Differential inhibition of hepatic morphine UDP-glucuronosyltransferases by metal ions.
The major metabolites of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), possess significant pharmacological properties. Whilst both metabolites bind to mu-opioid binding sites, M6G is a potent agonist whereas M3G antagonizes some of the effects of morphine and M6G. An inter-species comparison of in vitro hepatic morphine processing was performed. The results showed that not all species were able to produce M6G whereas all those tested did produce M3G. Guinea-pig liver produced the greatest amounts of M6G and was therefore chosen as a model to study morphine glucuronidation in further detail. Inclusion of the detergent Brij 58 (0.33 mg/mg protein) and Mg2+ (15 mM) in the standard assay incubation gave optimal production of both M3G and M6G by guinea-pig liver homogenates. A number of metal ions were investigated for their ability to inhibit glucuronidation of morphine in both the 3- and 6-positions. Some metal ions, namely Cu+, Cu2+ and Cd2+, were able to inhibit the production of M3G without affecting glucuronidation at the 6-position. Taken together, these data provide further evidence for the existence of UDP-glucuronosyltransferase isoenzymes responsible for the metabolism of morphine. In addition these isoenzymes can be differentially modulated and therefore it is possible to alter the ratio of M3G:M6G formed during in vitro metabolic studies.
Lawrence
A J
AJ
Pain Research Institute, Liverpool, U.K.
Michalkiewicz
A
A
Morley
J S
JS
MacKinnon
K
K
Billington
D
D
D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D019256:Cadmium Chloride; D002712:Chlorides / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D007477:Ions; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008670:Metals / Q000494:pharmacology*; D009020:Morphine / Q000378:metabolism*; D009022:Morphine Derivatives / Q000378:metabolism
D002712:Chlorides; D007477:Ions; D008670:Metals; D009022:Morphine Derivatives; D002104:Cadmium; C035349:morphine-6-glucuronide; D009020:Morphine; D003300:Copper; D014453:Glucuronosyltransferase; D019256:Cadmium Chloride; C018108:morphine-3-glucuronide; C029892:cupric chloride