UDPglucuronosyltransferase deficiency in man and animals.

Abstract

Deficient function of hepatic UDPglucuronosyltransferase (EC 2.4.1.17) is readily detected because affected individuals have non-haemolytic unconjugated hyperbilirubinaemia which is usually severe enough to produce clinical jaundice. Deficient hepatic UDPGT activity has been demonstrated in six pathobiologic states: (i) Gunn rats (Arias, 1959 ; Dutton, 1980), (ii) Crigler-Najjar syndrome (type I) patients (Wolkoff et al., 1983). (iii) Crigler-Najar syndrome (type 11) patients (Arias et al., 1969), (iv) Gilbert’s syndrome in man (Arias & London, 1957; Wolkoff et al., 1983), (v) Gilbert’s syndrome in Bolivian squirrel monkeys (Roy Chowdhury et al., 1982b,c), and the most common form, (vi) neonatal unconjugated hyperbilirubinaemia in man and monkeys (Gartner et al., 1977). In each disorder, reduced hepatic UDPGT activity was demonstrated when homogenates of microsomes were incubated with UDPGA and bilirubin or several other glucuronide acceptors (Roy Chowdhury et al., 1982~; Wolkoff et al., 1983). Only recently have advances in purification of UDPGT (see Burchell, 1981) permitted partial answers to be obtained to the following longstanding questions. (i) Is there a single UDPGT with varied affinity for different receptors forming acyl, alcoholic, ethereal, Nand S-linked glucuronides or is there a family of UDPGTs with overlapping substrate specificities? (ii) What is the role of microsomal membrane lipids in the expression and regulation of UDPGT activity? (iii) What is the specific structural and molecular defect in disorders characterized by deficient UDPGT activity? The number of these disorders, availability of mutant (Gunn) rats and squirrel (Bolivian) monkeys (Roy Chowdhury et al., 19826,~) and progress in UDPGT purification prompted our efforts to purify UDPGT(s) from the liver of normal and mutant rats, squirrel monkeys, and man. Our goal is to determine the structure of the enzymes and develop immunologic and molecular probes to characterize their regulation, development and response to pharmacologic and molecular manipulation. Based upon the accomplishments of others (Gorski & Kasper, 1977; Burchell, 1978; Bock etal., 1979; Weatherill & Burchell, 1980; Tukey & Tephly, 1981) and collaborations with Burchell and Tephly and their associates, we have made progress toward these aims as reported in this paper.