The effects of H2-receptor antagonists and imidazole on testosterone hydroxylations in mouse liver microsomes.

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Abstract
[Cimetidine, an H2-receptor antagonist widely used for the treatment of peptic ulcer, reduces the plasma clearance of a number of drugs in man and has an inhibitory effect on the oxidative metabolism of xenobiotics by hepatic microsomal monooxygenases in vitro.] A simple assay method for testosterone hydroxylase activity by TLC-UV spectrophotometry was developed. By using this method, the effects of various H2-receptor antagonists (cimetidine, CIM; metiamide, MET; ranitidine, RAN; famotidine, FAM) or imidazole (IMZ) on the hydroxylations of testosterone by mouse liver microsomal enzymes were studied in vitro. CIM and MET inhibited the 6.beta.-, 7.alpha.- and 16.alpha.-hydroxylations in a dose-dependent manner. RAN and FAM had little inhibitory effect on any hydroxylation. IMZ inhibited the 6.beta.-hydroxylation to the same degree as CIM and MET, while the effects on the 7.alpha.- and 16.alpha.-hydroxylations were very weak. The kinetic data indicated that these drugs inhibited the 3 hydroxylation reactions competitively and the affinities for each hydroxylase varied from drug to drug. The inhibitory actions of CIM or MET on the hydroxylations of testosterone are apparently due to the imidazole ring structure, and the side chain structures may play a role in the enhancement of affinity to the enzymes, particularly the 7.alpha.- and 16.alpha.-hydroxylases. RAN and FAM containing a ring structure different from imidazole had little effect on any testosterone hydroxylase.