GENE STRUCTURE AT THE HUMAN UGT1 LOCUS CREATES DIVERSITY IN ISOZYME STRUCTURE, SUBSTRATE-SPECIFICITY, AND REGULATION

This chapter focuses on the extraordinary features of the novel UGT1 gene complex, which encodes, unexpectedly, a subfamily of UDP glucuronosyltransferase (transferase) isozymes that metabolize either bilirubin or phenolic substrates. The relationship between substrates metabolized by the encoded enzymes and the mechanism by which diversity is achieved at the complex is remarkable. Based on exonic sequence data, exon–intron arrangement, consensus sequences for RNA splicing, and promoter elements for RNA polymerase II transcription initiation, the UGT1 locus provides for diversity in enzyme structure, and thus different substrate-specific isoforms that are independently regulated by the respective proximal promoter element. The origin of such a locus necessarily emanates from its critical function in coding for the enzyme responsible for clearing the complex and toxic chemical, bilirubin. A characteristic of transferase enzymes ideally suited to their function in the detoxification of lipophilic substances is their broad substrate specificity. Most transferases can catalyze the glucuronidation of multiple acceptor substrates. Only minimal progress has been made in characterizing the substrate specificity of individual UGT1 isozymes. The regulation of the UGT1 genes is an important aspect of the biology of this subfamily of isozymes and of the UDP-glucuronosyltransferases in general. Alterations in the amount of these enzymes resulting from altered gene expression have the potential to change the steady-state levels of a glucuronicate acceptor. © 1995, Academic Press Inc. All rights reserved.