UDP-glucuronosyltransferases: gene structures of UGT1 and UGT2 families

Abstract

In human, rat, and mice, a UGT1 complex locus provides for developmental-, inducer-, and cell-specific synthesis of a family of chemical-detoxifying isozymes, UDP-glucuronosyltransferases, which prevent toxicities, mutagenesis, and/or carcinogenesis. Between 10 and 14 first exons with individual promoter elements are tandemly arrayed upstream of 4 shared exons so as to synthesize independently as many overlapping primary transcripts. RNA splice sites allow a lead exon to join the common exons to generate mRNAs with unique 5' ends, but common 3' ends. Intra- and interspecies comparisons of amino acid sequences encoded by first exons show an evolutionary continuum; also, recognizable bilirubin- and phenol-specific catalytic units are differentially regulated by model compounds, phenobarbital, and/or aromatic hydrocarbons. Whereas UGT1 loci allow minimal changes to achieve new isozymes, a single deleterious mutation in a common exon negatively impacts the arrangement by inactivating the entire family of isozymes compared to an event at independent loci as seen in the UGT2 family. In humans, lethal hyperbilirubinemic Crigler-Najjar type 1 and milder diseases/syndromes are due to deleterious to mildly deleterious mutations in the bilirubin-specific UGT1A1 or a common exon. In addition, the number of TA repeats (N(5-8)) in the UGT1A1 proximal TATA box affects transcriptional rate and, thus, activity. Evidence also shows that polymorphisms in nonbilirubin-specific first exons also impact chemical detoxifications and other diseases.