Elsevier

Biochemical Pharmacology

Volume 38, Issue 17, 1 September 1989, Pages 2795-2799
Biochemical Pharmacology

The specificity of inhibition of debrisoquine 4-hydroxylase activity by quinidine and quinine in the rat is the inverse of that in man

https://doi.org/10.1016/0006-2952(89)90433-4Get rights and content

Abstract

The kinetics of inhibition of debrisoquine 4-hydroxylase activity by quinidine and quinine in rat and human liver microsomes have been compared. Quinidine is a potent inhibitor of debrisoquine 4-hydroxylase activity of human liver (ic50: 3.6 μM). However, its stereoisomer, quinine, is some 60 times less potent (ic50: 223 μM. Both compounds are able to inhibit > 95% of 4-hydroxylase activity. In rat liver microsomes quinine is approximately 50 times more potent an inhibitor (ic50: 2.4 μM) than quinidine (ic50: 137 μM). Again, 4-hydroxylase activity is inhibited by > 95%. Inhibition of debrisoquine 4-hydroxylase activity by both quinine and quinidine in human and rat liver is competitive. Values of Ki for quinidine in human and rat were 0.6 μM and 50μM, whereas with quinine the Ki values were 13μM and 1.7 μM, respectively. The data in this paper are consistent with 4-hydroxylation of debrisoquine in both rat and human liver catalysed by a specific form of cytochrome P-450. Although both quinidine and quinine are competitive inhibitors of debrisoquine 4-hydroxylase activity in rat and man, their potency is reversed. This suggests that the nature of the active site of cytochrome P-450dbl differs between the two species, and indicates that data on the specificity of this isoenzyme in the rat should be extrapolated to man with extreme caution.

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Present address: Department of Pharmacology, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan.

Present address: Clinical Mass. Spec. Lab., Department of Paediatrics, Children's Hospital Medical Center, Elland & Bethesda Avenues, Cincinnati, OH 45229, U.S.A.

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