Elsevier

Biochemical Pharmacology

Volume 36, Issue 16, 15 August 1987, Pages 2667-2672
Biochemical Pharmacology

Metabolic activation of hydralazine by rat liver microsomes

https://doi.org/10.1016/0006-2952(87)90549-1Get rights and content

Abstract

There is evidence to suggest that the oxidative metabolism of hydralazine (HP), an antihypertensive drug, may represent a toxic pathway which could account for some of the adverse effects of the drug. Experiments were done to determine whether the hepatic oxidative metabolism of HP is associated with the formation of reactive metabolites. In the presence of NADPH, HP was metabolized by rat liver microsomes to three major oxidation products, phthalazine, phthalazinone (PZ), and a dimer compound. Under similar incubation conditions, radioactivity derived from [14C]HP was covalently bound to microsomal protein. Metabolite formation and covalent binding increased following pretreatment of rats with phenobarbital. In contrast, pretreatment with 3-methylcholanthrene or with the monooxygenase inhibitor, piperonyl butoxide, slightly decreased both metabolite formation and covalent binding. Electron spin resonance (ESR) analyses indicated that nitrogen-centered radicals were formed when rat liver microsomes were incubated with HP under conditions similar to those required for covalent binding and for the production of the oxidative metabolites. In addition, reduced glutathione (GSH) caused concentration-dependent decreases in the production of phthalazine, PZ, and the dimer, in the covalent binding of HP to microsomal protein, and in the formation of nitrogen-centered radicals. The results of these investigations indicate that the oxidative metabolism of HP by rat liver microsomes is highly correlated with the formation of nitrogen-centered radicals and the production of metabolites that become covalently bound to microsomal protein. These observations support the hypothesis that the oxidation of HP generates reactive metabolites which may contribute to the toxicity of the drug.

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    This research was supported in part by NIH Research Grant GM 30261. Part of this material appeared in abstract form [Fedn Proc.44,1624 (1985)]and in a thesis submitted by L. B. L. in partial fulfilment of the requirements for the degree of Doctor of Philosophy in the School of Pharmacy, West Virginia University, 1985.

    Present address: Department of Biomedical Sciences, University of Illinois, College of Medicine at Rockford, 1601 Parkview Ave., Rockford, IL 61107.

    ∗∗

    Present address: Mylan Pharmaceuticals, 781 Chestnut Ridge Road, Morgantown, WV 26505.

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