In vitro evidence for the involvement of at least two forms of human liver UDP-glucuronosyltransferase in morphine 3-glucuronidation.
Morphine 3-glucuronidation kinetics and the inhibitory effects of a number of xenobiotics on morphine glucuronidation in human liver microsomes have been investigated. In both native and detergent-activated microsomes morphine glucuronidation exhibited biphasic kinetics, with a high affinity, low capacity component and a low affinity, high capacity component. These data suggest the involvement of at least two forms of human liver UDP-glucuronosyltransferase (UDPGT) in morphine glucuronidation. The high affinity morphine-UDPGT activity is likely to be of most importance in morphine glucuronidation in vivo. Chloramphenicol, 4-hydroxybiphenyl, 4-methylumbelliferone, 1-naphthol and 4-nitrophenol were all shown to inhibit the low affinity morphine-UDPGT activity, but only chloramphenicol and 1-naphthol were competitive inhibitors. Each of these xenobiotics were shown to be a non-inhibitor of the high affinity morphine-UDPGT activity, or at least to have considerably lower affinity for this enzyme form(s) than morphine itself. Overall the results provide further evidence for the heterogeneity of human liver UDPGT and, in conjunction with other recent studies (Miners JO et al., Kinetic and inhibitor studies of 4-methylumbelliferone and 1-naphthol glucuronidation in human liver microsomes, Biochem Pharmacol 37: 665-671, 1988) of the kinetics of human liver glucuronidation reactions, indicate that xenobiotic substrates such as morphine, 4-methylumbelliferone and 1-naphthol may be used to differentiate UDPGT isozyme activities in human liver microsomes.
D002701:Chloramphenicol / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000032:analysis* / Q000037:antagonists & inhibitors; D006801:Humans; D006923:Hymecromone / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D009022:Morphine Derivatives / Q000378:metabolism*; D009284:Naphthols / Q000494:pharmacology; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D009022:Morphine Derivatives; D009284:Naphthols; D014535:Uridine Diphosphate Glucuronic Acid; C029350:1-naphthol; D006923:Hymecromone; D002701:Chloramphenicol; D014453:Glucuronosyltransferase; C018108:morphine-3-glucuronide