The molecular mechanisms governing the regulation of the drug- detoxifying enzyme, UDP glucuronosyltransferase (transferase), and the structural differences between members of this family are being investigated in the rat. This animal, as exemplified by the Gunn rat, provides the only known animal model for investigating the defect in the glucuronidation of bilirubin and certain xenobiotics, characteristic of the Crigler-Najjar syndrome in humans. Certain strains of Wistar rat also have an inherited defect in the glucuronidation of steroid hormones. The isolation and sequencing of seven cDNA clones has demonstrated the existence of at least four different forms of transferase belonging to two gene subfamilies. Homologous genes of one of these subfamilies is located on mouse chromosome 5. All the forms have structural motifs in common, including a cleavable signal peptide and a carboxy-terminal transmembrane segment, which suggests that their active sites are on the luminal aspect of the endoplasmic reticulum. Expression of cDNAs in monkey COS cells demonstrated that three clones pUDPGT tau-2, 3 and 5 encode transferases which glucuronidate testosterone and dehydrotestosterone. In addition, UDPGT tau-2 is also active towards foreign chemicals. UDPGT tau-4, however, is more active towards the 3-hydroxy position of the androgens, androsterone and etiocholanolone. Genomic clones to UDPGT tau-4 have been isolated and are being sequenced. cDNA clones have been utilized to study the regulation of each form as a function of age, tissue distribution and administration of prototypic inducers.
