The novelUGT1 gene complex links bilirubin, xenobiotics, and therapeutic drug metabolism by encoding UDP-glucuronosyltransferase isozymes with a common carboxyl terminus

Abstract

The UDP-glucuronosyltransferase system (transferase) plays an important role in the pharmacokinetics of clearance of endogenous metabolites, therapeutic drugs, and xenobiotics. The human bilirubin and phenol transferases are encoded by the same gene complex which we designateUGT1. The gene arrangement indicates there are 6 exon 1s each with a promoter and each of which can predictably undergo differential splicing to the 4 common exons (2 through 5) to generate possibly 6 different mRNAs. The entire unique amino acid terminus of each isoform is encoded by an exon 1, and the common carboxyl terminus is encoded by the 4 common exons. Evidence supports the existence of other exon is upstream of the currently described locus. The 13-bp deletion in exon 2 represents the most common defect, to date, in the Crigler-Najjar, Type I individuals. Different point mutations in the 4 common exons and in exon 1 ofUGT1A, however, also account for defective bilirubin transferase activity. The gene arrangement, in conjunction with the toxicity data from the Gunn rat, leads to the prediction that detoxification of bilirubin, xenobiotics, and therapeutic drugs is linked to theUGT1 locus. The Crigler-Najjar syndromes are uncommon, but the Gilbert individuals are commonly represented in 6% of the population. It is expected that, similar to the deleterious mutations in the common region of theUGT1 locus in Crigler-Najjar, Type I individuals, there is a range of moderate to intermediate deleterious mutations in this region of the gene of at least some Gilbert's individuals. Linkages, therefore, at this locus could signal that these individuals are at risk for certain drug toxicities and/or idiosyncratic drug reactions.