Difference in the inhibition of nitric oxide synthase and cytochrome P-450 by some H(2)-antagonists.
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.
Paquay
J B
JB
Leiden/Amsterdam Center for Drug Research, Division of Molecular Pharmacology, Department of Pharmacochemistry, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Bolscher
M T
MT
Voss
H P
HP
Timmerman
H
H
Bast
A
A