1,272
Views
307
CrossRef citations to date
0
Altmetric
Research Article

The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism*

, , &
Pages 273-297 | Published online: 04 Mar 2002

REFERENCES

  • Eddershaw P.J., Beresford A.P., Bayliss M.K. ADME/PK as Part of a Rational Approach to Drug Discovery. Drug Discovery Today 2000; 5: 409–414
  • Riley R.J. The Potential Pharmacological and Toxicological Impact of P450 Screening. Curr. Opin. Drug Discovery Dev. 2001; 4: 45–54
  • Obach R.S. The Prediction of Human Clearance from Hepatic Microsomal Metabolism Data. Curr. Opin Drug Discovery Dev. 2001; 4: 36–44
  • Fisher M.B., Campanale K., Ackermann B.L., VandenBranden M., Wrighton S.A. In Vitro Glucuronidation Using Human Liver Microsomes and the Pore-Forming Peptide Alamethicin. Drug Metab. Dispos. 2000; 28: 560–566
  • Meech R., Mackenzie P.I. Structure and Function of Uridinediphosphate Glucuronosyltransferases. Clin. Exp. Pharmacol. Physiol. 1997; 24: 907–915
  • Miners J.O., Mackenzie P.I. Drug Glucuronidation in Humans. Pharmacol Ther. 1991; 51: 347–369
  • Radominska-Pandya A., Czernik P.J., Little J.M., Battaglia E., Mackenzie P.I. Structural and Functional Studies of UDP-Glucuronosyltransferases. Drug Metab. Rev. 1999; 31: 817–899
  • Mackenzie P.I., Owens I.S., Burchell B., Bock K.W., Bairoch A., Belanger A., Fournel-Gigleux S., Green M., Hum D.W., Iyanagi T., Lancet D., Louisot P., Magdalou J., Chowdhury J.R., Ritter J.K., Schachter H., Tephly T.R., Tipton K.F., Nebert D.W. The UDP-Glycosyltransferase Gene Superfamily: Recommended Nomenclature Update Based on Evolutionary Divergence. Pharmacogenetics 1997; 7: 255–269
  • Tukey R.H., Strassburg C.P. Human UDP-Glucuronosyltransferases: Metabolism, Expression, and Disease. Annu. Rev. Pharmacol. Toxicol. 2000; 40: 581–616
  • Ritter J.K. Roles of Glucuronidation and UDP-Glucuronosyltransferases in Xenobiotic Bioactivation Reactions. Chem. Biol. Interact. 2000; 129: 171–193
  • Rowland M., Tozer T.N. Clinical Pharmacokinetics: Concepts and Applications. 3rd Ed, Williams and Wilkins, Media, PA 1995
  • Hanninen O., Alanen K. The Competitive Inhibition of p-Nitrophenyl-β-d-Glucopyranosiduronic Acid Synthesis by Aliphatic Alcohols In Vitro. Biochem. Pharmacol. 1966; 15: 1465–1467
  • Yokota H., Ando F., Iwano H., Yuasa A. Inhibitory Effects of Uridine Diphosphate on UDP-Glucuronosyltransferase. Life Sci. 1998; 63: 1693–1699
  • Bechinger B. Structure and Functions of Channel-Forming Peptides: Magainins, Cecropins, Melittin, and Alamethicin. J. Membr. Biol. 1997; 156: 197–211
  • Wang T.-F., Guidotti G. Golgi Localization and Functional Expression of Human Uridine Diphosphatase. J. Biol. Chem. 1998; 273: 11392–11399
  • Puskas F., Braun L., Csala M., Kardon T., Marcolongo P., Benedetti A., Mandl J., Banhegyi G. Gulonolactone Oxidase Activity-Dependent Intravesicular Glutathione Oxidation in Rat Liver Microsomes. FEBS Lett. 1998; 430: 293–296
  • Banhegyi G., Csala M., Mand J., Burchell A., Burchell B., Marcolongo P., Fulceri R., Benedetti A. Fatty Acyl-CoA Esters and the Permeability of Rat Liver Microsomal Vesicles. Biochem. J. 1996; 320: 343–344
  • Banhegyi G., Marcolongo P., Fulceri R., Hinds C., Burchell A., Benedetti A. Demonstration of a Metabolically Active Glucose-6-Phosphate Pool in the Lumen of Liver Microsomal Vesicles. J. Biol. Chem. 1997; 272: 13584–13590
  • Vanstapel F., Blanckaert N. Topology and Regulation of Bilirubin UDP-Glucuronyltransferase in Sealed Native Microsomes from Rat Liver. Arch. Biochem. Biophys. 1988; 263: 216–225
  • Banhegyi G., Bellomo G., Fulceri R., Mandl J., Benedetti A. Intralumenal Calcium of the Liver Endoplasmic Reticulum Stimulates the Glucuronidation of p-Nitrophenol. Biochem. J. 1993; 292: 99–104
  • Little J.M., Lehman P.A., Nowell S., Samokyszyn V., Radominska A. Glucuronidation of all-trans-Retinoic Acid and 5,6-Epoxy-all-trans-Retinoic Acid. Drug Metab. Dispos. 1997; 25: 5–11
  • Fulceri R., Banhegyi G., Gamberucci A., Giunti R., Mandl J., Benedetti A. Evidence for the Intraluminal Positioning of p-Nitrophenol UDP-Glucuronosyltransferase Activity in Rat Liver Microsomal Vesicles. Arch. Biochem. Biophys. 1994; 309: 43–46
  • Zakim, D.; Goldenberg, J.; Vessey, D. A. Effects of Metals on the Properties of Hepatic Microsomal Uridine Diphosphate Glucuronyltransferase. Biochemistry 1973, 12, 4068–4074.
  • Yamamura N., Imura-Miyoshi K., Naganuma H. Panipenum, a Carbapenem Antibiotic, Increases the Level of Hepatic UDP-Glucuronic Acid in Rats. Drug Metab. Dispos. 2000; 28: 1484–1486
  • Sugiyama T., Goldman W.F. Measurement of SR Free Ca and Mg in Permeabilized Smooth Muscle Cells with Use of Furaptra. Am. J. Physiol. 1995; 269: C698–C705
  • Kim J.H., Johannes L., Goud B., Antony C., Lingwood C.A., Daneman R., Grinstein S. Noninvasive Measurement of the pH of the Endoplasmic Reticulum at Rest and During Calcium Release. Proc. Natl Acad. Sci. USA 1998; 95: 2997–3002
  • Yu W., Enriquez P. LC/MS/MS Analysis of Drug Conjugates: A Potential Error Source for Quantitation also Provides a Means for Assessing Drug Absorption. ISSX Proc. 1999; 15: 234
  • Coffman B.L., Rios G.R., King C.D., Tephly T.R. Human UGT2B7 Catalyzes Morphine Glucuronidation. Drug Metab. Dispos. 1997; 25: 1–4
  • Senafi S.B., Clarke D.J., Burchell B. Investigation of the Substrate Specificity of a Cloned Expressed Human Bilirubin UDP-Glucuronosyltransferase: UDP Sugar Specificity and Involvement in Steroid and Xenobiotic Glucuronidation. Biochem. J. 1994; 303: 233–240
  • Breyer-Pfaff U., Mey U., Green M.D., Tephly T.R. Comparative N-Glucuronidation Kinetics of Ketotifen and Amitryptyline by Expressed Human UDP-Glucuronosyltransferases and Liver Microsomes. Drug Metab. Dispos. 2000; 28: 869–872
  • Strassburg C.P., Kneip S., Topp J., Obermayer-Straub P., Barut A., Tukey R.H., Manns M.P. Polymorphic Gene Regulation and Interindividual Variation of UDP-Glucuronosyltransferase Activity in Human Small Intestine. J. Biol. Chem. 2000; 275: 36164–36171
  • McGurk K.A., Brierley C.H., Burchell B. Drug Glucuronidation by Human Renal UDP-Glucuronosyltransferases. Biochem. Pharmacol. 1998; 55: 1005–1012
  • Thummel K.E., Kunze K.L., Shen D.D. Enzyme-Catalyzed Processes of First-Pass Hepatic and Intestinal Drug Extraction. Adv. Drug Deliv. Rev. 1997; 27: 99–127
  • Fisher M.B., VandenBranden M., Findlay K., Burchell B., Thummel K.E., Hall S.D., Wrighton S.A. Tissue Distribution and Interindividual Variation in Human UDP-Glucuronosyltransferase Activity: Relationship Between UGT1A1 Promoter Genotype and Variability in a Liver Bank. Pharmacogenetics 2000; 10: 727–739
  • Czernick P.J., Little J.M., Barone G.W., Raufman J.-P., Radominska-Pandya A. Glucuronidation of Estrogens and Retinoic Acid and Expression of UDP-Glucuronosyltransferase 2B7 in Human Intestinal Mucosa. Drug Metab. Dispos. 2000; 28: 1210–1216
  • Paine M.F., Fisher M.B. Immunochemical Identification of UGT Isoforms in Human Small Bowel and in Caco-2 Cell Monolayers. Biochem. Biophys. Res. Commun. 2000; 273: 1053–1057
  • Radominska-Pandya A., Little J.M., Pandya J.T., Tephly T.R., King C.D., Barone G.W., Raufman J.-P. UDP-Glucuronosyltransferases in Human Intestinal Mucosa. Biochim. Biophys. Acta 1998; 1394: 199–208
  • Veroli P., O'Kelly B., Bertrand F., Trouvin J.H., Farinotti R., Ecoffey C. Extrahepatic Metabolism of Propofol in Man During the Anhepatic Phase of Orthotopic Liver Transplantation. Br. J. Anaesth. 1992; 68: 183–186
  • Raoof A.A., van Obbergh L.J., de Ville de Goyet J., Verbeeck R.K. Extrahepatic Glucuronidation of Propofol in Man: Possible Contribution of Gut Wall and Kidney. Eur. J. Clin. Pharmacol. 1996; 50: 91–96
  • Cheng Z., Radominska-Pandya A., Tephly T.R. Studies on the Substrate Specificity of Human Intestinal UDP-Glucuronosyltransferases 1A8 and 1A10. Drug Metab. Dispos. 1999; 27: 1165–1170
  • Ethell B.T., Beaumont K., Rance D.J., Burchell B. Use of Cloned and Expressed Human UDP-Glucuronosyltransferases for the Assessment of Human Drug Conjugation and Identification of Potential Drug Interactions. Drug Metab. Dispos. 2001; 29: 48–53
  • Fisher J.M., Wrighton S.A., Watkins P.B., Schmedlin-Ren P., Calamia J.C., Shen D.D., Kunze K.L., Thummel K.E. First-Pass Midazolam Metabolism Catalyzed by 1α,25-Dihydroxy Vitamin D3-Modified Caco-2 Cell Monolayers. J. Pharm. Exp. Ther. 1999; 289: 1134–1142
  • Paine M.F., Schmedlin-Ren P., Watkins P.B. Drug Metab. Dispos. 1999; 27: 360–364
  • Ritter J.K., Kessler F.K., Thompson M.T., Grove A.D., Auyeung D.J., Fisher R.A. Expression and Inducibility of the Human Bilirubin UDP-Glucuronosyltransferase UGT1A1 in Liver and Cultured Primary Hepatocytes: Evidence for Both Genetic and Environmental Influences. Hepatology 1999; 30: 476–484
  • Yue Q., Odar-Cederlof I., Svensson J.-O., Sawe J. Glucuronidation of Morphine in Human Kidney. Pharmacol. Toxicol. 1988; 63: 337–341
  • Yue Q., von Bahr C., Odar-Cederlof I., Sawe J. Glucuronidation of Codeine and Morphine in Human Liver and Kidney Microsomes: Effect of Inhibitors. Pharmacol. Toxicol. 1990; 66: 221–226
  • Brunelle F.M., Verbeeck R.K. Glucuronidation of Diflunisal in Liver and Kidney Microsomes of Rat and Man. Xenobiotica 1996; 26: 123–131
  • Vietri M., Pietrabissa A., Mosca F., Pacifici G.M. Mycophenolic Acid Glucuronidation and Its Inhibition by Non-steroidal Anti-Inflammatory Drugs in Liver and Kidney. Eur. J. Clin. Pharmacol. 2000; 56: 659–664
  • Little J.M., Lester R., Kuipers F., Vonk R., Mackenzie P.I., Drake R.R., Frame L., Radominska-Pandya A. Variability of Human Hepatic UDP-Glucuronosyltransferase Activity. Acta Biochim. Pol. 1999; 46: 351–363
  • Lacarelle B., Rajaonarison J.F., Gauthier T., Placidi M., Catalin J., Rahmani R. Use of a Human Liver Bank in Drug Glucuronidation Studies. Toxicol. In Vitro 1991; 5: 559–562
  • Burchell B., Soars M., Monaghan G., Cassidy A., Smith D., Ethell B. Drug-Mediated Toxicity Caused by Genetic Deficiency of UDP-Glucuronosyltransferases. Toxicol. Lett. 2000; 112–113: 333–340
  • Mackenzie P.I., Miners J.O., McKinnon R.A. Polymorphisms in UDP-Glucuronosyltransferase Genes: Functional Consequences and Clinical Relevance. Clin. Chem. Lab. Med. 2000; 38: 889–892
  • Beutler E., Gelbart T., Demina A. Racial Variability in the UDP-Glucuronosyltransferase 1 (UGT1A1) Promoter: a Balanced Polymorphism for Regulation of Bilirubin Metabolism?. Proc. Natl Acad. Sci. USA 1998; 95: 8170–8174
  • Monaghan G., Ryan M., Seddon R., Hume R., Burchell B. Genetic Variation in Bilirubin UDP-Glucuronosyltransferase Gene Promoter and Gilbert's Syndrome. Lancet 1996; 347: 578–581
  • Burchell B., Hume R. Molecular Genetic Basis of Gilbert's Syndrome. J. Gastroenterol. Hepatol. 1999; 14: 960–966
  • Trapnell C.B., Klecker R.W., Jamis-Dow C., Collins J.M. Glucuronidation of 3′-Azido-3′-Deoxythymidine (Zidovudine) by Human Liver Microsomes: Relevance to Clinical Pharmacokinetic Interactions with Atovaquone, Fluconazole, Methadone, and Valproic Acid. Antimicrob. Agents Chemother. 1998; 42: 1592–1596
  • Galijatovic A., Walle U.K., Walle T. Induction of UDP-Glucuronosyltransferase by the Flavonoids Chrysin and Quercetin in Caco-2 Cells. Pharm. Res. 2000; 17: 21–26
  • Munzel P.A., Schmohl S., Heel H., Kalberer K., Bock-Hennig B.S., Bock K.W. Induction of Human UDP-Glucuronosyltransferases (UGT1A6, UGT1A9, and UGT2B7) by t-Butylhydroquinone and 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Caco-2 cells. Drug Metab. Dispos. 1999; 27: 569–573
  • Brierley C.H., Senafi S.B., Clarke D., Hsu M.-H., Johnson E.F., Burchell B. Regulation of the Human Bilirubin UDP-Glucuronosyltransferase Gene. Adv. Enzyme Regul. 1996; 36: 85–97
  • Belanger A., Hum D.W., Beaulieu M., Levesque E., Guillemette C., Tchernof A., Belanger G., Turgeon D., Dubois S. Characterization and Regulation of UDP-Glucuronosyltransferases in Steroid Target Tissues. J. Steroid Biochem. 1998; 65: 301–310
  • Levesque E., Beaulieu M., Guillemette C., Hum D.W., Belanger A. Effect of Interleukins on UGT2B15 and UGT2B17 Steroid Uridine Diphosphate-Glucuronosyltransferase Expression and Activity in the LNCaP Cell Line. Endocrinology 1998; 139: 2375–2381
  • de Wildt S.N., Kearns G.L., Leeder J.S., van den Anker J.N. Glucuronidation in Humans: Pharmacogenetic and Developmental Aspects. Clin. Pharmacokinet. 1999; 36: 439–452
  • Bouska J.J., Bell R.L., Goodfellow C.L., Stewart A.O., Brooks C.D.W., Carter G.W. Improving the In Vivo Duration of 5-Lipoxygenase Inhibitors. Drug Metab. Dispos. 1997; 25: 1032–1038
  • Houston J.B., Kenworthy K.E. In Vitro–In Vivo Scaling of CYP Kinetic Data Not Consistent with the Classical Michaelis–Menten Model. Drug Metab. Dispos. 2000; 28: 246–254
  • Reisine T., Pasternak G. Opioid Analgesics and Antagonists. Goodman and Gilman's The Pharmacological Basis of Therapeutics, J.G. Hardman, A.G. Gilman, L.E. Limbird. McGraw-Hill, New York 1996; 521–556, Chap. 23
  • Mistry M., Houston J.B. Glucuronidation In Vitro and In Vivo: Comparison of Intestinal and Hepatic Conjugation of Morphine, Naloxone, and Buprenorphine. Drug Metab. Dispos. 1987; 15: 710–717
  • Bruni S., Chang T.M.S. Kinetic Studies of Hepatocytes UDP-Glucuronosyltransferase: Evidence of an Allosteric Enzyme. Art. Cells Blood Subs. Immob. Biotechnol. 1999; 27: 343–356
  • Beckmann J.D., Henry T., Ulphani J., Lee P. Cooperative Ligand Binding by Bovine Phenol Sulfotransferase. Chem.–Biol. Interact. 1998; 109: 93–105
  • Ekins S., Ring B.J., Binkley S.N., Hall S.D., Wrighton S.A. Autoactivation and Activation of the Cytochrome P450s. Int. J. Clin. Pharmacol. Ther. 1998; 36: 642–651
  • Korzekwa K.R., Krishnamachary N., Shou M., Ogai A., Parise R.A., Rettie A.E., Gonzalez F.J., Tracy T.S. Evaluation of Atypical Cytochrome P450 Kinetics with Two-Substrate Models: Evidence that Multiple Substrates Can Simultaneously Bind to Cytochrome P450 Active Sites. Biochemistry 1998; 37: 4137–4147
  • Schrag M.L., Wienkers L.C. Topological Alteration of the CYP3A4 Active Site by the Divalent Cation Mg2+. Drug Metab. Dispos. 2000; 28: 1198–1201
  • Jakoby W.B., Ziegler D.M. The Enzymes of Detoxication. J. Biol. Chem. 1990; 265: 20715–20718
  • Shou M., Dai R., Cui D., Korzekwa K.R., Baillie T.A., Rushmore T.H. A Kinetic Model for the Metabolic Interaction of Two Substrates at the Active Site of Cytochrome P450 3A4. J. Biol. Chem. 2001; 276: 2256–2262
  • Weiss J.N. The Hill Equation Revisited: Uses and Misuses. FASEB J. 1997; 11: 835–841
  • Vree T.B., van Dongen R.T.M., Koopman-Kimenai P.M. Codeine Analgesia Is Due to Codeine-6-Glucuronide, Not Morphine. IJCP 2000; 54: 395–398
  • Wrighton S.A., Schuetz E.G., Thummel K.E., Shen D.D., Korzekwa K.R., Watkins P.B. The Human CYP3A Subfamily: Practical Considerations. Drug Metab. Rev. 2000; 32: 339–361
  • Paine M.F., Khalighi M., Fisher J.M., Shen D.D., Kunze K.L., Marsh C.L., Perkins J.D., Thummel K.E. Characterization of Interintestinal and Intraintestinal Variations in Human CYP3A-Dependent Metabolism. J. Pharm. Exp. Ther. 1997; 283: 1552–1562
  • Iyer L., Hall D., Das S., Mortell M.A., Ramirez J., Kim S., Di Rienzo A., Ratain M.J. Phenotype–Genotype Correlation of In Vitro SN-38 (Active Metabolite of Irinotecan) and Bilirubin Glucuronidation in Human Liver Tissue with UGT1A1 Promoter Polymorphism. Clin. Pharmacol. Ther. 1999; 65: 576–582
  • Lin J.H., Lu A.Y.H. Role of Pharmacokinetics and Metabolism in Drug Discovery and Development. Pharmacol. Rev. 1997; 49: 403–449
  • Guengerich F.P. Pharmacogenomics of Cytochrome P450 and Other Enzymes Involved in Biotransformation of Xenobiotics. Drug Dev. Res. 2000; 49: 4–16

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.