Elsevier

Biochemical Pharmacology

Volume 43, Issue 11, 9 June 1992, Pages 2335-2340
Biochemical Pharmacology

Differential inhibition of hepatic morphine UDP-glucuronosyltransferases by metal ions

https://doi.org/10.1016/0006-2952(92)90311-6Get rights and content

Abstract

The major metabolites of morphine, morphine-3-glucuronide (M3G) and morphine-6-glu-curonide (M6G), possess significant pharmacological properties. Whilst both metabolites bind to μ-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.

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