Several novel UDP glycosyltransferase (UGT) genes, mainly UDP glucuronosyltransferases, have been identified in the human, mouse and rat genomes and in other mammalian species. This review provides an update of the UGT nomenclature to include these new genes and prevent the confusion that arises when the same gene is given different names. The new genes are named following previously established recommendations, taking into consideration evolutionary relatedness and the names already in general usage in the literature. The mammalian UGT gene superfamily currently has 117 members that can be divided into four families, UGT1, UGT2, UGT3 and UGT8. The 5-exon genes of the UGT1 family each contain a unique first exon, plus four exons that are shared between the genes; the exons 1 appear to have evolved by a process of duplication, leading to the synthesis of proteins with identical carboxyl-terminal and variable amino-terminal domains. Exon-sharing is also seen with the 6-exon UGT2A1 and UGT2A2 genes. However, UGT2A3 and those of the UGT2B (six exons), UGT3 (seven exons) and UGT8 gene families (five or six exons) do not share exons and most likely were derived by a process of duplication of all exons in the gene. Most UGT1 and UGT8 enzymes have been characterized in detail; however, the catalytic functions of the UGT3A enzymes and several UGT2 enzymes remain to be characterized.

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.

7-Ethyl-10-hydroxycamptothecin (SN-38) is the pharmacologically active metabolite of irinotecan, in addition to being responsible for severe toxicity. Glucuronidation is the main metabolic pathway of SN-38 and has been shown to protect against irinotecan-induced gastrointestinal toxicity. The purpose of this study was to determine whether common polymorphic UDP-glucuronosyltransferase (UGT) affects SN-38 glucuronidation. First, kinetic characterization of SN-38-glucuronide (SN-38-G) formation was assessed for all known human UGT1A and UGT2B overexpressed in human embryonic kidney 293 cells. To assess the relative activity of UGT isoenzymes for SN-38, rates of formation of SN-38-G were monitored by liquid chromatography/mass spectrometry analysis and normalized by level of UGT cellular expression. Determination of intrinsic clearances predicts that hepatic UGT1A1 and UGT1A9 and the extrahepatic UGT1A7 are major components in SN-38-G formation, whereas a minor role is suggested for UGT1A6, UGT1A8, and UGT1A10. In support of the involvement of UGT1A9, a strong coefficient of correlation was observed in the glucuronidation of SN-38 and a substrate, mainly glucuronidate, by UGT1A9 (flavopiridol) by human liver microsomes (coefficient of correlation, 0.905;p = 0.002). In vitro functional experiments revealed a negative impact of the UGT1A1 allelic variants. Residual activities of 49, 7, 8, and 11% were observed for UGT1A1*6 (G⁷¹R), UGT1A1*27 (P²²⁹Q), UGT1A1*35 (L²³³R), and UGT1A1*7 (Y⁴⁸⁶D), respectively. Common variants of UGT1A7, UGT1A7*3 (N¹²⁹K;R¹³¹K;W²⁰⁸R), and UGT1A7*4 (W²⁰⁸R), displayed residual activities of 41 and 28% compared with the UGT1A7*1 allele. Taken together, these data provide the evidence that molecular determinants of irinotecan response may include the UGT1A polymorphisms studied herein and common genetic variants of the hepatic UGT1A9 isoenzyme yet to be described.

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 Molecular Pharmacology. The report covers research from the authors9 laboratories on the structure and regulation of UDP-glucuronosyltransferase (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.

Mycophenolic acid (MPA), a standard immunosuppressive drug, is characterized by unexplained highly variable pharmacokinetics in transplant recipients. The primary metabolic pathway of MPA is glucuronidation; however, literature reports are inconsistent and the contribution of all human UDP-glucuronosyltransferases (UGTs) has never been systematically assessed. Sixteen heterologously expressed UGTs were studied for MPA 7-O-glucuronidation and compared with liver, kidney, and intestine microsomes. For direct measurement of MPA and mycophenolic acid 7-O-glucuronide (MPAG), we used a liquid chromatography-mass spectrometry protocol. Metabolic studies demonstrated that the glucuronidation of MPA in humans occurs mainly in the liver at variable rates, as well as in the kidney and the intestine. Kinetic data normalized for UGT expression levels point to 1A8 and 1A9 as the main UGTs, as well as to low-activity enzymes, 1A1, 1A7, and 1A10. According to their expression profiles, 1A8 and 1A9 are proposed, respectively, as the main extra-hepatic and the only hepatic enzymes involved. The effects of naturally occurring 1A8 (^*2 and ^*3) and 1A9 (^*2 and ^*3) variants on MPA 7-O-glucuronidation were studied and data suggest that the C²⁷⁷Y of 1A8 and the M³³T of 1A9 may influence MPAG levels. A number of low-activity alleles were also identified in 1A1 [^*6 (G⁷¹R), ^*7 (Y⁴⁸⁶D), ^*27 (P²²⁹Q), and ^*35 (L²³³R)], 1A7 [^*3 (K¹²⁹K¹³¹R²⁰⁸), ^*4 (R²⁰⁸), ^*5 (S¹¹⁵), ^*8 (K¹²⁹K¹³¹D¹³⁹R²⁰⁸), and ^*9 (S¹¹⁵K¹²⁹K¹³¹)], and 1A10 [^*2 (E¹³⁹K)]. Our study provides preliminary evidences that genetic factors, especially in the hepatic UGT1A9, may contribute to the variability of MPA pharmacokinetics observed in transplant patients.