2,544
Views
7
CrossRef citations to date
0
Altmetric
Research Paper

Phenylpropionic acid produced by gut microbiota alleviates acetaminophen-induced hepatotoxicity

, , , , , , , , & ORCID Icon show all
Article: 2231590 | Received 19 Mar 2023, Accepted 27 Jun 2023, Published online: 11 Jul 2023

References

  • Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther. 1973;187:185–27.
  • Weber LW, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 2003;33(2):105–136. doi:10.1080/713611034.
  • Sarges P, Steinberg JM, Lewis JH. Drug-induced liver injury: highlights from a review of the 2015 literature. Drug Saf. 2016;39(9):801–821. doi:10.1007/s40264-016-0427-8.
  • Lee WM. Drug-induced acute liver failure. Clin Liver Dis. 2013;17(4):575–586. viii. doi:10.1016/j.cld.2013.07.001.
  • Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiødt FV, Ostapowicz G, Shakil AO, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42(6):1364–1372. doi:10.1002/hep.20948.
  • Lee WM. Acute liver failure in the United States. Semin Liver Dis. 2003;23(3):217–226.
  • Harrill AH, Watkins PB, Su S, Ross PK, Harbourt DE, Stylianou IM, Boorman GA, Russo MW, Sackler RS, Harris SC, et al. Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res. 2009;19(9):1507–1515. doi:10.1101/gr.090241.108.
  • Louvet A, Ntandja Wandji LC, Lemaitre E, Khaldi M, Lafforgue C, Artru F, Quesnel B, Lassailly G, Dharancy S, Mathurin P, et al. Acute liver injury with therapeutic doses of acetaminophen: a prospective study. Hepatology. 2021;73(5):1945–1955. doi:10.1002/hep.31678.
  • Zaher H, Buters JT, Ward JM, Bruno MK, Lucas AM, Stern ST, Cohen SD, Gonzalez FJ. Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. Toxicol Appl Pharmacol. 1998;152(1):193–199. doi:10.1006/taap.1998.8501.
  • Jaeschke H, Ramachandran A, Chao X, Ding WX. Emerging and established modes of cell death during acetaminophen-induced liver injury. Arch Toxicol. 2019;93(12):3491–3502. doi:10.1007/s00204-019-02597-1.
  • Kaplowitz N. Acetaminophen hepatoxicity: what do we know, what don’t we know, and what do we do next? Hepatology. 2004;40:23–26. doi:10.1002/hep.20312.
  • Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296(1):87–93. doi:10.1001/jama.296.1.87.
  • Schmidt LE, Dalhoff K, Poulsen HE. Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity. Hepatology. 2002;35(4):876–882. doi:10.1053/jhep.2002.32148.
  • Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proceedings of the National Academy of Sciences of the United States of America; 2009; 106:14728–14733.
  • Thaiss CA, Levy M, Korem T, Dohnalova L, Shapiro H, Jaitin DA, David E, Winter DR, Gury-BenAri M, Tatirovsky E, et al. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell. 2016;167(6):1495–510.e12. doi:10.1016/j.cell.2016.11.003.
  • Gong S, Lan T, Zeng L, Luo H, Yang X, Li N, Chen X, Liu Z, Li R, Win S, et al. Gut microbiota mediates diurnal variation of acetaminophen induced acute liver injury in mice. J Hepatol. 2018;69(1):51–59. doi:10.1016/j.jhep.2018.02.024.
  • Sharma S, Chaturvedi J, Chaudhari BP, Singh RL, Kakkar P. Probiotic enterococcus lactis IITRHR1 protects against acetaminophen-induced hepatotoxicity. Nutrition. 2012;28(2):173–181. doi:10.1016/j.nut.2011.02.012.
  • Saeedi BJ, Liu KH, Owens JA, Hunter-Chang S, Camacho MC, Eboka RU, Chandrasekharan B, Baker NF, Darby TM, Robinson BS, et al. Gut-resident lactobacilli activate hepatic Nrf2 and protect against oxidative liver injury. Cell Metab. 2020;31(5):956–968.e5. doi:10.1016/j.cmet.2020.03.006.
  • Kolodziejczyk AA, Federici S, Zmora N, Mohapatra G, Dori-Bachash M, Hornstein S, Leshem A, Reuveni D, Zigmond E, Tobar A, et al. Acute liver failure is regulated by MYC- and microbiome-dependent programs. Nat Med. 2020;26(12):1899–1911. doi:10.1038/s41591-020-1102-2.
  • Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Man Lei Y, Jabri B, Alegre M-L, et al. Commensal bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy. Science. 2015;350(6264):1084–1089. doi:10.1126/science.aac4255.
  • Win S, Min RW, Chen CQ, Zhang J, Chen Y, Li M, Suzuki A, Abdelmalek MF, Wang Y, Aghajan M, et al. Expression of mitochondrial membrane–linked SAB determines severity of sex-dependent acute liver injury. J Clin Invest. 2019;129(12):5278–5293. doi:10.1172/JCI128289.
  • Du K, Williams CD, McGill MR, Jaeschke H. Lower susceptibility of female mice to acetaminophen hepatotoxicity: role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase. Toxicol Appl Pharmacol. 2014;281(1):58–66. doi:10.1016/j.taap.2014.09.002.
  • Caruso R, Ono M, Bunker ME, Nunez G, Inohara N. Dynamic and asymmetric changes of the microbial communities after cohousing in laboratory Mice. Cell Rep. 2019;27(11):3401–3412.e3. doi:10.1016/j.celrep.2019.05.042.
  • Koh A, De Vadder F, Kovatcheva-Datchary P, Backhed F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell. 2016;165(6):1332–1345. doi:10.1016/j.cell.2016.05.041.
  • Xia J, Lv L, Liu B, Wang S, Zhang S, Wu Z, Yang L, Bian X, Wang Q, Wang K, et al. Akkermansia muciniphila ameliorates acetaminophen-induced liver injury by regulating gut microbial composition and metabolism. Microbiol Spectr. 2022;10(1):e0159621. doi:10.1128/spectrum.01596-21.
  • Dodd D, Spitzer MH, Van Treuren W, Merrill BD, Hryckowian AJ, Higginbottom SK, Le A, Cowan TM, Nolan GP, Fischbach MA, et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature. 2017;551(7682):648–652. doi:10.1038/nature24661.
  • Elsden SR, Hilton MG, Waller JM. The end products of the metabolism of aromatic amino acids by Clostridia. Arch Microbiol. 1976;107(3):283–288. doi:10.1007/BF00425340.
  • Badenhorst CP, Erasmus E, van der Sluis R, Nortje C, van Dijk AA. A new perspective on the importance of glycine conjugation in the metabolism of aromatic acids. Drug Metab Rev. 2014;46(3):343–361. doi:10.3109/03602532.2014.908903.
  • Pruss KM, Chen H, Liu Y, Van Treuren W, Higginbottom SK, Jarman JB, Fischer CR, Mak J, Wong B, Cowan TM, et al. Host-microbe co-metabolism via MCAD generates circulating metabolites including hippuric acid. Nat Commun. 2023;14(1):512. doi:10.1038/s41467-023-36138-3.
  • Gutierrez-Diaz I, Fernandez-Navarro T, Salazar N, Bartolome B, Moreno-Arribas MV, Lopez P, Suárez A, de Los Reyes-Gavilán CG, Gueimonde M, González S, et al. Could fecal phenylacetic and phenylpropionic acids be used as indicators of health status? J Agric Food Chem. 2018;66(40):10438–10446. doi:10.1021/acs.jafc.8b04102.
  • Gao X, Pujos-Guillot E, Sebedio JL. Development of a quantitative metabolomic approach to study clinical human fecal water metabolome based on trimethylsilylation derivatization and GC/MS analysis. Anal Chem. 2010;82(15):6447–6456. doi:10.1021/ac1006552.
  • Feng HP, Huang CL, Zhang LT, Li RF. Pharmacokinetics and bioavailability of cinnamic acid in mice. J China Pharm Univ. 2004;35:328–330.
  • Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. II. role of covalent binding in vivo. J Pharmacol Exp Ther. 1973;187:195–202.
  • Lee SS, Buters JT, Pineau T, Fernandez-Salguero P, Gonzalez FJ. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem. 1996;271(20):12063–12067. doi:10.1074/jbc.271.20.12063.
  • Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther. 2000;67(3):275–282. doi:10.1067/mcp.2000.104736.
  • Tonge RP, Kelly EJ, Bruschi SA, Kalhorn T, Eaton DL, Nebert DW, Nelson SD. Role of CYP1A2 in the hepatotoxicity of acetaminophen: investigations using Cyp1a2 null mice. Toxicol Appl Pharmacol. 1998;153(1):102–108. doi:10.1006/taap.1998.8543.
  • Robin MA, Anandatheerthavarada HK, Fang JK, Cudic M, Otvos L, Avadhani NG. Mitochondrial targeted cytochrome P450 2E1 (P450 MT5) contains an intact N terminus and requires mitochondrial specific electron transfer proteins for activity. J Biol Chem. 2001;276(27):24680–24689. doi:10.1074/jbc.M100363200.
  • Song BJ, Veech RL, Park SS, Gelboin HV, Gonzalez FJ. Induction of rat hepatic N-nitrosodimethylamine demethylase by acetone is due to protein stabilization. J Biol Chem. 1989;264(6):3568–3572. doi:10.1016/S0021-9258(18)94103-7.
  • Pratt-Hyatt M, Lin HL, Hollenberg PF. Mechanism-based inactivation of human CYP2E1 by diethyldithocarbamate. Drug Metab Dispos. 2010;38(12):2286–2292. doi:10.1124/dmd.110.034710.
  • Roberts BJ, Song BJ, Soh Y, Park SS, Shoaf SE. Ethanol induces CYP2E1 by protein stabilization. Role of ubiquitin conjugation in the rapid degradation of CYP2E1. J Biol Chem. 1995;270(50):29632–29635. doi:10.1074/jbc.270.50.29632.
  • Dickert S, Pierik AJ, Buckel W. Molecular characterization of phenyllactate dehydratase and its initiator from clostridium sporogenes. Mol Microbiol. 2002;44(1):49–60. doi:10.1046/j.1365-2958.2002.02867.x.
  • Kovacs K, Banoczi G, Varga A, Szabo I, Holczinger A, Hornyanszky G, Zagyva I, Paizs C, Vértessy BG, Poppe L, et al. Expression and properties of the highly alkalophilic phenylalanine ammonia-lyase of thermophilic Rubrobacter xylanophilus. PLoS One. 2014;9(1):e85943. doi:10.1371/journal.pone.0085943.
  • Weise NJ, Ahmed ST, Parmeggiani F, Galman JL, Dunstan MS, Charnock SJ, Leys D, Turner NJ. Zymophore identification enables the discovery of novel phenylalanine ammonia lyase enzymes. Sci Rep. 2017;7(1):13691. doi:10.1038/s41598-017-13990-0.
  • Xiang L, Moore BS. Biochemical characterization of a prokaryotic phenylalanine ammonia lyase. J Bacteriol. 2005;187(12):4286–4289. doi:10.1128/JB.187.12.4286-4289.2005.
  • Moffitt MC, Louie GV, Bowman ME, Pence J, Noel JP, Moore BS. Discovery of two cyanobacterial phenylalanine ammonia lyases: kinetic and structural characterization. Biochemistry. 2007;46(4):1004–1012. doi:10.1021/bi061774g.
  • Williams JS, Thomas M, Clarke DJ. The gene stlA encodes a phenylalanine ammonia-lyase that is involved in the production of a stilbene antibiotic in Photorhabdus luminescens TT01. Microbiol. 2005;151(8):2543–2550. doi:10.1099/mic.0.28136-0.
  • Almodovar AJ, Luther RJ, Stonebrook CL, Wood PA. Genomic structure and genetic drift in C57BL/6 congenic metabolic mutant mice. Mol Genet Metab. 2013;110(3):396–400. doi:10.1016/j.ymgme.2013.06.019.
  • Bourdi M, Davies JS, Pohl LR. Mispairing C57BL/6 substrains of genetically engineered mice and wild-type controls can lead to confounding results as it did in studies of JNK2 in acetaminophen and concanavalin a liver injury. Chem Res Toxicol. 2011;24(6):794–796. doi:10.1021/tx200143x.
  • Duan L, Davis JS, Woolbright BL, Du K, Cahkraborty M, Weemhoff J, Jaeschke H, Bourdi M. Differential susceptibility to acetaminophen-induced liver injury in sub-strains of C57BL/6 mice: 6N versus 6J. Food Chem Toxicol. 2016;98:107–118. doi:10.1016/j.fct.2016.10.021.
  • Nickel AG, von Hardenberg A, Hohl M, Loffler JR, Kohlhaas M, Becker J, Reil J-C, Kazakov A, Bonnekoh J, Stadelmaier M, et al. Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure. Cell Metab. 2015;22(3):472–484. doi:10.1016/j.cmet.2015.07.008.
  • Smith EA, Macfarlane GT. Enumeration of human colonic bacteria producing phenolic and indolic compounds: effects of pH, carbohydrate availability and retention time on dissimilatory aromatic amino acid metabolism. J Appl Bacteriol. 1996;81(3):288–302. doi:10.1111/j.1365-2672.1996.tb04331.x.
  • Burdock GA. Encyclopedia of food and color additives. Boca Raton: CRC Press; 1997.
  • Mattia A, Sipes GI. WHO food additives series: 46. (JECFA) ECoFA ed. Safety evaluation of certain food additives and contaminants. 2001. [accessed 2023 Jun 12].https://www.inchem.org/documents/jecfa/jecmono/v46je07.htm
  • Colosimo DA, Kohn JA, Luo PM, Piscotta FJ, Han SM, Pickard AJ, Rao A, Cross JR, Cohen LJ, Brady SF, et al. Mapping interactions of microbial metabolites with human g-protein-coupled receptors. Cell Host & Microbe. 2019;26(2):273–282.e7. doi:10.1016/j.chom.2019.07.002.
  • Peters A, Krumbholz P, Jager E, Heintz-Buschart A, Cakir MV, Rothemund S, Gaudl A, Ceglarek U, Schöneberg T, Stäubert C, et al. Metabolites of lactic acid bacteria present in fermented foods are highly potent agonists of human hydroxycarboxylic acid receptor 3. PLoS Genet. 2019;15(5):e1008145. doi:10.1371/journal.pgen.1008145.
  • Husted AS, Trauelsen M, Rudenko O, Hjorth SA, Schwartz TW. GPCR-Mediated signaling of metabolites. Cell Metabolism. 2017;25:777–796. doi:10.1016/j.cmet.2017.03.008.
  • Correia MA. Hepatic cytochrome P450 degradation: mechanistic diversity of the cellular sanitation brigade. Drug Metab Rev. 2003;35(2–3):107–143. doi:10.1081/DMR-120023683.
  • Guengerich FP, Kim DH, Iwasaki M. Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol. 1991;4(2):168–179. doi:10.1021/tx00020a008.
  • Roy U, Joshua R, Stark RL, Balazy M. Cytochrome P450/NADPH-dependent biosynthesis of 5,6-trans-epoxyeicosatrienoic acid from 5,6-trans-arachidonic acid. Biochem J. 2005;390:719–727. doi:10.1042/BJ20050681.
  • Bondoc FY, Bao Z, Hu WY, Gonzalez FJ, Wang Y, Yang CS, Hong J-Y. Acetone catabolism by cytochrome P450 2E1: studies with CYP2E1-null mice. Biochem Pharmacol. 1999;58(3):461–463. doi:10.1016/S0006-2952(99)00111-2.
  • Adas F, Berthou F, Picart D, Lozac’h P, Beauge F, Amet Y. Involvement of cytochrome P450 2E1 in the (ω–1)-hydroxylation of oleic acid in human and rat liver microsomes. J Lipid Res. 1998;39(6):1210–1219. doi:10.1016/S0022-2275(20)32545-1.
  • Laethem RM, Balazy M, Falck JR, Laethem CL, Koop DR. Formation of 19(S)-, 19(R)-, and 18(R)-hydroxyeico-satetraenoic acids by alcohol-inducible cytochrome P450 2E1. J Biol Chem. 1993;268:12912–12918. doi:10.1016/S0021-9258(18)31472-8.
  • Beresford-Jones BS, Forster SC, Stares MD, Notley G, Viciani E, Browne HP, Boehmler DJ, Soderholm AT, Kumar N, Vervier K, et al. The Mouse gastrointestinal bacteria catalogue enables translation between the mouse and human gut microbiotas via functional mapping. Cell Host & Microbe. 2022;30(1):124–138.e8. doi:10.1016/j.chom.2021.12.003.
  • Liu Y, Chen H, Van Treuren W, Hou BH, Higginbottom SK, Dodd D. Clostridium sporogenes uses reductive Stickland metabolism in the gut to generate ATP and produce circulating metabolites. Nature Microbiology. 2022;7:695–706. doi:10.1038/s41564-022-01109-9.
  • Leung TM, Nieto N. CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease. J Hepatol. 2013;58:395–398. doi:10.1016/j.jhep.2012.08.018.
  • Zong H, Armoni M, Harel C, Karnieli E, Pessin JE. Cytochrome P-450 CYP2E1 knockout mice are protected against high-fat diet-induced obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2012;302:E532–9. doi:10.1152/ajpendo.00258.2011.
  • Abdelmegeed MA, Banerjee A, Yoo SH, Jang S, Gonzalez FJ, Song BJ. Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis. J Hepatol. 2012;57:860–866. doi:10.1016/j.jhep.2012.05.019.
  • Wang Z, Hall SD, Maya JF, Li L, Asghar A, Gorski JC. Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans. Br J Clin Pharmacol. 2003;55:77–85. doi:10.1046/j.1365-2125.2003.01731.x.
  • O’Shea D, Davis SN, Kim RB, Wilkinson GR. Effect of fasting and obesity in humans on the 6-hydroxylation of chlorzoxazone: a putative probe of CYP2E1 activity. Clin Pharmacol Ther. 1994;56:359–367. doi:10.1038/clpt.1994.150.
  • Thakare R, Chhonker YS, Gautam N, Alamoudi JA, Alnouti Y. Quantitative analysis of endogenous compounds. J Pharm Biomed Anal. 2016;128:426–437. doi:10.1016/j.jpba.2016.06.017.
  • Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Huntley J, Fierer N, Owens SM, Betley J, Fraser L, Bauer M, et al. Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. Isme J. 2012;6:1621–1624. doi:10.1038/ismej.2012.8.
  • Bolyen E, Rideout JR, Dillon MR, Bokulich NA, Abnet CC, Al-Ghalith GA, Alexander H, Alm EJ, Arumugam M, Asnicar F, et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat Biotechnol. 2019;37:852–857. doi:10.1038/s41587-019-0209-9.
  • Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, Holmes SP. DADA2: high-resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13:581–583. doi:10.1038/nmeth.3869.
  • McCarthy DJ, Chen Y, Smyth GK. Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 2012;40(10):4288–4297. doi:10.1093/nar/gks042.
  • Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–140. doi:10.1093/bioinformatics/btp616.
  • Benjamini Y, Hochberg Y. Controlling the false discovery rate - a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57(1):289–300. doi:10.1111/j.2517-6161.1995.tb02031.x.
  • Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C. Metagenomic biomarker discovery and explanation. Genome Biol. 2011;12(6):R60. doi:10.1186/gb-2011-12-6-r60.
  • Wieckowski MR, Giorgi C, Lebiedzinska M, Duszynski J, Pinton P. Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells. Nat Protoc. 2009;4:1582–1590. doi:10.1038/nprot.2009.151.
  • Laine JE, Auriola S, Pasanen M, Juvonen RO. Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes. Xenobio Fate Foreign Comp Bio Sys. 2009;39:11–21. doi:10.1080/00498250802512830.
  • Patten CJ, Thomas PE, Guy RL, Lee M, Gonzalez FJ, Guengerich FP, Yang CS. Cytochrome P450 enzymes involved in acetaminophen activation by rat and human liver microsomes and their kinetics. Chem Res Toxicol. 1993;6(4):511–518. doi:10.1021/tx00034a019.
  • McGill MR, Lebofsky M, Norris HR, Slawson MH, Bajt ML, Xie Y, Williams CD, Wilkins DG, Rollins DE, Jaeschke H, et al. Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: dose–response, mechanisms, and clinical implications. Toxicol Appl Pharmacol. 2013;269(3):240–249. doi:10.1016/j.taap.2013.03.026.
  • McGill MR, Yan HM, Ramachandran A, Murray GJ, Rollins DE, Jaeschke H. HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity. Hepatology. 2011;53(3):974–982. doi:10.1002/hep.24132.
  • Ju C, Reilly TP, Bourdi M, Radonovich MF, Brady JN, George JW, Pohl LR. Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice. Chem Res Toxicol. 2002;15(12):1504–1513. doi:10.1021/tx0255976.
  • Michael SL, Pumford NR, Mayeux PR, Niesman MR, Hinson JA. Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species. Hepatology. 1999;30:186–195. doi:10.1002/hep.510300104.
  • Kim BR, Hu R, Keum YS, Hebbar V, Shen G, Nair SS, Kong ANT. Effects of glutathione on antioxidant response element-mediated gene expression and apoptosis elicited by sulforaphane. Cancer Res. 2003;63:7520–7525.