Human bilirubin UDP-glucuronosyltransferase catalyzes the glucuronidation of ethinylestradiol.
The synthetic estrogen ethinylestradiol is extensively eliminated as glucuronide 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 stably expressed in V79 cell lines. Two cloned expressed human enzymes, a bilirubin UGT and a phenol UGT, were observed to catalyze the glucuronidation of ethinylestradiol. High performance liquid chromatographic analysis of the products formed revealed that the expressed bilirubin UGT specifically produced ethinylestradiol-3-glucuronide. In human liver microsomes the ratio of 3-glucuronide/17-glucuronide was 97:3. Subsequent study of the cloned expressed enzymes and human liver microsomes from Crigler-Najjar patients by kinetic analysis and by substrate inhibition strongly indicated that a human liver bilirubin UGT was largely responsible for glucuronidation of ethinylestradiol. These results may provide an explanation for jaundice caused by ethinylestradiol in certain susceptible individuals.
Ebner
T
T
Department of Biochemical Medicine, Ninewells Medical School, University of Dundee, Scotland, UK.
Remmel
R P
RP
Burchell
B
B
D000818:Animals; D002384:Catalysis; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004997:Ethinyl Estradiol / Q000378:metabolism* / Q000494:pharmacology; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D011994:Recombinant Proteins / Q000378:metabolism
D005965:Glucuronates; D007527:Isoenzymes; D011994:Recombinant Proteins; D004997:Ethinyl Estradiol; D014453:Glucuronosyltransferase