Multiplicity and ligand selectivity

At present, 17 functional human UGTs have been identified: UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10, 2A1, 2B4, 2B7, 2B8, 2B10, 2B11, 2B15, and 2B17. Numerous heterologous expression systems have been developed, and membrane preparations containing most of the recombinant human isoforms are commercially available.100 Our knowledge of their substrate specificity comes largely from in vitro studies with the recombinant proteins, but also in some cases from clinical and pharamcogenetic studies performed in vivo.99

UGT1A1 is probably the most widely studied isoform because it is the most abundant UGT in liver, and it has long been recognized to be the primary enzyme responsible for the glucuronidation of bilirubin. A common genetic polymorphism in the promoter region of the gene (UGT1A1*28) underlies the relatively benign hyperbilirubinemia or Gilbert's disease, whereas rare polymorphisms in the coding region of the UGT1A gene lead to the much more serious Crigler-Najjar syndromes.101 In addition to bilirubin, an important substrate for UGT1A1 is SN-38, the active metabolite of the anticancer drug irinotecan. Accumulation of SN-38, prominent in carriers of UGT1A1*28, causes dose-limiting toxicity. Human UGT1A4 and UGT2B7 have also attracted considerable attention because of their roles in amine glucuronidation and opiate metabolism, respectively. UGT1A4 is of particular interest because many drugs contain imidazoles and tetrazoles, and because aryl amine glucuronidation may be a modulating factor in colon and bladder cancer.102

Selective inhibitors of several human UGT isoforms are known, but these are generally low-potency compounds that are also used as selective substrates for the enzyme. Examples include bilirubin for UGT1A1, propofol for UGT1A9, and 3'-azido-3'-deoxythymidine for UGT2B7.103 Structure

No crystal or solution structures have yet been solved for the UGTs. Evidence does exist that the recombinant proteins can be N-glycosylated and phosphorylated104 but the relevance of these posttranslational modifications to enzyme function is not well understood. The UDPGA cofactor likely binds mainly to the conserved C-terminus of the protein, whereas binding determinants for the aglycone probably reside in the more variable N-terminus. An important step in the catalytic mechanism is activation of the xenobiotic substrate to an optimized nucleophile prior to displacement of glucuronic acid from UDPGA. Site-directed mutagenesis experiments implicate histidine residues in enzyme function,105 but whether such basic residues are specifically involved in this substrate activation step remains to be determined.

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