HUMAN BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE CATALYZES THE GLUCURONIDATION OF ETHINYLESTRADIOL

The synthetic estrogen ethinylestradiol is extensively eliminated as g lucuronide metabolites in humans, but the UDP-glucuronosyltransferases (UGTs) catalyzing this reaction have not been identified. Therefore, ethinylestradiol was tested as a substrate for cloned human UGTs stabl y expressed in V79 cell lines. Two cloned expressed human enzymes, a b ilirubin UGT and a phenol UGT, were observed to catalyze the glucuroni dation of ethinylestradiol. High performance liquid chromatographic an alysis of the products formed revealed that the expressed bilirubin UG T specifically produced ethinylestradiol-3-glucuronide. In human liver microsomes the ratio of 3-glucuronide/17-glucuronide was 97:3. Subseq uent study of the cloned expressed enzymes and human liver microsomes from Crigler-Najjar patients by kinetic analysis and by substrate inhi bition strongly indicated that a human liver bilirubin UGT was largely responsible for glucuronidation of ethinylestradiol. These results ma y provide an explanation for jaundice caused by ethinylestradiol in ce rtain susceptible individuals.