Genetic and Environmental Factors Associated with Variation of Human Xenobiotic Glucuronidation and Sulfation
Brian Burchell and Michael W.H. Coughtrie
Department of Biochemical Medicine, Ninewells Medical School, The University, Dundee, Scotland
Abstract
Glucuronidation and sulfation are phase 2 metabolic reactions catalyzed by large families of different isoenzymes in man. The textbook view that glucuronidation and sulfation lead to the production of harmless conjugates for simple excretion is not valid. Biologically active and toxic sulfates and glucuronides are produced and lead to adverse drug reactions, including immune hypersensitivity. Considerable variation in xenobiotic conjugation is observed as a result of altered expression of UDP-glucuronosyltransferases (UGTs) and sulfotransferases (STs). Recent cloning and expression of human cDNA encoding UGTs and STs has facilitated characterization of isoform substrate specificity, which has been further validated using specific antibodies and human tissue fractions. The availability of cloned/expressed human enzymes and specific antibodies has enabled the investigation of xenobiotic induction and metabolic disruption leading to adverse responses. Genetic polymorphisms of glucuronidation and sulfation are known to exist although the characterization and assessment of the importance of these variations are hampered by appropriate ethical studies in man with suitable safe model compounds. Genetic analysis has allowed molecular identification of defects in well-known hyperbilirubinemias. However, full characterization of the specific functional roles of human UGTs and STs requires rigorous kinetic and molecular analyses of the role of each enzyme in vivo through the use of specific antibodies and inhibitors. This will lead to the better prediction of variation of xenobiotic glucuronidation and sulfation in man. -- Environ Health Perspect 105(Suppl 4):739-747 (1997)
Key words: polymorphisms, enzyme induction, inhibition, gene families, cloned/expressed enzymes, antibodies, toxic conjugates, acylglucuronidation
This paper was prepared as background for the Workshop on Susceptibility to Environmental Hazards convened by the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC) held 17-22 March 1996 in Espoo, Finland. Manuscript received at EHP 5 November 1996; accepted 18 November 1996.
We thank The Wellcome Trust (BB) and the Commission of the European Communities (Contracts BMH1-CT92-0097; EV5V-CT94-0410, MWHC) for their support of the research work in our laboratories.
Address correspondence to Dr. B. Burchell, University Department of Biochemical Medicine, Ninewells Hospital and Medical School, DUNDEE DD1 9SY, Scotland, UK. Telephone: 44 1382 632164. Fax: 44 1382 644620. E- mail: bburchell@ninewells.dundee.ac.uk
Abbreviations used: CN, Crigler-Najjar syndrome; GS, Gilbert's syndrome; PAPS, 3´-phosphoadenosine 5´-phosphosulfate; ST, sulfotransferase; UGT, UDP-glucuronosyltransferase; YAC, yeast-affiliated chromosome.
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