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Toxicol In Vitro. 1997 Dec;11(6):775-8.

Difference in the inhibition of nitric oxide synthase and cytochrome P-450 by some H(2)-antagonists.

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Leiden/Amsterdam Center for Drug Research, Division of Molecular Pharmacology, Department of Pharmacochemistry, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.


The enzyme nitric oxide synthase (NOS) is reported to have some similarities to the family of cytochrome P-450 enzymes. In this study the histamine H(2)-antagonists 2-methyl-4(4-isopropylaminomethyleneiminophenyl) imidazole (DA 5047), 2-guanidino-4(3-methylaminomethyleneiminophenyl)thiazole (DA 4643), tiotidine and cimetidine, which all display cytochrome P-450 inhibition were tested in a rat brain constitutive NOS (cNOS) assay. It was found that all four compounds inhibit rat brain cNOS in a competitive way. This was compared with the inhibition of cytochrome P-450 by these compounds reported previously by Rekka et al. (Rekka et al., 1989). The pIC(50) for cNOS inhibition correlated negatively with the pIC(50) found for P-450 inhibition. Apparently, the H(2)-antagonists interact differently to NOS compared with cytochrome P-450, indicating that there is a functional difference in the molecular mechanism of both enzymes in contrast to what has been suggested.


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