Symposium Article GLUCURONIDATION AND THE UDP-GLUCURONOSYLTRANSFERASES IN HEALTH AND DISEASE Peter G. Wells, 1 Peter I. Mackenzie, 1 Jayanta Roy Chowdhury, 1 Chantal Guillemette, 1 Philip A. Gregory, Yuji Ishii, Antony J. Hansen, Fay K. Kessler, Perry M. Kim, Namita Roy Chowdhury, and Joseph K. Ritter 1 Faculty of Pharmacy and Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada (P.G.W., P.M.K.); Department of Clinical Pharmacology, Flinders Medical Centre, Adelaide, South Australia, Australia (P.I.M., P.A.G., A.J.H.); Graduate School of Pharmaceutical Sciences, Kyushu University (Y.I.), Fukuoka-shi, Kyushu, Japan; Albert Einstein College of Medicine, Yeshiva University, Bronx, New York (J.R.C., N.R.C.); Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada (C.G.); and Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (J.K.R., F.K.K.) (Received October 10, 2003; accepted December 11, 2003) This article is available online at http://dmd.aspetjournals.org ABSTRACT: This article is an updated report of a symposium held at the June 2000 annual meeting of the American Society for Pharmacology and Experimental Therapeutics in Boston. The symposium was sponsored by the ASPET Divisions for Drug Metabolism and Mo- lecular Pharmacology. The report covers research from the au- thors’ laboratories on the structure and regulation of UDP-glucu- ronosyltransferase (UGT) genes, glucuronidation of xenobiotics and endobiotics, the toxicological relevance of UGTs, the role of UGT polymorphisms in cancer susceptibility, and gene therapy for UGT deficiencies. For most xenobiotics and many endobiotics, glucuronidation con- stitutes a major route of elimination and thereby may substantially modulate substrate concentrations and effects. In some cases, glucu- ronidation forms the biologically active molecule. Recent studies have revealed an extensive superfamily of UDP-glucuronosyltransferases (UGTs), 2 previously termed glucuronyl transferases, which catalyze the conjugation of UDP-glucuronic acid with lipid-soluble substrates to form polar conjugates that are excreted in the urine and feces. These studies have provided fundamental insights into UGT gene structure and regulation, isozyme substrate selectivity, and interindividual vari- ability. Whereas there remains much to learn about the potential biological relevance of UGTs, deficient glucuronidation can result in either elevated tissue concentrations and direct toxicity of substrates, as with the endobiotic bilirubin, or, alternatively, enhanced bioacti- vation of substrates to toxic reactive intermediates, as in the case of acetaminophen and benzo[a]pyrene. Interindividual UGT variability likely plays an important role in drug efficacy and xenobiotic toxicity, as well as in hormonal regulation and certain diseases, which in some cases may be amenable to therapeutic manipulations including gene therapy. Structure and Tissue-Specific Regulation of UGT Genes (P.I.M., P.A.G., Y.I., A.J.H.) The UGT content of cells and tissues is a major determinant of our response to those chemicals that are primarily eliminated by conju- gation with glucuronic acid. There are marked interindividual differ- ences in the content of UGTs in the liver and other organs including the gastrointestinal tract. For example, only one third of the popula- tion appears to express UGT1A1, UGT1A3, and UGT1A6 in their gastric epithelium (Strassburg et al., 1998). Studies on the mecha- nisms that regulate UGT genes, in a temporal and tissue-specific manner, should contribute significantly to understanding the basis for these differences. Such studies should also aid in the design of molecular probes to assess the capacity of individuals to metabolize specific drugs and toxins, before exposure to these agents. The genes encoding UGTs that use UDP-glucuronic acid as sugar donor have been assigned to two families (Mackenzie et al., 1997). The UGT1 family constitutes a complex gene locus on human chro- mosome 2q37 and comprises 13 first exons that encode the unique This work was supported in part by grants from the Canadian Institutes of Health Research (P.G.W., C.G.), the National Health and Medical Research Coun- cil of Australia and the Anti-Cancer Foundation of South Australia (P.I.M., P.A.G., A.J.H., Y.I.), the Canada Research Chair Program and the Fonds de la Recherche en Sante du Quebec (C.G.), and United States Public Health Service Grants R01-DK46057, R01-DK34357 and P30DK41296 (J.R.C., N.R.C.), and R01ES07762 (J.K.R.). 1 These authors contributed equally as symposium speakers. 2 Abbreviations used are: UGT, UDP-glucuronosyltransferase; B[a]P, benzo- [a]pyrene; CN-1, Crigler-Najjar syndrome type 1; HCA, heterocyclic amine; HNF1, hepatocyte nuclear factor 1; OR, odds ratio; SN-38, 7-ethyl-10-hydroxycampto- thecin; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; P450, cytochrome P450; rAAV, recombinant adenoassociated virus. Address correspondence to: Dr. Joseph K. Ritter, Dept. of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, 410 N. 12th St., P.O. Box 980613, Richmond, VA 23298-0613. E-mail: jritter@mail2.vcu.edu 0090-9556/04/3203-281–290$20.00 DRUG METABOLISM AND DISPOSITION Vol. 32, No. 3 Copyright © 2004 by The American Society for Pharmacology and Experimental Therapeutics 1299/1135075 DMD 32:281–290, 2004 Printed in U.S.A. 281 at ASPET Journals on December 18, 2017 dmd.aspetjournals.org Downloaded from