GLUCURONIDATION OF AMINE SUBSTRATES BY PURIFIED AND EXPRESSED UDP-GLUCURONOSYLTRANSFERASE PROTEINS

Conjugation of many primary, secondary, and tertiary amine-containing xenobiotics with glucuronic acid can result in the formation of N-gluc uronide metabolites. For carcinogenic arylamines and their N-hydroxyla ted metabolites, N-glucuronidation can result in the formation of eith er inactive metabolites or labile conjugates, which can be transported to their target tissue (urinary bladder) where they may be converted to reactive metabolites. Drugs with primary amine (e.g. dapsone) or se condary amine moieties (e.g. sulfadimethoxine and clozapine) can also be metabolized to N-glucuronides. The metabolism of a number of tertia ry amine-containing pharmacological agents to quaternary ammonium-link ed glucuronides represents a unique and important metabolic pathway fo r these compounds that is highly species-dependent. This review summar izes our present knowledge of the uridine diphosphate (UDP)-glucuronos yltransferase enzymes involved in catalyzing N-glucuronide formation. Of the more than 30 UDP-glucuronosyltransferases that have been purifi ed or cloned and expressed, many catalyze N-glucuronide formation for primary and secondary amine substrates. In contrast, only human UDP-gl ucuronosyltransferases 1A3 and 1A4 have been shown to catalyze quatern ary ammonium-linked glucuronide formation for aliphatic tertiary amine s. The structure of the UGT1 gene complex is highly conserved across s pecies, and it appears that a mutation in the first exon encoding UDP- glucuronosyltransferase 1A4, resulting in a pseudo-gene, may explain t he inability of some species to form quaternary ammonium-linked glucur onides.