UDP-glucuronosyltransferase (UGT) enzymes comprise a superfamily of key proteins that catalyze the glucuronidation reaction on a wide range of structurally diverse endogenous and exogenous chemicals. Glucuronidation is one of the major phase II drug-metabolizing reactions that contributes to drug biotransformation. This biochemical process is also involved in the protection against environmental toxicants, carcinogens, dietary toxins and participates in the homeostasis of numerous endogenous molecules, including bilirubin, steroid hormones and biliary acids. Over the years, significant progress was made in the field of glucuronidation, especially with regard to the identification of human UGTs, study of their tissue distribution and substrate specificities. More recently, the degree of allelic diversity has also been revealed for several human UGT genes. Some polymorphic UGTs have demonstrated a significant pharmacological impact in addition to being relevant to drug-induced adverse reactions and cancer susceptibility. This review focuses on human UGTs, the description of the nature of polymorphic variations and their functional impact. The pharmacogenomic implication of polymorphic UGTs is presented, more specifically the role of UGT polymorphisms in modifying cancer risk and their impact on individual risk to drug-induced toxicities.
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Dr Guillemete is chairholder of the Canada Research Chair in Parmacogenomics funded by the Canada Research Chair Program. This work was supported by the Canadian Institutes of Health Research (CIHR MOP-42392; MSH-46809; MOP-44032) and the Fonds de la Recherche en Santé du Québec (FRSQ 13100-166). Special thanks to Dr Louis-Charles Fortier for critical reading of the manuscript and preparation of material for this review and Dr Claude Labrie for critical reading. Thanks to Lyne Villeneuve for preparation of the bibliography, and Yannick Duguay and Julie Pageau for their help in the preparation of tables and figures. Thanks to Dr Eric Levesque and Dr Philip Lazarus for helpful discussion.
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Guillemette, C. Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 3, 136–158 (2003). https://doi.org/10.1038/sj.tpj.6500171
- genetic polymorphism
- drug metabolism
- cancer susceptibility
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