Human UDP-glucuronosyltransferases: Metabolism, expression, and disease

In vertebrates, the glucuronidation of small lipophilic agents is catalyzed by the endoplasmic reticulum UDP-glucuronosyltransferases (UGTs). This met abolic pathway leads to the formation of water-soluble metabolites originat ing from normal dietary processes, cellular catabolism, or exposure to drug s and xenobiotics, This classic detoxification process, which led to the di scovery nearly 50 years ago of the cosubstrate UDP-glucuronic acid (19), is now known to be carried out by 15 human UGTs. Characterization of the indi vidual gene products using cDNA expression experiments has led to the ident ification of over 350 individual compounds that serve as substrates for thi s superfamily of proteins. This data, coupled with the introduction of soph isticated RNA detection techniques designed to elucidate patterns of gene e xpression of the UGT superfamily in human liver and extrahepatic tissues of the gastrointestinal tract, has aided in understanding the contribution of glucuronidation toward epithelial first-pass metabolism. In addition, char acterization of the UGT1A locus and genetic studies directed at understandi ng the role of bilirubin glucuronidation and the biochemical basis of the c linical symptoms found in unconjugated hyperbilirubinemia have uncovered th e structural gene polymorphisms associated with Crigler-Najjar's and Gilber t's syndrome. The role of the UGTs in metabolism and different disease stat es in humans is the topic of this review.