharmacol 45:1583–1591.
  • Alison MR, Islam S, Lim S. (2009). Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly. J Pathol 217:282–298.
  • Allen JW, Bhatia SN. (2003). Formation of steady-state oxygen gradients in vitro: application to liver zonation. Biotechnol Bioeng 82:253–262.
  • Andersen ME, Krewski D. (2010). The vision of toxicity testing in the 21st century: moving from discussion to action. Toxicol Sci 117:17–24.
  • Angulo P, Lindor KD. (2002). Non-alcoholic fatty liver disease. J Gastroenterol Hepatol 17 Suppl:S186–S190.
  • Anundi I, Lähteenmäki T, Rundgren M, Moldeus P, Lindros KO. (1993). Zonation of acetaminophen metabolism and cytochrome P450 2E1-mediated toxicity studied in isolated periportal and perivenous hepatocytes. Biochem Pharmacol 45:1251–1259.
  • Apte U, Thompson MD, Cui S, Liu B, Cieply B, Monga SP. (2008). Wnt/beta-catenin signaling mediates oval cell response in rodents. Hepatology 47:288–295.
  • Arterburn LM, Zurlo J, Yager JD, Overton RM, Heifetz AH. (1995). A morphological study of differentiated hepatocytes in vitro. Hepatology 22:175–187.
  • Asahina K, Tsai SY, Li P, Ishii M, Maxson RE Jr, Sucov HM, Tsukamoto H. (2009). Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascular mesenchymal cells during mouse liver development. Hepatology 49:998–1011.
  • Badr MZ, Belinsky SA, Kauffman FC, Thurman RG. (1986). Mechanism of hepatotoxicity to periportal regions of the liver lobule due to allyl alcohol: role of oxygen and lipid peroxidation. J Pharmacol Exp Ther 238:1138–1142.
  • Baker M. (2011). Tissue models: a living system on a chip. Nature 471:661–665.
  • Balagaddé FK, You L, Hansen CL, Arnold FH, Quake SR. (2005). Long-term monitoring of bacteria undergoing programmed population control in a microchemostat. Science 309:137–140.
  • Banales JM, Prieto J, Medina JF. (2006). Cholangiocyte anion exchange and biliary bicarbonate excretion. World J Gastroenterol 12:3496–3511.
  • Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Quinn G, Okochi H, Ochiya T. (2007). Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology 46:219–228.
  • Basma H, Soto-Gutiérrez A, Yannam GR, Liu L, Ito R, Yamamoto T, Ellis E, Carson SD, Sato S, Chen Y, Muirhead D, Navarro-Alvarez N, Wong RJ, Roy-Chowdhury J, Platt JL, Mercer DF, Miller JD, Strom SC, Kobayashi N, Fox IJ. (2009). Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology 136:990–999.
  • Baum B, Georgiou M. (2011). Dynamics of adherens junctions in epithelial establishment, maintenance, and remodeling. J Cell Biol 192:907–917.
  • Bayad J, Sabolovic N, Bagrel D, Magdalou J, Siest G. (1991). Influence of the isolation method on the stability of differentiated phenotype in cultured rat hepatocytes. J Pharmacol Methods 25:85–94.
  • Ben-Ze’ev A, Robinson GS, Bucher NL, Farmer SR. (1988). Cell-cell and cell-matrix interactions differentially regulate the expression of hepatic and cytoskeletal genes in primary cultures of rat hepatocytes. Proc Natl Acad Sci USA 85:2161–2165.
  • Berry MN, Edwards AM, Barritt GJ. (1991). Isolated Hepatocytes: Preparation, Properties and Applications. New York: Elsevier Sciences Publishing Co.
  • Bessems M, ‘t Hart NA, Tolba R, Doorschodt BM, Leuvenink HG, Ploeg RJ, Minor T, van Gulik TM. (2006). The isolated perfused rat liver: standardization of a time-honoured model. Lab Anim 40:236–246.
  • Bhattacharya S, Zhang Q, Carmichael PL, Boekelheide K, Andersen ME. (2011). Toxicity testing in the 21 century: defining new risk assessment approaches based on perturbation of intracellular toxicity pathways. PLoS ONE 6:e20887.
  • Binda D, Lasserre-Bigot D, Bonet A, Thomassin M, Come MP, Guinchard C, Bars R, Jacqueson A, Richert L. (2003). Time course of cytochromes P450 decline during rat hepatocyte isolation and culture: effect of L-NAME. Toxicol In Vitro 17:59–67.
  • Bioulac-Sage P, Lebail B. Balabaud C. (2007). Liver and biliary tract histology. In: Rodés J, Benhamou J-P, Blei AT, Reichen J Rizzetto M (eds.) Textbook of hepatology: from basic science to clinical practice. 3rd edition. Malden: Wiley-Blackwell Publishing.
  • Bird TG, Lorenzini S, Forbes SJ. (2008). Activation of stem cells in hepatic diseases. Cell Tissue Res 331:283–300.
  • Bissell DM, Arenson DM, Maher JJ, Roll FJ. (1987). Support of cultured hepatocytes by a laminin-rich gel. Evidence for a functionally significant subendothelial matrix in normal rat liver. J Clin Invest 79:801–812.
  • Bissell DM, Caron JM, Babiss LE, Friedman JM. (1990a). Transcriptional regulation of the albumin gene in cultured rat hepatocytes. Role of basement-membrane matrix. Mol Biol Med 7:187–197.
  • Bissell DM, Choun MO. (1988). The role of extracellular matrix in normal liver. Scand J Gastroenterol Suppl 151:1–7.
  • Black M. (1984). Acetaminophen hepatotoxicity. Annu Rev Med 35:577–593.
  • Bogert PT, LaRusso NF. (2007). Cholangiocyte biology. Curr Opin Gastroenterol 23:299–305.
  • Bradley SE, Ingelfinger FJ. (1945). The estimation of hepatic blood flow in man. J Clin Invest 24:890–897.
  • Braet F, Wisse E. (2002). Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp Hepatol 1:1.
  • Braga VM, Yap AS. (2005). The challenges of abundance: epithelial junctions and small GTPase signalling. Curr Opin Cell Biol 17:466–474.
  • Brophy CM, Luebke-Wheeler JL, Amiot BP, Khan H, Remmel RP, Rinaldo P, Nyberg SL. (2009). Rat hepatocyte spheroids formed by rocked technique maintain differentiated hepatocyte gene expression and function. Hepatology 49:578–586.
  • Bucher NL, Robinson GS, Farmer SR. (1990). Effects of extracellular matrix on hepatocyte growth and gene expression: implications for hepatic regeneration and the repair of liver injury. Semin Liver Dis 10:11–19.
  • Bullock P, Gemzik B, Johnson D, Thomas P, Parkinson A. (1991). Evidence from dwarf rats that growth hormone may not regulate the sexual differentiation of liver cytochrome P450 enzymes and steroid 5 alpha-reductase. Proc Natl Acad Sci USA 88:5227–5231.
  • Burczynski ME, Penning TM. (2000). Genotoxic polycyclic aromatic hydrocarbon ortho-quinones generated by aldo-keto reductases induce CYP1A1 via nuclear translocation of the aryl hydrocarbon receptor. Cancer Res 60:908–915.
  • Bustelo XR, Sauzeau V, Berenjeno IM. (2007). GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. Bioessays 29:356–370.
  • Capila I, Linhardt RJ. (2002). Heparin-protein interactions. Angew Chem Int Ed Engl 41:391–412.
  • Castell JV, Jover R, Martínez-Jiménez CP, Gómez-Lechón MJ. (2006). Hepatocyte cell lines: their use, scope and limitations in drug metabolism studies. Expert Opin Drug Metab Toxicol 2:183–212.
  • Celli A, Que FG, Gores GJ, LaRusso NF. (1998). Glutathione depletion is associated with decreased Bcl-2 expression and increased apoptosis in cholangiocytes. Am J Physiol 275:G749–G757.
  • Celton-Morizur S, Desdouets C. (2010). Polyploidization of liver cells. Adv Exp Med Biol 676:123–135.
  • Chao P, Maguire T, Novik E, Cheng KC, Yarmush ML. (2009). Evaluation of a microfluidic based cell culture platform with primary human hepatocytes for the prediction of hepatic clearance in human. Biochem Pharmacol 78:625–632.
  • Chapman LM, Eddy EM. (1989). A protein associated with the mouse and rat hepatocyte junctional complex. Cell Tissue Res 257:333–341.
  • Chazouilleres O, Housset C. (2007). Intrahepatic cholestasis. In: Rodes J, Benhamou J, Blei AT, Reichen J, Rizzetto M. (eds.) Textbook of Hepatology: From Basic Science to Clinical Practice. 3rd edition. Malden, MA: Wiley-Blackwell Publishing.
  • Choi K, Joo H, Campbell JL Jr, Clewell RA, Andersen ME, Clewell HJ 3rd. (2012). In vitro metabolism of di(2-ethylhexyl) phthalate (DEHP) by various tissues and cytochrome P450s of human and rat. Toxicol In Vitro 26:315–322.
  • Clement B, Guguen-Guillouzo C, Campion JP, Glaise D, Bourel M, Guillouzo A. (1984). Long-term co-cultures of adult human hepatocytes with rat liver epithelial cells: modulation of albumin secretion and accumulation of extracellular material. Hepatology 4:373–380.
  • Clement B, Guguen-Guillouzo C, Grimaud JA, Rissel M, Guillouzo A. (1988a). Effect of hydrocortisone on deposition of types I and IV collagen in primary culture of rat hepatocytes. Cell Mol Biol 34:449–460.
  • Clement B, Laurent M, Guguen-Guillouzo C, Lebeau G, Guillouzo A. (1988b). Types I and IV procollagen gene expression in cultured rat hepatocytes. Coll Relat Res 8:349–359.
  • Clément B, Rescan PY, Baffet G, Loréal O, Lehry D, Campion JP, Guillouzo A. (1988c). Hepatocytes may produce laminin in fibrotic liver and in primary culture. Hepatology 8:794–803.
  • Clevers H. (2006). Wnt/beta-catenin signaling in development and disease. Cell 127:469–480.
  • Clewell HJ, Tan YM, Campbell JL, Andersen ME. (2008). Quantitative interpretation of human biomonitoring data. Toxicol Appl Pharmacol 231:122–133.
  • Coger R, Moghe P, Ezzell RM, Yarmush M, Toner, M. (1997). Hepatocyte Aggregation and the Reorganization of EHS Matrix Gel. Tissue Engineering 3, 375–390.
  • Cogger VC, McNerney GP, Nyunt T, DeLeve LD, McCourt P, Smedsrød B, Le Couteur DG, Huser TR. (2010). Three-dimensional structured illumination microscopy of liver sinusoidal endothelial cell fenestrations. J Struct Biol 171:382–388.
  • Corcoran GB, Mitchell JR, Vaishnav YN, Horning EC. (1980). Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyl-p-benzoquinoneimine. Mol Pharmacol 18:536–542.
  • Cullen JM, Ruebner BH. (1919). A histopathologic classification of chemical-induced injury of the liver. In: Meeks RG, Harrison SD, Bull RJ. (eds.) Hepatotoxicology. Boca Raton, FL: CRC Press.
  • Dash A, Inman W, Hoffmaster K, Sevidal S, Kelly J, Obach RS, Griffith LG, Tannenbaum SR. (2009). Liver tissue engineering in the evaluation of drug safety. Expert Opin Drug Metab Toxicol 5:1159–1174.
  • De Bartolo L, Bader A. (2001). Review of a flat membrane bioreactor as a bioartificial liver. Ann Transplant 6:40–46.
  • De Pablo C, Orden S, Apostolova N, Blanquer A, Esplugues JV, Alvarez A. (2010). Abacavir and didanosine induce the interaction between human leukocytes and endothelial cells through Mac-1 upregulation. AIDS 24:1259–1266.
  • De Simone V, Cortese R. (1991). Transcriptional regulation of liver-specific gene expression. Curr Opin Cell Biol 3:960–965.
  • De Simone V, Cortese R. (1992). Transcription factors and liver-specific genes. Biochim Biophys Acta 1132:119–126.
  • Deaciuc II, D’souza NB, Fortunato F, Hill DB, Sarphie TG, Mcclain CJ. (2001). Alcohol-induced sinusoidal endothelial cell dysfunction in the mouse is associated with exacerbated liver apoptosis and can be reversed by caspase inhibition. Hepatol Res, 19, 85–97.
  • DeLeve LD. (2007a). The hepatic sinusoidal endothelial cells. In: Aird W. (eds.) Endothelial biomedicine. Cambridge University Press.
  • DeLeve LD. (2007b). Hepatic microvasculature in liver injury. Semin Liver Dis 27:390–400.
  • Deleve LD, Wang X, Guo Y. (2008). Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 48:920–930.
  • DeLeve LD, Wang X, Hu L, McCuskey MK, McCuskey RS. (2004). Rat liver sinusoidal endothelial cell phenotype is maintained by paracrine and autocrine regulation. Am J Physiol Gastrointest Liver Physiol 287:G757–G763.
  • DeLeve LD, Wang X, Kaplowitz N, Shulman HM, Bart JA, van der Hoek A. (1997). Sinusoidal endothelial cells as a target for acetaminophen toxicity. Direct action versus requirement for hepatocyte activation in different mouse strains. Biochem Pharmacol 53:1339–1345.
  • DeLeve LD, Wang X, McCuskey MK, McCuskey RS. (2006). Rat liver endothelial cells isolated by anti-CD31 immunomagnetic separation lack fenestrae and sieve plates. Am J Physiol Gastrointest Liver Physiol 291:G1187–G1189.
  • Derman E, Krauter K, Walling L, Weinberger C, Ray M, Darnell JE Jr (1981). Transcriptional control in the production of liver-specific mRNAs. Cell 23:731–739.
  • Desai RA, Gao L, Raghavan S, Liu WF, Chen CS. (2009). Cell polarity triggered by cell-cell adhesion via E-cadherin. J Cell Sci 122:905–911.
  • Desantis AJ, Blei AT. (2007). The effect of endocrine diseases on liver function. In: Rodes J, Benhamou J, Blei A, Reichen J, Rizzetto M. (eds.) Textbook of Hepatology: From Basic Science to Clinical Practice. 3 ed. Malden, MA: Wiley-Blackwell Publishing.
  • Dhainaut JF, Marin N, Mignon A, Vinsonneau C. (2001). Hepatic response to sepsis: interaction between coagulation and inflammatory processes. Crit Care Med 29:S42–S47.
  • Dich J, Grunnet N. (1990). Primary cultures of rat hepatocytes. Methods Mol Biol 5:161–176.
  • Dich J, Grunnet N. (1992). A perifusion system for cultured hepatocytes. Anal Biochem 206:68–72.
  • Dilworth C, Hamilton GA, George E, Timbrell JA. (2000). The use of liver spheroids as an in vitro model for studying induction of the stress response as a marker of chemical toxicity. Toxicol In Vitro 14:169–176.
  • Domansky K, Inman W, Serdy J, Dash A, Lim MH, Griffith LG. (2010). Perfused multiwell plate for 3D liver tissue engineering. Lab Chip 10:51–58.
  • Donato MT, Castell JV, Gómez-Lechón MJ. (1991). Co-cultures of hepatocytes with epithelial-like cell lines: expression of drug-biotransformation activities by hepatocytes. Cell Biol Toxicol 7:1–14.
  • Donato MT, Gómez-Lechón MJ, Castell JV. (1990). Drug metabolizing enzymes in rat hepatocytes co-cultured with cell lines. In Vitro Cell Dev Biol 26:1057–1062.
  • Donato MT, Gómez-Lechón MJ, Castell JV. (1993). A microassay for measuring cytochrome P450IA1 and P450IIB1 activities in intact human and rat hepatocytes cultured on 96-well plates. Anal Biochem 213:29–33.
  • Doshi U, Li AP. (2011). Luciferin IPA-based higher throughput human hepatocyte screening assays for CYP3A4 inhibition and induction. J Biomol Screen 16:903–909.
  • Dunn JC, Tompkins RG, Yarmush ML. (1991). Long-term in vitro function of adult hepatocytes in a collagen sandwich configuration. Biotechnol Prog 7:237–245.
  • Dunn JC, Yarmush ML, Koebe HG, Tompkins RG. (1989). Hepatocyte function and extracellular matrix geometry: long-term culture in a sandwich configuration. FASEB J 3:174–177.
  • Dvir-Ginzberg M, Gamlieli-Bonshtein I, Agbaria R, Cohen S. (2003). Liver tissue engineering within alginate scaffolds: effects of cell-seeding density on hepatocyte viability, morphology, and function. Tissue Eng 9:757–766.
  • Edling Y, Sivertsson LK, Butura A, Ingelman-Sundberg M, Ek M. (2009). Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro 23:1387–1395.
  • Edwards AM, Glistak ML, Lucas CM, Wilson PA. (1984). 7-Ethoxycoumarin deethylase activity as a convenient measure of liver drug metabolizing enzymes: regulation in cultured rat hepatocytes. Biochem Pharmacol 33:1537–1546.
  • Enat R, Jefferson DM, Ruiz-Opazo N, Gatmaitan Z, Leinwand LA, Reid LM. (1984). Hepatocyte proliferation in vitro: its dependence on the use of serum-free hormonally defined medium and substrata of extracellular matrix. Proc Natl Acad Sci USA 81:1411–1415.
  • Engler AJ, Sen S, Sweeney HL, Discher DE. (2006). Matrix elasticity directs stem cell lineage specification. Cell 126:677–689.
  • Esch MB, King TL, Shuler ML. (2011). The role of body-on-a-chip devices in drug and toxicity studies. Annu Rev Biomed Eng 13:55–72.
  • Ezzell RM, Toner M, Hendricks K, Dunn JC, Tompkins RG, Yarmush ML. (1993). Effect of collagen gel configuration on the cytoskeleton in cultured rat hepatocytes. Exp Cell Res 208:442–452.
  • Fava G, Glaser S, Francis H, Alpini G. (2005). The immunophysiology of biliary epithelium. Semin Liver Dis 25:251–264.
  • Ferri D, Moro L, Mastrodonato M, Capuano F, Marra E, Liquori GE, Greco M. (2005). Ultrastructural zonal heterogeneity of hepatocytes and mitochondria within the hepatic acinus during liver regeneration after partial hepatectomy. Biol Cell 97:277–288.
  • Fladmark KE, Gjertsen BT, Molven A, Mellgren G, Vintermyr OK, Døskeland SO. (1997). Gap junctions and growth control in liver regeneration and in isolated rat hepatocytes. Hepatology 25:847–855.
  • Forbes S, Vig P, Poulsom R, Thomas H, Alison M. (2002). Hepatic stem cells. J Pathol 197:510–518.
  • Francis H, Glaser S, Demorrow S, Gaudio E, Ueno Y, Venter J, Dostal D, Onori P, Franchitto A, Marzioni M, Vaculin S, Vaculin B, Katki K, Stutes M, Savage J, Alpini G. (2008). Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway. Am J Physiol, Cell Physiol 295:C499–C513.
  • Friedman SL. (2006). Transcriptional regulation of stellate cell activation. J Gastroenterol Hepatol 21 Suppl 3:S79–S83.
  • Friedman SL. (2008). Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88:125–172.
  • Gaudio E, Carpino G, Cardinale V, Franchitto A, Onori P, Alvaro D. (2009). New insights into liver stem cells. Dig Liver Dis 41:455–462.
  • Gebhardt R. (1992). Metabolic zonation of the liver: regulation and implications for liver function. Pharmacol Ther 53:275–354.
  • Gebhardt R, Fischer S. (1995). Enhanced sensitivity of perifused primary rat hepatocytes to mitogens and growth modulation by carcinogens. Toxicol In Vitro 9:445–451.
  • Gebhardt R, Hengstler JG, Müller D, Glöckner R, Buenning P, Laube B, Schmelzer E, Ullrich M, Utesch D, Hewitt N, Ringel M, Hilz BR, Bader A, Langsch A, Koose T, Burger HJ, Maas J, Oesch F. (2003). New hepatocyte in vitro systems for drug metabolism: metabolic capacity and recommendations for application in basic research and drug development, standard operation procedures. Drug Metab Rev 35:145–213.
  • Gebhardt R, Mecke D. (1979a). Perifused monolayer cultures of rat hepatocytes as an improved in vitro system for studies on ureogenesis. Exp Cell Res 124:349–359.
  • Gebhardt R, Mecke D. (1979b). The role of growth hormone, dexamethasone and triiodothyronine in the regulation of glutamine synthetase in primary cultures of rat hepatocytes. Eur J Biochem 100:519–525.
  • Gebhardt R, Wegner H, Alber J. (1996). Perifusion of co-cultured hepatocytes: optimization of studies on drug metabolism and cytotoxicity in vitro. Cell Biol Toxicol 12:57–68.
  • Geerts A. (2001). History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis 21:311–335.
  • Geiger B, Ayalon O. (1992). Cadherins. Annu Rev Cell Biol 8:307–332.
  • Gemzik B, Jacob S, Jennings S, Veltman J, Parkinson A. (1992). Species differences in 5 alpha-androstane-3 beta,17 beta-diol hydroxylation by rat, monkey, and human prostate microsomes. Arch Biochem Biophys 296:374–383.
  • Glaser S, Francis H, Demorrow S, Lesage G, Fava G, Marzioni M, Venter J, Alpini G. (2006). Heterogeneity of the intrahepatic biliary epithelium. World J Gastroenterol 12:3523–3536.
  • Glaser SS, Gaudio E, Miller T, Alvaro D, Alpini G. (2009). Cholangiocyte proliferation and liver fibrosis. Expert Rev Mol Med 11:e7.
  • Glicklis R, Merchuk JC, Cohen S. (2004). Modeling mass transfer in hepatocyte spheroids via cell viability, spheroid size, and hepatocellular functions. Biotechnol Bioeng 86:672–680.
  • Golosow N, Grobstein C. (1962). Epitheliomesenchymal interaction in pancreatic morphogenesis. Dev Biol 4:242–255.
  • Gómez-Lechón MJ, Castell JV, Donato MT. (2008). An update on metabolism studies using human hepatocytes in primary culture. Expert Opin Drug Metab Toxicol 4:837–854.
  • Gómez-Lechón MJ, Lahoz A, Gombau L, Castell JV, Donato MT. (2010). In vitro evaluation of potential hepatotoxicity induced by drugs. Curr Pharm Des 16:1963–1977.
  • Grant MH, Melvin MA, Shaw P, Melvin WT, Burke MD. (1985). Studies on the maintenance of cytochromes P-450 and b5, monooxygenases and cytochrome reductases in primary cultures of rat hepatocytes. FEBS Lett 190:99–103.
  • Griffith LG, Swartz MA. (2006). Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol 7:211–224.
  • Grisham JW, Hartroft WS. (1961). Morphologic identification by electron microscopy of “oval” cells in experimental hepatic degeneration. Lab Invest 10:317–332.
  • Guguen-Guillouzo C, Clément B, Baffet G, Beaumont C, Morel-Chany E, Glaise D, Guillouzo A. (1983). Maintenance and reversibility of active albumin secretion by adult rat hepatocytes co-cultured with another liver epithelial cell type. Exp Cell Res 143:47–54.
  • Guguen-Guillouzo C, Corlu A, Guillouzo A. (2010). Stem cell-derived hepatocytes and their use in toxicology. Toxicology 270:3–9.
  • Guillouzo A, Corlu A, Aninat C, Glaise D, Morel F, Guguen-Guillouzo C. (2007). The human hepatoma HepaRG cells: a highly differentiated model for studies of liver metabolism and toxicity of xenobiotics. Chem Biol Interact 168:66–73.
  • Guillouzo A, Guguen-Guillouzo C. (2008). Evolving concepts in liver tissue modeling and implications for in vitro toxicology. Expert Opin Drug Metab Toxicol 4:1279–1294.
  • Guillouzo A, Morel F, Ratanasavanh D, Chesne C, Guguen-Guillouzo C. (1990). Long-term culture of functional hepatocytes. Toxicol In Vitro 4:415–427.
  • Gupta S. (2000). Hepatic polyploidy and liver growth control. Semin Cancer Biol 10:161–171.
  • Hamilton GA, Jolley SL, Gilbert D, Coon DJ, Barros S, LeCluyse EL. (2001). Regulation of cell morphology and cytochrome P450 expression in human hepatocytes by extracellular matrix and cell-cell interactions. Cell Tissue Res 306:85–99.
  • Hariparsad N, Carr BA, Evers R, Chu X. (2008). Comparison of immortalized Fa2N-4 cells and human hepatocytes as in vitro models for cytochrome P450 induction. Drug Metab Dispos 36:1046–1055.
  • Harries HM, Fletcher ST, Duggan CM, Baker VA. (2001). The use of genomics technology to investigate gene expression changes in cultured human liver cells. Toxicol In Vitro 15:399–405.
  • Harris AJ, Dial SL, Casciano DA. (2004). Comparison of basal gene expression profiles and effects of hepatocarcinogens on gene expression in cultured primary human hepatocytes and HepG2 cells. Mutat Res 549:79–99.
  • Hastings NE, Feaver RE, Lee MY, Wamhoff BR, Blackman BR. (2009). Human IL-8 regulates smooth muscle cell VCAM-1 expression in response to endothelial cells exposed to atheroprone flow. Arterioscler Thromb Vasc Biol 29:725–731.
  • Hastings NE, Simmers MB, McDonald OG, Wamhoff BR, Blackman BR. (2007). Atherosclerosis-prone hemodynamics differentially regulates endothelial and smooth muscle cell phenotypes and promotes pro-inflammatory priming. Am J Physiol, Cell Physiol 293:C1824–C1833.
  • Hay DC, Fletcher J, Payne C, Terrace JD, Gallagher RC, Snoeys J, Black JR, Wojtacha D, Samuel K, Hannoun Z, Pryde A, Filippi C, Currie IS, Forbes SJ, Ross JA, Newsome PN, Iredale JP. (2008). Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling. Proc Natl Acad Sci USA 105:12301–12306.
  • Hayes A, Tudor D, Nowell M, Caterson B, Hughes, C. (2007). Unique forms of chondroitin sulfate proteoglycans in stem cell niches. J Histochem Cytochem 56, 125–138.
  • Hendriks HF, Verhoofstad WA, Brouwer A, de Leeuw AM, Knook DL. (1985). Perisinusoidal fat-storing cells are the main vitamin A storage sites in rat liver. Exp Cell Res 160:138–149.
  • Hewitt NJ, de Kanter R, LeCluyse E. (2007a). Induction of drug metabolizing enzymes: a survey of in vitro methodologies and interpretations used in the pharmaceutical industry–do they comply with FDA recommendations? Chem Biol Interact 168:51–65.
  • Hewitt NJ, Lechón MJ, Houston JB, Hallifax D, Brown HS, Maurel P, Kenna JG, Gustavsson L, Lohmann C, Skonberg C, Guillouzo A, Tuschl G, Li AP, LeCluyse E, Groothuis GM, Hengstler JG. (2007b). Primary hepatocytes: current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metab Rev 39:159–234.
  • Hewitt NJ, LeCluyse EL, Ferguson SS. (2007c). Induction of hepatic cytochrome P450 enzymes: methods, mechanisms, recommendations, and in vitro-in vivo correlations. Xenobiotica 37:1196–1224.
  • Higuchi S, Wu R, Zhou M, Ravikumar TS, Wang P. (2007). Downregulation of hepatic cytochrome P-450 isoforms and PPAR-gamma: their role in hepatic injury and proinflammatory responses in a double-hit model of hemorrhage and sepsis. J Surg Res 137:46–52.
  • Hoebe KH, Witkamp RF, Fink-Gremmels J, Van Miert AS, Monshouwer M. (2001). Direct cell-to-cell contact between Kupffer cells and hepatocytes augments endotoxin-induced hepatic injury. Am J Physiol Gastrointest Liver Physiol 280:G720–G728.
  • Hong Y, Müller UR, Lai F. (2003). Discriminating two classes of toxicants through expression analysis of HepG2 cells with DNA arrays. Toxicol In Vitro 17:85–92.
  • Houck KA, Dix DJ, Judson RS, Kavlock RJ, Yang J, Berg EL. (2009). Profiling bioactivity of the ToxCast chemical library using BioMAP primary human cell systems. J Biomol Screen 14:1054–1066.
  • Houck KA, Kavlock RJ. (2008). Understanding mechanisms of toxicity: insights from drug discovery research. Toxicol Appl Pharmacol 227:163–178.
  • Hsu HC, Tseng HJ, Lai PL, Lee PH, Peng SY. (1993b). Expression of p53 gene in 184 unifocal hepatocellular carcinomas: association with tumor growth and invasiveness. Cancer Res 53:4691–4694.
  • Hu M, Kurobe M, Jeong YJ, Fuerer C, Ghole S, Nusse R, Sylvester KG. (2007). Wnt/beta-catenin signaling in murine hepatic transit amplifying progenitor cells. Gastroenterology 133:1579–1591.
  • Huang S, Ingber DE. (1999). The structural and mechanical complexity of cell-growth control. Nat Cell Biol 1:E131–E138.
  • Huang SB, Wu MH, Wang SS, Lee GB. (2011). Microfluidic cell culture chip with multiplexed medium delivery and efficient cell/scaffold loading mechanisms for high-throughput perfusion 3-dimensional cell culture-based assays. Biomed Microdevices 13:415–430.
  • Huang SM, Temple R, Throckmorton DC, Lesko LJ. (2007). Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin Pharmacol Ther 81:298–304.
  • Hubbard AL, Bartles JR, Braiterman LT. (1985). Identification of rat hepatocyte plasma membrane proteins using monoclonal antibodies. J Cell Biol 100:1115–1125.
  • Hughes RC, Stamatoglou SC. (1987). Adhesive interactions and the metabolic activity of hepatocytes. J Cell Sci Suppl 8:273–291.
  • Hwa AJ, Fry RC, Sivaraman A, So PT, Samson LD, Stolz DB, Griffith LG. (2007). Rat liver sinusoidal endothelial cells survive without exogenous VEGF in 3D perfused co-cultures with hepatocytes. FASEB J 21:2564–2579.
  • Ichihara A. (1991). Mechanisms controlling growth of hepatocytes in primary culture. Dig Dis Sci 36:489–493.
  • Ingber DE. (1993). Cellular tensegrity: defining new rules of biological design that govern the cytoskeleton. J Cell Sci 104 (Pt 3):613–627.
  • Ishak KG, Zimmerman HJ. (1987). Hepatotoxic effects of the anabolic/androgenic steroids. Semin Liver Dis 7:230–236.
  • Ishibashi H, Nakamura M, Komori A, Migita K, Shimoda S. (2009). Liver architecture, cell function, and disease. Semin Immunopathol 31:399–409.
  • Ishihara Y, Shiba D, Shimamoto N. (2005). Primary hepatocyte apoptosis is unlikely to relate to caspase-3 activity under sustained endogenous oxidative stress. Free Radic Res 39:163–173.
  • Ito Y, Bethea NW, Abril ER, McCuskey RS. (2003). Early hepatic microvascular injury in response to acetaminophen toxicity. Microcirculation 10:391–400.
  • Ito Y, McCuskey, R. (2007). Hepatic microcirculation. In: Rodes J, Benhamou J, Blei A, Reichen J, Rizzetto M.. (eds.) Textbook of Hepatology: From Basic Sciences to Clinical Practice. 3rd edition. Malden, MA: Wiley-Blackwell Publishing.
  • Jaeschke H. (2007). Kupffer cells.. In: Rodes J, Benhamou J, Blei A, Reichen J Rizzetto M. (eds.) Textbook of hepatology: from basic science to clinical practice. 3rd edition. Malden, MA: Wiley-Blackwell Publishing.
  • Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ. (2002). Mechanisms of hepatotoxicity. Toxicol Sci 65:166–176.
  • Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, Browning B, Michaelson JS, Baetscher M, Baestcher M, Wang B, Bissell DM, Burkly LC. (2005). TWEAK induces liver progenitor cell proliferation. J Clin Invest 115:2330–2340.
  • Jennen DG, Magkoufopoulou C, Ketelslegers HB, van Herwijnen MH, Kleinjans JC, van Delft JH. (2010). Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci 115:66–79.
  • Jennings GS, Oesch F, Steinberg P.. (1992). In vivo formation of aflatoxin B1-DNA adducts in parenchymal and non-parenchymal cells of rat liver. Carcinogenesis 13:831–835.
  • Judson RS, Houck KA, Kavlock RJ, Knudsen TB, Martin MT, Mortensen HM, Reif DM, Rotroff DM, Shah I, Richard AM, Dix DJ. (2010). In vitro screening of environmental chemicals for targeted testing prioritization: the ToxCast project. Environ Health Perspect 118:485–492.
  • Jungermann K, Kietzmann T. (1996). Zonation of parenchymal and nonparenchymal metabolism in liver. Annu Rev Nutr 16:179–203.
  • Kanebratt KP, Andersson TB. (). Evaluation of HepaRG cells as an in vitro model for human drug metabolism studies. Drug Metab Dispos 36:1444–1452.
  • Kanebratt KP, Andersson TB. (2008b). HepaRG cells as an in vitro model for evaluation of cytochrome P450 induction in humans. Drug Metab Dispos 36:137–145.
  • Katoonizadeh A, Nevens F, Verslype C, Pirenne J, Roskams T. (2006). Liver regeneration in acute severe liver impairment: a clinicopathological correlation study. Liver Int 26:1225–1233.
  • Kemper R, Studwell D, Huang Z, Moore A, Shi J, Khetani S. (2011). Identification of Human Hepatotoxicants by High Content Imaging in Micropatterned Human Hepatocyte Cocultures. SOT 2011 Annual Meeting Baltimore, MD.
  • Khan Z, Crawford JM, Stolz D. (2007). Ultrastructure of the hepatocyte. In: Rodes J, Benhamou J, Blei A, Reichen J. Rizzetto, M. (eds.) Textbook of Hepatology: From Basic Science to CLinical Practice. Malden, MA: Wiley-Blackwell Publishing.
  • Khetani S, Krzyzewski S, Moore A, Gaffney J, Mcgeehan J, Weiwei Wang W, Funk C, Duignan D, Obach R. (2010). Microscale Engineered Human Liver Model for Investigative Toxicology, Drug Metabolism and Efficacy Assessment ISSX 2010 Annual Meeting.
  • Khetani SR, Bhatia SN. (2008). Microscale culture of human liver cells for drug development. Nat Biotechnol 26:120–126.
  • Kinch MS, Clark GJ, Der CJ, Burridge K. (1995). Tyrosine phosphorylation regulates the adhesions of ras-transformed breast epithelia. J Cell Biol 130:461–471.
  • Kinsner-Ovaskainen A, Akkan Z, Casati S, Coecke S, Corvi R, Dal Negro G, De Bruijn J, De Silva O, Gribaldo L, Griesinger C, Jaworska J, Kreysa J, Maxwell G, McNamee P, Price A, Prieto P, Schubert R, Tosti L, Worth A, Zuang V. (2009a). Overcoming barriers to validation of non-animal partial replacement methods/Integrated Testing Strategies: the report of an EPAA-ECVAM workshop. Altern Lab Anim 37:437–444.
  • Kinsner-Ovaskainen A, Bulgheroni A, Hartung T, Prieto P. (2009b). ECVAM’s ongoing activities in the area of acute oral toxicity. Toxicol In Vitro 23:1535–1540.
  • Klaassen CD, Aleksunes LM. (2010). Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev 62:1–96.
  • Klaassen CD, Watkins JB 3rd. (1984). Mechanisms of bile formation, hepatic uptake, and biliary excretion. Pharmacol Rev 36:1–67.
  • Klaus A, Birchmeier W. (2008). Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8:387–398.
  • Klein S, Gebhardt R. (1997). Sensitive detection of growth stimulating tumour promoters in perifused primary rat hepatocyte cultures. Toxicol In Vitro 11:543–547.
  • Klune JR, Tsung A. (2010). Molecular biology of liver ischemia/reperfusion injury: established mechanisms and recent advancements. Surg Clin North Am 90:665–677.
  • Kmiec Z. (2001). Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol 161:III–XIII, 1.
  • Knasmüller S, Parzefall W, Sanyal R, Ecker S, Schwab C, Uhl M, Mersch-Sundermann V, Williamson G, Hietsch G, Langer T, Darroudi F, Natarajan AT. (1998). Use of metabolically competent human hepatoma cells for the detection of mutagens and antimutagens. Mutat Res 402:185–202.
  • Koide N, Sakaguchi K, Koide Y, Asano K, Kawaguchi M, Matsushima H, Takenami T, Shinji T, Mori M, Tsuji T. (1990). Formation of multicellular spheroids composed of adult rat hepatocytes in dishes with positively charged surfaces and under other nonadherent environments. Exp Cell Res 186:227–235.
  • Koide N, Shinji T, Tanabe T, Asano K, Kawaguchi M, Sakaguchi K, Koide Y, Mori M, Tsuji T. (1989). Continued high albumin production by multicellular spheroids of adult rat hepatocytes formed in the presence of liver-derived proteoglycans. Biochem Biophys Res Commun 161:385–391.
  • Kolios G, Valatas V, Kouroumalis E. (2006). Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol 12:7413–7420.
  • Kostrubsky SE, Sinclair JF, Strom SC, Wood S, Urda E, Stolz DB, Wen YH, Kulkarni S, Mutlib A. (2005). Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes. Toxicol Sci 87:146–155.
  • Koutsiaris AG, Tachmitzi SV, Batis N, Kotoula MG, Karabatsas CH, Tsironi E, Chatzoulis DZ. (2007). Volume flow and wall shear stress quantification in the human conjunctival capillaries and post-capillary venules in vivo. Biorheology 44:375–386.
  • Krewski D, Acosta D Jr, Andersen M, Anderson H, Bailar JC 3rd., Boekelheide K, Brent R, Charnley G, Cheung VG, Green S Jr, Kelsey KT, Kerkvliet NI, Li AA, McCray L, Meyer O, Patterson RD, Pennie W, Scala RA, Solomon GM, Stephens M, Yager J, Zeise L. (2010). Toxicity testing in the 21st century: a vision and a strategy. J Toxicol Environ Health B Crit Rev 13:51–138.
  • Krutovskikh VA, Mesnil M, Mazzoleni G, Yamasaki H. (1995). Inhibition of rat liver gap junction intercellular communication by tumor-promoting agents in vivo. Association with aberrant localization of connexin proteins. Lab Invest 72:571–577.
  • Kuri-Harcuch W, Mendoza-Figueroa T. (1989). Cultivation of adult rat hepatocytes on 3T3 cells: expression of various liver differentiated functions. Differentiation 41:148–157.
  • Lalor PF, Adams DH. (1999). Adhesion of lymphocytes to hepatic endothelium. MP, Mol Pathol 52:214–219.
  • Landry J, Bernier D, Ouellet C, Goyette R, Marceau N. (1985). Spheroidal aggregate culture of rat liver cells: histotypic reorganization, biomatrix deposition, and maintenance of functional activities. J Cell Biol 101:914–923.
  • Langsch A, Giri S, Acikgöz A, Jasmund I, Frericks B, Bader A. (2009). Interspecies difference in liver-specific functions and biotransformation of testosterone of primary rat, porcine and human hepatocyte in an organotypical sandwich culture. Toxicol Lett 188:173–179.
  • Laskin JD, Heck DE, Gardner CR, Laskin DL. (2001). Prooxidant and antioxidant functions of nitric oxide in liver toxicity. Antioxid Redox Signal 3:261–271.
  • LeCluyse E, Bullock P, Madan A, Carroll K, Parkinson A. (1999). Influence of extracellular matrix overlay and medium formulation on the induction of cytochrome P-450 2B enzymes in primary cultures of rat hepatocytes. Drug Metab Dispos 27:909–915.
  • LeCluyse E, Bullock P, Parkinson A. (1996a). Strategies for restoration and maintenance of normal hepatic structure and function in long-term cultures of rat hepatocytes. Adv Drug Deliv Rev, 22, 133–186.
  • LeCluyse EL, Bullock PL, Parkinson A, Hochman JH.. 1996b). Cultured rat hepatocytes. Pharm Biotechnol 8:121–159.
  • LeCluyse E, Madan A, Hamilton G, Carroll K, DeHaan R, Parkinson A. (2000). Expression and regulation of cytochrome P450 enzymes in primary cultures of human hepatocytes. J Biochem Mol Toxicol 14:177–188.
  • LeCluyse EL. (2001). Human hepatocyte culture systems for the in vitro evaluation of cytochrome P450 expression and regulation. Eur J Pharm Sci 13:343–368.
  • LeCluyse EL, Alexandre E, Hamilton GA, Viollon-Abadie C, Coon DJ, Jolley S, Richert L. (2005). Isolation and culture of primary human hepatocytes. Methods Mol Biol 290:207–229.
  • LeCluyse EL, Audus KL, Hochman JH. (1994). Formation of extensive canalicular networks by rat hepatocytes cultured in collagen-sandwich configuration. Am J Physiol 266:C1764–C1774.
  • LeCluyse EL Rowlands J. (2007). Species differences in receptor-medicated gene regulation. In: Ekins S. (ed.) Computational toxicology: risk assessment for pharmaceutical and environmental chemicals. Hoboken: John Wiley & Sons.
  • Lee J, Cuddihy MJ, Cater GM, Kotov NA. (2009a). Engineering liver tissue spheroids with inverted colloidal crystal scaffolds. Biomaterials 30:4687–4694.
  • Lee J, Lilly GD, Doty RC, Podsiadlo P, Kotov NA. (2009b). In vitro toxicity testing of nanoparticles in 3D cell culture. Small 5:1213–1221.
  • Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, Chou SH, Chen JR, Chen YP, Lee OK. (2004). In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology 40:1275–1284.
  • Lee PJ, Hung PJ, Lee LP. (2007). An artificial liver sinusoid with a microfluidic endothelial-like barrier for primary hepatocyte culture. Biotechnol Bioeng 97:1340–1346.
  • Leibold E, Schwarz LR. (1993). Intercellular communication in primary cultures of putative preneoplastic and ‘normal’ hepatocytes. Carcinogenesis 14:2127–2129.
  • Lescoat G, Theze N, Clement B, Guillouzo A, Guguen-Guillouzo C. (1985). Modulation of fetal and neonatal rat hepatocyte functional activity by glucocorticoids in co-culture. Cell Differ 16:259–268.
  • Li AP. (2009). The use of the Integrated Discrete Multiple Organ Co-culture (IdMOC) system for the evaluation of multiple organ toxicity. Altern Lab Anim 37:377–385.
  • Li AP. (2010). Evaluation of drug metabolism, drug-drug interactions, and in vitro hepatotoxicity with cryopreserved human hepatocytes. Methods Mol Biol 640:281–294.
  • Li AP, Colburn SM, Beck DJ. (1992). A simplified method for the culturing of primary adult rat and human hepatocytes as multicellular spheroids. In Vitro Cell Dev Biol 28A:673–677.
  • Li AP, Lu C, Brent JA, Pham C, Fackett A, Ruegg CE, Silber PM. (1999). Cryopreserved human hepatocytes: characterization of drug-metabolizing enzyme activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability, and drug-drug interaction potential. Chem Biol Interact 121:17–35.
  • Libbrecht L, De Vos R, Cassiman D, Desmet V, Aerts R, Roskams T. (2001). Hepatic progenitor cells in hepatocellular adenomas. Am J Surg Pathol 25:1388–1396.
  • Libbrecht L, Desmet V, Van Damme B, Roskams T. (2000). Deep intralobular extension of human hepatic ‘progenitor cells’ correlates with parenchymal inflammation in chronic viral hepatitis: can ‘progenitor cells’ migrate? J Pathol 192:373–378.
  • Liguori MJ, Blomme EA, Waring JF. (2008). Trovafloxacin-induced gene expression changes in liver-derived in vitro systems: comparison of primary human hepatocytes to HepG2 cells. Drug Metab Dispos 36:223–233.
  • Lilienblum W, Dekant W, Foth H, Gebel T, Hengstler JG, Kahl R, Kramer PJ, Schweinfurth H, Wollin KM. (2008). Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH). Arch Toxicol 82:211–236.
  • Lin JH. (2006). CYP induction-mediated drug interactions: in vitro assessment and clinical implications. Pharm Res 23:1089–1116.
  • Lindblad WJ, Schuetz EG, Redford KS, Guzelian PS. (1991). Hepatocellular phenotype in vitro is influenced by biophysical features of the collagenous substratum. Hepatology 13:282–288.
  • Lindros KO. (1997). Zonation of cytochrome P450 expression, drug metabolism and toxicity in liver. Gen Pharmacol 28:191–196.
  • Lindros KO, Oinonen T, Issakainen J, Nagy P, Thorgeirsson SS. (1997). Zonal distribution of transcripts of four hepatic transcription factors in the mature rat liver. Cell Biol Toxicol 13:257–262.
  • Liu L, LeCluyse EL, Liu J, Klaassen CD. (1996). Sulfotransferase gene expression in primary cultures of rat hepatocytes. Biochem Pharmacol 52:1621–1630.
  • Loeper J, Descatoire V, Letteron P, Moulis C, Degott C, Dansette P, Fau D, Pessayre D. (1994). Hepatotoxicity of germander in mice. Gastroenterology 106:464–472.
  • Lozoya OA, Wauthier E, Turner RA, Barbier C, Prestwich GD, Guilak F, Superfine R, Lubkin SR, Reid LM. (2011). Regulation of hepatic stem/progenitor phenotype by microenvironment stiffness in hydrogel models of the human liver stem cell niche. Biomaterials 32:7389–7402.
  • Luebke-Wheeler JL, Nedredal G, Yee L, Amiot BP, Nyberg SL. (2009). E-cadherin protects primary hepatocyte spheroids from cell death by a caspase-independent mechanism. Cell Transplant 18:1281–1287.
  • MacDonald BT, Tamai K, He X. (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17:9–26.
  • Mackie JT, Atshaves BP, Payne HR, McIntosh AL, Schroeder F, Kier AB. (2009). Phytol-induced hepatotoxicity in mice. Toxicol Pathol 37:201–208.
  • Maguire TJ, Novik E, Chao P, Barminko J, Nahmias Y, Yarmush ML, Cheng KC. (2009). Design and application of microfluidic systems for in vitro pharmacokinetic evaluation of drug candidates. Curr Drug Metab 10:1192–1199.
  • Mammoto T, Ingber DE. (2010). Mechanical control of tissue and organ development. Development 137:1407–1420.
  • Martinez-Hernandez A. (1984). The hepatic extracellular matrix. I. Electron immunohistochemical studies in normal rat liver. Lab Invest 51:57–74.
  • Martinez-Hernandez A, Amenta PS. (1993). The hepatic extracellular matrix. I. Components and distribution in normal liver. Virchows Arch A Pathol Anat Histopathol 423:1–11.
  • Martinez-Hernandez A, Amenta PS. (1995). The extracellular matrix in hepatic regeneration. FASEB J 9:1401–1410.
  • Marzioni M, Glaser SS, Francis H, Phinizy JL, LeSage G, Alpini G. (2002). Functional heterogeneity of cholangiocytes. Semin Liver Dis 22:227–240.
  • Maurice M, Durand-Schneider AM, Garbarz M, Feldmann G. (1985). Characterization of rat hepatocyte plasma membrane domains by monoclonal antibodies. Eur J Cell Biol 39:122–129.
  • Mazzoleni G, Di Lorenzo D, Steimberg N. (2009). Modelling tissues in 3D: the next future of pharmaco-toxicology and food research? Genes Nutr 4:13–22.
  • McClelland R, Wauthier E, Uronis J, Reid L. (2008). Gradients in the liver’s extracellular matrix chemistry from periportal to pericentral zones: influence on human hepatic progenitors. Tissue Eng Part A 14:59–70.
  • McCuskey RS, Bethea NW, Wong J, McCuskey MK, Abril ER, Wang X, Ito Y, DeLeve LD. (2005). Ethanol binging exacerbates sinusoidal endothelial and parenchymal injury elicited by acetaminophen. J Hepatol 42:371–377.
  • McGinnity DF, Soars MG, Urbanowicz RA, Riley RJ. (2004). Evaluation of fresh and cryopreserved hepatocytes as in vitro drug metabolism tools for the prediction of metabolic clearance. Drug Metab Dispos 32:1247–1253.
  • McIntosh MB, Corner SM, Amiot BP, Nyberg SL. (2009). Engineering analysis and development of the spheroid reservoir bioartificial liver. Conf Proc IEEE Eng Med Biol Soc 2009:5985–5988.
  • McMillian M, Nie AY, Parker JB, Leone A, Kemmerer M, Bryant S, Herlich J, Yieh L, Bittner A, Liu X, Wan J, Johnson MD. (2004). Inverse gene expression patterns for macrophage activating hepatotoxicants and peroxisome proliferators in rat liver. Biochem Pharmacol 67:2141–2165.
  • Mees C, Nemunaitis J, Senzer N. (2009). Transcription factors: their potential as targets for an individualized therapeutic approach to cancer. Cancer Gene Ther 16:103–112.
  • Meijer DK. (1987). Current concepts on hepatic transport of drugs. J Hepatol 4:259–268.
  • Meijer DK, Mol WE, Müller M, Kurz G. (1990). Carrier-mediated transport in the hepatic distribution and elimination of drugs, with special reference to the category of organic cations. J Pharmacokinet Biopharm 18:35–70.
  • Meng Q. (2010). Three-dimensional culture of hepatocytes for prediction of drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 6:733–746.
  • Menjo M, Murata Y, Fujii T, Nimura Y, Seo H. (1993). Effects of thyroid and glucocorticoid hormones on the level of messenger ribonucleic acid for iodothyronine type I 5′-deiodinase in rat primary hepatocyte cultures grown as spheroids. Endocrinology 133:2984–2990.
  • Mertens K, Rogiers V, Sonck W, Vercruysse A. (1991). Reduced and oxidized glutathione contents in adult rat hepatocytes under various culture conditions. Cell Biol Toxicol 7:101–110.
  • Mertens K, Rogiers V, Vercruysse A. (1993). Glutathione dependent detoxication in adult rat hepatocytes under various culture conditions. Arch Toxicol 67:680–685.
  • Michaels JE, Hung JT, Garfield SA, Cardell RR Jr. (1984). Lobular and cellular patterns of early hepatic glycogen deposition in the rat as observed by light and electron microscopic radioautography after injection of 3H-galactose. Am J Anat 170:23–37.
  • Michalopoulos G, Pitot HC. (1975). Primary culture of parenchymal liver cells on collagen membranes. Morphological and biochemical observations. Exp Cell Res 94:70–78.
  • Mills JB, Rose KA, Sadagopan N, Sahi J, de Morais SM. (2004). Induction of drug metabolism enzymes and MDR1 using a novel human hepatocyte cell line. J Pharmacol Exp Ther 309:303–309.
  • Mitchell JR, Thorgeirsson SS, Potter WZ, Jollow DJ, Keiser H. (1974). Acetaminophen-induced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther 16:676–684.
  • Moghe PV, Berthiaume F, Ezzell RM, Toner M, Tompkins RG, Yarmush ML. (1996). Culture matrix configuration and composition in the maintenance of hepatocyte polarity and function. Biomaterials 17:373–385.
  • Moon KH, Lee YM, Song BJ. (2010). Inhibition of hepatic mitochondrial aldehyde dehydrogenase by carbon tetrachloride through JNK-mediated phosphorylation. Free Radic Biol Med 48:391–398.
  • Mooney D, Hansen L, Vacanti J, Langer R, Farmer S, Ingber D. (1992). Switching from differentiation to growth in hepatocytes: control by extracellular matrix. J Cell Physiol 151:497–505.
  • Moore KA, Lemischka IR. (2006). Stem cells and their niches. Science 311:1880–1885.
  • Moreau A, Maurel P, Vilarem MJ, Pascussi JM. (2007). Constitutive androstane receptor-vitamin D receptor crosstalk: consequence on CYP24 gene expression. Biochem Biophys Res Commun 360:76–82.
  • Morgan ET. (2001). Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos 29:207–212.
  • Morgan ET. (2009). Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther 85:434–438.
  • Morin O, Normand C. (1986). Long-term maintenance of hepatocyte functional activity in co-culture: requirements for sinusoidal endothelial cells and dexamethasone. J Cell Physiol 129:103–110.
  • Mugford CA, Kedderis GL. (1998). Sex-dependent metabolism of xenobiotics. Drug Metab Rev 30:441–498.
  • Musat AI, Sattler CA, Sattler GL, Pitot HC. (1993). Reestablishment of cell polarity of rat hepatocytes in primary culture. Hepatology 18:198–205.
  • Nagaki M, Shidoji Y, Yamada Y, Sugiyama A, Tanaka M, Akaike T, Ohnishi H, Moriwaki H, Muto Y. (1995). Regulation of hepatic genes and liver transcription factors in rat hepatocytes by extracellular matrix. Biochem Biophys Res Commun 210:38–43.
  • Nakao A, Sakagami K, Nakata Y, Komazawa K, Amimoto T, Nakashima K, Isozaki H, Takakura N, Tanaka N. (2000). Multiple hepatic adenomas caused by long-term administration of androgenic steroids for aplastic anemia in association with familial adenomatous polyposis. J Gastroenterol 35:557–562.
  • Napolitano AP, Chai P, Dean DM, Morgan JR. (2007). Dynamics of the self-assembly of complex cellular aggregates on micromolded nonadhesive hydrogels. Tissue Eng 13:2087–2094.
  • Naughton BA, San Roman J, Sibanda B, Weintraub JP. 1994. Expansion of rat progenitor cells in long-term culture by transfer to freshly prepared stromal matrices: Production of a progenitor cell-rich template for grafting. Hematology Reviews 8, 37–49.
  • Nelson WJ, Nusse R. (2004). Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303:1483–1487.
  • Nguyen LN, Furuya MH, Wolfraim LA, Nguyen AP, Holdren MS, Campbell JS, Knight B, Yeoh GC, Fausto N, Parks WT. (2007). Transforming growth factor-beta differentially regulates oval cell and hepatocyte proliferation. Hepatology 45:31–41.
  • Niessen CM, Leckband D, Yap AS. (2011). Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation. Physiol Rev 91:691–731.
  • Nirmalanandhan VS, Sittampalam GS. (2009). Stem cells in drug discovery, tissue engineering, and regenerative medicine: emerging opportunities and challenges. J Biomol Screen 14:755–768.
  • Novik E, Maguire TJ, Chao P, Cheng KC, Yarmush ML. (2010). A microfluidic hepatic coculture platform for cell-based drug metabolism studies. Biochem Pharmacol 79:1036–1044.
  • National Research Council. Toxicity Testing in the 21st Century: A Vision and a Strategy. (2007). Washington, DC: The National Academies Press.
  • Obach RS. (2009). Predicting drug-drug interactions from in vitro drug metabolism data: challenges and recent advances. Curr Opin Drug Discov Devel 12:81–89.
  • Obach RS, Kalgutkar AS, Soglia JR, Zhao SX. (2008). Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. Chem Res Toxicol 21:1814–1822.
  • Oda H, Yoshida Y, Kawamura A, Kakinuma A. (2008). Cell shape, cell-cell contact, cell-extracellular matrix contact and cell polarity are all required for the maximum induction of CYP2B1 and CYP2B2 gene expression by phenobarbital in adult rat cultured hepatocytes. Biochem Pharmacol 75:1209–1217.
  • Ogawa K, Minase T, Onhoe T. (1974). Demonstration of glucose 6-phosphatase activity in the oval cells of rat liver and the significance of the oval cells in azo dye carcinogenesis. Cancer Res 34:3379–3386.
  • Ogawa S, Tagawa Y, Kamiyoshi A, Suzuki A, Nakayama J, Hashikura Y, Miyagawa S. (2005). Crucial roles of mesodermal cell lineages in a murine embryonic stem cell-derived in vitro liver organogenesis system. Stem Cells 23:903–913.
  • Ohmura T, Enomoto K, Satoh H, Sawada N, Mori M. (1993). Establishment of a novel monoclonal antibody, SE-1, which specifically reacts with rat hepatic sinusoidal endothelial cells. J Histochem Cytochem 41:1253–1257.
  • Olsavsky KM, Page JL, Johnson MC, Zarbl H, Strom SC, Omiecinski CJ. (2007). Gene expression profiling and differentiation assessment in primary human hepatocyte cultures, established hepatoma cell lines, and human liver tissues. Toxicol Appl Pharmacol 222:42–56.
  • Ong SY, Dai H, Leong KW. (2006). Hepatic differentiation potential of commercially available human mesenchymal stem cells. Tissue Eng 12:3477–3485.
  • Orkin RW, Gehron P, McGoodwin EB, Martin GR, Valentine T, Swarm R. (1977). A murine tumor producing a matrix of basement membrane. J Exp Med 145:204–220.
  • Pampaloni F, Stelzer EH, Masotti A. (2009). Three-dimensional tissue models for drug discovery and toxicology. Recent Pat Biotechnol 3:103–117.
  • Parola M, Pinzani M. (2009). Hepatic wound repair. Fibrogenesis Tissue Repair 2:4.
  • Pasco DS, Fagan JB. (1989). Efficient DNA-mediated gene transfer into primary cultures of adult rat hepatocytes. DNA 8:535–541.
  • Pascussi JM, Robert A, Nguyen M, Walrant-Debray O, Garabedian M, Martin P, Pineau T, Saric J, Navarro F, Maurel P, Vilarem MJ. (2005). Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia. J Clin Invest 115:177–186.
  • Pearce R, Greenway D, Parkinson A. (1992). Species differences and interindividual variation in liver microsomal cytochrome P450 2A enzymes: effects on coumarin, dicumarol, and testosterone oxidation. Arch Biochem Biophys 298:211–225.
  • Pearce RE, McIntyre CJ, Madan A, Sanzgiri U, Draper AJ, Bullock PL, Cook DC, Burton LA, Latham J, Nevins C, Parkinson A. (1996). Effects of freezing, thawing, and storing human liver microsomes on cytochrome P450 activity. Arch Biochem Biophys 331:145–169.
  • Perri R, Shah V. (2005). Hepatic sinusoidal endothelial cells. In: Dufour J-F, Clavien P-A, Trautwein C. Graf R.. (eds.) Signaling pathways in liver disease. Berlin: Springer.
  • Peters SJ, Vanhaecke T, Papeleu P, Rogiers V, Haagsman HP, van Norren K. (2010). Co-culture of primary rat hepatocytes with rat liver epithelial cells enhances interleukin-6-induced acute-phase protein response. Cell Tissue Res 340:451–457.
  • Popoff MR, Geny B. (2009). Multifaceted role of Rho, Rac, Cdc42 and Ras in intercellular junctions, lessons from toxins. Biochim Biophys Acta 1788:797–812.
  • Powers MJ, Domansky K, Kaazempur-Mofrad MR, Kalezi A, Capitano A, Upadhyaya A, Kurzawski P, Wack KE, Stolz DB, Kamm R, Griffith LG. (2002a). A microfabricated array bioreactor for perfused 3D liver culture. Biotechnol Bioeng 78:257–269.
  • Powers MJ, Griffith LG. (1998). Adhesion-guided in vitro morphogenesis in pure and mixed cell cultures. Microsc Res Tech 43:379–384.
  • Powers MJ, Janigian DM, Wack KE, Baker CS, Beer Stolz D, Griffith LG. (2002b). Functional behavior of primary rat liver cells in a three-dimensional perfused microarray bioreactor. Tissue Eng 8:499–513.
  • Powers MJ, Rodriguez RE, Griffith LG. (1997). Cell-substratum adhesion strength as a determinant of hepatocyte aggregate morphology. Biotechnol Bioeng 53:415–426.
  • Probst I, Jungermann K. (1983). The glucagon-insulin antagonism and glucagon-dexamethasone synergism in the induction of phosphoenolpyruvate carboxykinase in cultured rat hepatocytes. Hoppe-Seyler’s Z Physiol Chem 364:1739–1746.
  • Przybocki JM, Reuhl KR, Thurman RG, Kauffman FC. (1992). Involvement of nonparenchymal cells in oxygen-dependent hepatic injury by allyl alcohol. Toxicol Appl Pharmacol 115:57–63.
  • Ramadori G, Moriconi F, Malik I, Dudas J. (2008). Physiology and pathophysiology of liver inflammation, damage and repair. J Physiol Pharmacol 59 Suppl 1:107–117.
  • Rana B, Mischoulon D, Xie Y, Bucher NL, Farmer SR. (1994). Cell-extracellular matrix interactions can regulate the switch between growth and differentiation in rat hepatocytes: reciprocal expression of C/EBP alpha and immediate-early growth response transcription factors. Mol Cell Biol 14:5858–5869.
  • Rappaport AM. (1977). Microcirculatory units in the mammalian liver. Their arterial and portal components. Bibl Anat :116–120.
  • Rautou PE, Mansouri A, Lebrec D, Durand F, Valla D, Moreau R. (2010). Autophagy in liver diseases. J Hepatol 53:1123–1134.
  • Reid LM. (1990). Stem cell biology, hormone/matrix synergies and liver differentiation. Curr Opin Cell Biol 2:121–130.
  • Reid LM, Fiorino AS, Sigal SH, Brill S, Holst PA. (1992). Extracellular matrix gradients in the space of Disse: relevance to liver biology. Hepatology 15:1198–1203.
  • Reid LM, Gaitmaitan Z, Arias I, Ponce P, Rojkind M. (1980). Long-term cultures of normal rat hepatocytes on liver biomatrix. Ann N Y Acad Sci 349:70–76.
  • Renton KW. (2001). Alteration of drug biotransformation and elimination during infection and inflammation. Pharmacol Ther 92:147–163.
  • Rhee SW, Taylor AM, Tu CH, Cribbs DH, Cotman CW, Jeon NL. (2005). Patterned cell culture inside microfluidic devices. Lab Chip 5:102–107.
  • Richert L, Binda D, Hamilton G, Viollon-Abadie C, Alexandre E, Bigot-Lasserre D, Bars R, Coassolo P, LeCluyse E. (2002). Evaluation of the effect of culture configuration on morphology, survival time, antioxidant status and metabolic capacities of cultured rat hepatocytes. Toxicol In Vitro 16:89–99.
  • Richert L, Liguori MJ, Abadie C, Heyd B, Mantion G, Halkic N, Waring JF. (2006). Gene expression in human hepatocytes in suspension after isolation is similar to the liver of origin, is not affected by hepatocyte cold storage and cryopreservation, but is strongly changed after hepatocyte plating. Drug Metab Dispos 34:870–879.
  • Ripp SL, Mills JB, Fahmi OA, Trevena KA, Liras JL, Maurer TS, de Morais SM. (2006). Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction. Drug Metab Dispos 34:1742–1748.
  • Roberts RA, Ganey PE, Ju C, Kamendulis LM, Rusyn I, Klaunig JE. (2007). Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol Sci 96:2–15.
  • Roberts RA, Soames AR. (1993). Hepatocyte spheroids: prolonged hepatocyte viability for in vitro modeling of nongenotoxic carcinogenesis. Fundam Appl Toxicol 21:149–158.
  • Rodés J, Benhamou J-P, Blei A, Reichen J, Rizzetto M. (2007). Textbook of Hepatology: From Basic Science to Clinical Practice, Malden, MA: Wiley-Blackwell Publishing.
  • Rogiers V, Vandenberghe Y, Callaerts A, Verleye G, Cornet M, Mertens K, Sonck W, Vercruysse A. (1990). Phase I and phase II xenobiotic biotransformation in cultures and co-cultures of adult rat hepatocytes. Biochem Pharmacol 40:1701–1706.
  • Rojkind M, Gatmaitan Z, Mackensen S, Giambrone MA, Ponce P, Reid LM. (1980). Connective tissue biomatrix: its isolation and utilization for long-term cultures of normal rat hepatocytes. J Cell Biol 87:255–263.
  • Rojkind M, Novikoff PM, Greenwel P, Rubin J, Rojas-Valencia L, de Carvalho AC, Stockert R, Spray D, Hertzberg EL, Wolkoff AW. (1995). Characterization and functional studies on rat liver fat-storing cell line and freshly isolated hepatocyte coculture system. Am J Pathol 146:1508–1520.
  • Roman LM, Hubbard AL. (1983). A domain-specific marker for the hepatocyte plasma membrane: localization of leucine aminopeptidase to the bile canalicular domain. J Cell Biol 96:1548–1558.
  • Rosales C, O’Brien V, Kornberg L, Juliano R. (1995). Signal transduction by cell adhesion receptors. Biochim Biophys Acta 1242:77–98.
  • Roth L, Harbison RD, James RC, Tobin T, Roberts SM. (1992). Cocaine hepatotoxicity: influence of hepatic enzyme inducing and inhibiting agents on the site of necrosis. Hepatology 15:934–940.
  • Sacerdoti D, Gatta A, McGiff JC. (2003). Role of cytochrome P450-dependent arachidonic acid metabolites in liver physiology and pathophysiology. Prostaglandins Other Lipid Mediat 72:51–71.
  • Sakai Y, Tanaka T, Fukuda J, Nakazawa K. (2010a). Alkoxyresorufin O-dealkylase assay using a rat hepatocyte spheroid microarray. J Biosci Bioeng 109:395–399.
  • Sakai Y, Yamagami S, Nakazawa K. (2010b). Comparative analysis of gene expression in rat liver tissue and monolayer- and spheroid-cultured hepatocytes. Cells Tissues Organs (Print) 191:281–288.
  • Santoni-Rugiu E, Jelnes P, Thorgeirsson SS, Bisgaard HC. (2005). Progenitor cells in liver regeneration: molecular responses controlling their activation and expansion. APMIS 113:876–902.
  • Sato M, Suzuki S, Senoo H. (2003). Hepatic stellate cells: unique characteristics in cell biology and phenotype. Cell Struct Funct 28:105–112.
  • Sawada N, Tomomura A, Sattler CA, Sattler GL, Kleinman HK, Pitot HC. (1987). Effects of extracellular matrix components on the growth and differentiation of cultured rat hepatocytes. In Vitro Cell Dev Biol 23:267–273.
  • Schechtman LM. (2002). Implementation of the 3Rs (refinement, reduction, and replacement): validation and regulatory acceptance considerations for alternative toxicological test methods. ILAR J 43 Suppl:S85–S94.
  • Schlemper B, Harrison J, Garner RC, Oesch F, Steinberg P.. (1991). DNA binding, adduct characterisation and metabolic activation of aflatoxin B1 catalysed by isolated rat liver parenchymal, Kupffer and endothelial cells. Arch Toxicol 65:633–639.
  • Schoen JM, Wang HH, Minuk GY, Lautt WW. (2001). Shear stress-induced nitric oxide release triggers the liver regeneration cascade. Nitric Oxide 5:453–464.
  • Schrenk D, Eisenmann-Tappe I, Gebhardt R, Mayer D, el Mouelhi M, Röhrdanz E, Münzel P, Bock KW. (1991). Drug metabolizing enzyme activities in rat liver epithelial cell lines, hepatocytes and bile duct cells. Biochem Pharmacol 41:1751–1757.
  • Schuetz EG, Li D, Omiecinski CJ, Muller-Eberhard U, Kleinman HK, Elswick B, Guzelian PS. (1988). Regulation of gene expression in adult rat hepatocytes cultured on a basement membrane matrix. J Cell Physiol 134:309–323.
  • Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, Lund T, Lenvik T, Johnson S, Hu WS, Verfaillie CM. (2002). Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 109:1291–1302.
  • Shah I, Houck K, Judson RS, Kavlock RJ, Martin MT, Reif DM, Wambaugh J, Dix DJ. (2011). Using nuclear receptor activity to stratify hepatocarcinogens. PLoS ONE 6:e14584.
  • Shah I, Wambaugh J. (2010). Virtual tissues in toxicology. J Toxicol Environ Health B Crit Rev 13:314–328.
  • Shaw PJ, Ganey PE, Roth RA. (2010). Idiosyncratic drug-induced liver injury and the role of inflammatory stress with an emphasis on an animal model of trovafloxacin hepatotoxicity. Toxicol Sci 118:7–18.
  • Shay JW, Wright WE. (2005). Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 26:867–874.
  • Shiraki N, Umeda K, Sakashita N, Takeya M, Kume K, Kume S. (2008). Differentiation of mouse and human embryonic stem cells into hepatic lineages. Genes Cells 13:731–746.
  • Sibanda B, Kamali V, San Roman J, Weintraub JP, Gee J, Naughton BA. (1994). Co-cultures of liver-derived stromal cells and hepatic parenchyma on nylon screen templates exhibit long-term expression of liver specific function and can be used to assess toxicity. In Vitro Toxicology 7, 329–337.
  • Sibanda B, San Roman J, Zeigler F, Weintraub JP, Kamali V, Pavelec R, Naughton BA. (1993). A novel hepatocyte culture system: Its characterization and application. FASEB Journal, 7, A146.
  • Sidhu JS, Farin F, Kavanagh T, Omiecinski C. (1994). Effect of tissue-culture substratum and extracellular matrix overlay on liver-selective and xenobiotic inducible gene expression in primary rat hepatocytes. In Vitro Toxicol 7, 225–242.
  • Sidhu JS, Omiecinski CJ. (1995). Modulation of xenobiotic-inducible cytochrome P450 gene expression by dexamethasone in primary rat hepatocytes. Pharmacogenetics 5:24–36.
  • Silverman JF, Pories WJ, Caro JF. (1989). Liver pathology in diabetes mellitus and morbid obesity. Clinical, pathological, and biochemical considerations. Pathol Annu 24 Pt 1:275–302.
  • Simons K, Fuller SD. (1985). Cell surface polarity in epithelia. Annu Rev Cell Biol 1:243–288.
  • Singh R. (2010). Autophagy and regulation of lipid metabolism. Results Probl Cell Differ 52:35–46.
  • Sirica AE, Richards W, Tsukada Y, Sattler CA, Pitot HC. (1979). Fetal phenotypic expression by adult rat hepatocytes on collagen gel/nylon meshes. Proc Natl Acad Sci USA 76:283–287.
  • Sivaraman A, Leach JK, Townsend S, Iida T, Hogan BJ, Stolz DB, Fry R, Samson LD, Tannenbaum SR, Griffith LG. (2005). A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction. Curr Drug Metab 6:569–591.
  • Slikker W Jr, Andersen ME, Bogdanffy MS, Bus JS, Cohen SD, Conolly RB, David RM, Doerrer NG, Dorman DC, Gaylor DW, Hattis D, Rogers JM, Setzer RW, Swenberg JA, Wallace K. (2004a). Dose-dependent transitions in mechanisms of toxicity: case studies. Toxicol Appl Pharmacol 201:226–294.
  • Slikker W, Andersen ME, Bogdanffy MS, Bus JS, Cohen SD, Conolly RB, David RM, Doerrer NG, Dorman DC, Gaylor DW, Hattis D, Rogers JM, Woodrow Setzer R, Swenberg JA, Wallace K. (2004b). Dose-dependent transitions in mechanisms of toxicity. Toxicol Appl Pharmacol 201:203–225.
  • Smith CM, Nolan CK, Edwards MA, Hatfield JB, Stewart TW, Ferguson SS, LeCluyse EL, Sahi J. (2012). A comprehensive evaluation of metabolic activity and intrinsic clearance in suspensions and monolayer cultures of cryopreserved primary human hepatocytes. J Pharm Sci. In Press.
  • Smith MT, Wills ED. (1981). Effects of dietary lipid and phenobarbitone on the distribution and concentration of cytochrome P-450 in the liver studied by quantitative cytochemistry. FEBS Lett 127:33–36.
  • Snykers S, De Kock J, Rogiers V, Vanhaecke T. (2009). In vitro differentiation of embryonic and adult stem cells into hepatocytes: state of the art. Stem Cells 27:577–605.
  • Snykers S, Vanhaecke T, Papeleu P, Luttun A, Jiang Y, Vander Heyden Y, Verfaillie C, Rogiers V. (2006). Sequential exposure to cytokines reflecting embryogenesis: the key for in vitro differentiation of adult bone marrow stem cells into functional hepatocyte-like cells. Toxicol Sci 94:330–41; discussion 235.
  • Stamatoglou SC, Hughes RC. (1994). Cell adhesion molecules in liver function and pattern formation. FASEB J 8:420–427.
  • Steinbrecher UP, Lisbona R, Huang SN, Mishkin S. (1981). Complete regression of hepatocellular adenoma after withdrawal of oral contraceptives. Dig Dis Sci 26:1045–1050.
  • Stevenson BR, Siliciano JD, Mooseker MS, Goodenough DA. (1986). Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol 103:755–766.
  • Strazzabosco M, Fabris L. (2008). Functional anatomy of normal bile ducts. Anat Rec (Hoboken) 291:653–660.
  • Streetz K, Fregien B, Plümpe J, Körber K, Kubicka S, Sass G, Bischoff SC, Manns MP, Tiegs G, Trautwein C. (2001a). Dissection of the intracellular pathways in hepatocytes suggests a role for Jun kinase and IFN regulatory factor-1 in Con A-induced liver failure. J Immunol 167:514–523.
  • Streetz KL, Wüstefeld T, Klein C, Manns MP, Trautwein C. (2001b). Mediators of inflammation and acute phase response in the liver. Cell Mol Biol (Noisy-le-grand) 47:661–673.
  • Strey CW, Gestrich J, Beckhaus T, Marquez-Pinilla RM, Oppermann E, Mönch C, Lambris JD, Karas M, Bechstein WO. (2010). Hypoxia and reoxygenation of primary human hepatocytes induce proteome changes of glucose metabolism, oxidative protection and peroxisomal function. Int J Mol Med 26:577–584.
  • Strick-Marchand H, Weiss MC. (2002). Inducible differentiation and morphogenesis of bipotential liver cell lines from wild-type mouse embryos. Hepatology 36:794–804.
  • Sullivan GJ, Hay DC, Park IH, Fletcher J, Hannoun Z, Payne CM, Dalgetty D, Black JR, Ross JA, Samuel K, Wang G, Daley GQ, Lee JH, Church GM, Forbes SJ, Iredale JP, Wilmut I. (2010). Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology 51:329–335.
  • Sunman JA, Hawke RL, LeCluyse EL, Kashuba AD. (2004). Kupffer cell-mediated IL-2 suppression of CYP3A activity in human hepatocytes. Drug Metab Dispos 32:359–363.
  • Swartz MA, Fleury ME. (2007). Interstitial flow and its effects in soft tissues. Annu Rev Biomed Eng 9:229–256.
  • Taipale J, Keski-Oja J. (1997). Growth factors in the extracellular matrix. FASEB J 11:51–59.
  • Takabatake H, Koide N, Tsuji T. (1991). Encapsulated multicellular spheroids of rat hepatocytes produce albumin and urea in a spouted bed circulating culture system. Artif Organs 15:474–480.
  • Takeshita K, Bowen WC, Michalopoulos GK. (1998). Three-dimensional culture of hepatocytes in a continuously flowing medium. In Vitro Cell Dev Biol Anim 34:482–485.
  • Thorgeirsson SS. (1996). Hepatic stem cells in liver regeneration. FASEB J 10:1249–1256.
  • Tietz PS, Larusso NF. (2006). Cholangiocyte biology. Curr Opin Gastroenterol 22:279–287.
  • Tomasi A, Albano E, Biasi F, Slater TF, Vannini V, Dianzani MU. (1985). Activation of chloroform and related trihalomethanes to free radical intermediates in isolated hepatocytes and in the rat in vivo as detected by the ESR-spin trapping technique. Chem Biol Interact 55:303–316.
  • Tong JZ, Bernard O, Alvarez F. (1990). Long-term culture of rat liver cell spheroids in hormonally defined media. Exp Cell Res 189:87–92.
  • Tong JZ, De Lagausie P, Furlan V, Cresteil T, Bernard O, Alvarez F. (1992). Long-term culture of adult rat hepatocyte spheroids. Exp Cell Res 200:326–332.
  • Tostões RM, Leite SB, Miranda JP, Sousa M, Wang DI, Carrondo MJ, Alves PM. (2011). Perfusion of 3D encapsulated hepatocytes–a synergistic effect enhancing long-term functionality in bioreactors. Biotechnol Bioeng 108:41–49.
  • Traber PG, Chianale J, Gumucio JJ. (1988). Physiologic significance and regulation of hepatocellular heterogeneity. Gastroenterology 95:1130–1143.
  • Tsao CC, Coulter SJ, Chien A, Luo G, Clayton NP, Maronpot R, Goldstein JA, Zeldin DC. (2001). Identification and localization of five CYP2Cs in murine extrahepatic tissues and their metabolism of arachidonic acid to regio- and stereoselective products. J Pharmacol Exp Ther 299:39–47.
  • Tsutsui M, Ogawa S, Inada Y, Tomioka E, Kamiyoshi A, Tanaka S, Kishida T, Nishiyama M, Murakami M, Kuroda J, Hashikura Y, Miyagawa S, Satoh F, Shibata N, Tagawa Y. (2006). Characterization of cytochrome P450 expression in murine embryonic stem cell-derived hepatic tissue system. Drug Metab Dispos 34:696–701.
  • Tukov FF, Maddox JF, Amacher DE, Bobrowski WF, Roth RA, Ganey PE. (2006). Modeling inflammation-drug interactions in vitro: a rat Kupffer cell-hepatocyte coculture system. Toxicol In Vitro 20:1488–1499.
  • Turner R, Lozoya O, Wang Y, Cardinale V, Gaudio E, Alpini G, Mendel G, Wauthier E, Barbier C, Alvaro D, Reid LM. (2011). Human hepatic stem cell and maturational liver lineage biology. Hepatology 53:1035–1045.
  • Turner WS, Schmelzer E, McClelland R, Wauthier E, Chen W, Reid LM. (2007). Human hepatoblast phenotype maintained by hyaluronan hydrogels. J Biomed Mater Res Part B Appl Biomater 82:156–168.
  • Turner WS, Seagle C, Galanko JA, Favorov O, Prestwich GD, Macdonald JM, Reid LM. (2008). Nuclear magnetic resonance metabolomic footprinting of human hepatic stem cells and hepatoblasts cultured in hyaluronan-matrix hydrogels. Stem Cells 26:1547–1555.
  • Turpeinen M, Tolonen A, Chesne C, Guillouzo A, Uusitalo J, Pelkonen O. (2009). Functional expression, inhibition and induction of CYP enzymes in HepaRG cells. Toxicol In Vitro 23:748–753.
  • Tuschl G, Hrach J, Walter Y, Hewitt PG, Mueller SO. (2009). Serum-free collagen sandwich cultures of adult rat hepatocytes maintain liver-like properties long term: a valuable model for in vitro toxicity and drug-drug interaction studies. Chem Biol Interact 181:124–137.
  • Uchiyama Y, Asari A. (1984). A morphometric study of the variations in subcellular structures of rat hepatocytes during 24 hours. Cell Tissue Res 236:305–315.
  • Ugele B, Kempen HJ, Kempen JM, Gebhardt R, Meijer P, Burger HJ, Princen HM. (1991). Heterogeneity of rat liver parenchyma in cholesterol 7 alpha-hydroxylase and bile acid synthesis. Biochem J 276 (Pt 1):73–77.
  • Utesch D, Oesch F. (1992). Dependency of the in vitro stabilization of differentiated functions in liver parenchymal cells on the type of cell line used for co-culture. In Vitro Cell Dev Biol 28A:193–198.
  • van Midwoud PM, Verpoorte E, Groothuis GM. (2011). Microfluidic devices for in vitro studies on liver drug metabolism and toxicity. Integr Biol (Camb) 3:509–521.
  • van Montfoort JE, Hagenbuch B, Groothuis GM, Koepsell H, Meier PJ, Meijer DK. (2003). Drug uptake systems in liver and kidney. Curr Drug Metab 4:185–211.
  • Vermeir M, Annaert P, Mamidi RN, Roymans D, Meuldermans W, Mannens G. (2005). Cell-based models to study hepatic drug metabolism and enzyme induction in humans. Expert Opin Drug Metab Toxicol 1:75–90.
  • Vessey CJ, de la Hall PM. (2001). Hepatic stem cells: a review. Pathology 33:130–141.
  • Vig P, Russo FP, Edwards RJ, Tadrous PJ, Wright NA, Thomas HC, Alison MR, Forbes SJ. (2006). The sources of parenchymal regeneration after chronic hepatocellular liver injury in mice. Hepatology 43:316–324.
  • Vinci B, Duret C, Klieber S, Gerbal-Chaloin S, Sa-Cunha A, Laporte S, Suc B, Maurel P, Ahluwalia A, Daujat-Chavanieu M. (2011). Modular bioreactor for primary human hepatocyte culture: medium flow stimulates expression and activity of detoxification genes. Biotechnol J 6:554–564.
  • Volberg T, Zick Y, Dror R, Sabanay I, Gilon C, Levitzki A, Geiger B. (1992). The effect of tyrosine-specific protein phosphorylation on the assembly of adherens-type junctions. EMBO J 11:1733–1742.
  • Vollmar B, Menger MD. (2009). The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev 89:1269–1339.
  • Wandzioch E, Kolterud A, Jacobsson M, Friedman SL, Carlsson L. (2004). Lhx2-/- mice develop liver fibrosis. Proc Natl Acad Sci USA 101:16549–16554.
  • Wang H, LeCluyse EL. (2003). Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet 42:1331–1357.
  • Wang N, Tytell JD, Ingber DE. (2009). Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat Rev Mol Cell Biol 10:75–82.
  • Wang WW, Khetani SR, Krzyzewski S, Duignan DB, Obach RS. (2010a). Assessment of a micropatterned hepatocyte coculture system to generate major human excretory and circulating drug metabolites. Drug Metab Dispos 38:1900–1905.
  • Wang Y, Yao HL, Cui CB, Wauthier E, Barbier C, Costello MJ, Moss N, Yamauchi M, Sricholpech M, Gerber D, Loboa EG, Reid LM.. (2010b). Paracrine signals from mesenchymal cell populations govern the expansion and differentiation of human hepatic stem cells to adult liver fates. Hepatology 52:1443–1454.
  • Wang Y, Cui CB, Yamauchi M, Miguez P, Roach M, Malavarca R, Costello MJ, Cardinale V, Wauthier E, Barbier C, Gerber DA, Alvaro D, Reid LM. (2011). Lineage restriction of human hepatic stem cells to mature fates is made efficient by tissue-specific biomatrix scaffolds. Hepatology 53:293–305.
  • Waxman DJ, Holloway MG. (2009). Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol 76:215–228.
  • Westerink WM, Schoonen WG. (2007). Phase II enzyme levels in HepG2 cells and cryopreserved primary human hepatocytes and their induction in HepG2 cells. Toxicol In Vitro 21:1592–1602.
  • Wilkening S, Stahl F, Bader A. (2003). Comparison of primary human hepatocytes and hepatoma cell line Hepg2 with regard to their biotransformation properties. Drug Metab Dispos 31:1035–1042.
  • Wojcik E, Dvorak C, Chianale J, Traber PG, Keren D, Gumucio JJ. (1988). Demonstration by in situ hybridization of the zonal modulation of rat liver cytochrome P-450b and P-450e gene expression after phenobarbital. J Clin Invest 82:658–666.
  • Wölfle D, Jungermann K. (1985). Long-term effects of physiological oxygen concentrations on glycolysis and gluconeogenesis in hepatocyte cultures. Eur J Biochem 151:299–303.
  • Wolkoff AW, Novikoff PM. (2007). Cell Biology of the hepatocyte. In: Rodes J, Benhamou J, Blei A, Reichen J Rizzetto M. (eds.) Textbook of hepatology: from basic to clinical practice. Malden, MA: Wiley-Blackwell Publishing.
  • Woodcroft KJ, Hafner MS, Novak RF. (2002). Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression. Hepatology 35:263–273.
  • Wu MH, Huang SB, Lee GB. (2010). Microfluidic cell culture systems for drug research. Lab Chip 10:939–956.
  • Wu R, Cui X, Dong W, Zhou M, Simms HH, Wang P. (2006). Suppression of hepatocyte CYP1A2 expression by Kupffer cells via AhR pathway: the central role of proinflammatory cytokines. Int J Mol Med 18:339–346.
  • Wu YM, Joseph B, Berishvili E, Kumaran V, Gupta S. (2008). Hepatocyte transplantation and drug-induced perturbations in liver cell compartments. Hepatology 47:279–287.
  • Xanthopoulos KG, Mirkovitch J. (1993). Gene regulation in rodent hepatocytes during development, differentiation and disease. Eur J Biochem 216:353–360.
  • Xia X, Francis H, Glaser S, Alpini G, LeSage G. (2006). Bile acid interactions with cholangiocytes. World J Gastroenterol 12:3553–3563.
  • Xie G, Wang L, Wang X, Wang L, DeLeve LD. (2010). Isolation of periportal, midlobular, and centrilobular rat liver sinusoidal endothelial cells enables study of zonated drug toxicity. Am J Physiol Gastrointest Liver Physiol 299:G1204–G1210.
  • Yagi K, Yamada C, Serada M, Sumiyoshi N, Michibayashi N, Miura Y, Mizoguchi T. (1995). Reciprocal regulation of prothrombin secretion and tyrosine aminotransferase induction in hepatocytes. Eur J Biochem 227:753–756.
  • Yamasaki C, Tateno C, Aratani A, Ohnishi C, Katayama S, Kohashi T, Hino H, Marusawa H, Asahara T, Yoshizato K. (2006). Growth and differentiation of colony-forming human hepatocytes in vitro. J Hepatol 44:749–757.
  • Yan B, Yang D, Bullock P, Parkinson A. (1995). Rat serum carboxylesterase. Cloning, expression, regulation, and evidence of secretion from liver. J Biol Chem 270:19128–19134.
  • Yang F, Mei Y, Langer R, Anderson DG. (2009). High throughput optimization of stem cell microenvironments. Comb Chem High Throughput Screen 12:554–561.
  • Yang W, Yan HX, Chen L, Liu Q, He YQ, Yu LX, Zhang SH, Huang DD, Tang L, Kong XN, Chen C, Liu SQ, Wu MC, Wang HY. (2008). Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res 68:4287–4295.
  • Yarmush ML, Toner M, Dunn JC, Rotem A, Hubel A, Tompkins RG. (1992). Hepatic tissue engineering. Development of critical technologies. Ann N Y Acad Sci 665:238–252.
  • Youdim KA, Tyman CA, Jones BC, Hyland R. (2007). Induction of cytochrome P450: assessment in an immortalized human hepatocyte cell line (Fa2N4) using a novel higher throughput cocktail assay. Drug Metab Dispos 35:275–282.
  • Yuasa C, Tomita Y, Shono M, Ishimura K, Ichihara A. (1993). Importance of cell aggregation for expression of liver functions and regeneration demonstrated with primary cultured hepatocytes. J Cell Physiol 156:522–530.
  • Zangar RC, Woodcroft KJ, Kocarek TA, Novak RF. (1995). Xenobiotic-enhanced expression of cytochrome P450 2E1 and 2B1/2B2 in primary cultured rat hepatocytes. Drug Metab Dispos 23:681–687.
  • Zaphiropoulos PG, Ström A, Robertson JA, Gustafsson JA. (1990a). Structural and regulatory analysis of the male-specific rat liver cytochrome P-450 g: repression by continuous growth hormone administration. Mol Endocrinol 4:53–58.
  • Zaphiropoulos PG, Westin S, Ström A, Mode A, Gustafsson JA. (1990b). Structural and regulatory analysis of a cytochrome P450 gene (CYP2C12) expressed predominantly in female rat liver. DNA Cell Biol 9:49–56.
  • Zaret KS, DiPersio CM, Jackson DA, Montigny WJ, Weinstat DL. (1988). Conditional enhancement of liver-specific gene transcription. Proc Natl Acad Sci USA 85:9076–9080.
  • Zhang J, Huang W, Chua SS, Wei P, Moore DD. (2002). Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science 298:422–424.
  • Zhang L, Theise N, Chua M, Reid LM. (2008). The stem cell niche of human livers: symmetry between development and regeneration. Hepatology 48:1598–1607.
  • Zhang L, Zhang YD, Zhao P, Huang SM. (2009). Predicting drug-drug interactions: an FDA perspective. AAPS J 11:300–306.