DIFFERENCE IN THE INHIBITION OF NITRIC-OXIDE SYNTHASE AND CYTOCHROME-P-450 BY H-2-ANTAGONISTS

The enzyme nitric oxide synthase (NOS) is reported to have some simila rities to the family of cytochrome P-450 enzymes. In this study the hi stamine H-2-antagonists hyl-4(4-isopropylaminomethyleneiminophenyl)imi dazo le (DA 5047), idino-4(3-methylaminomethyleneiminophenyl)thiatele (DA 4643), tiotidine and cimetidine, which all display cytochrome P-45 0 inhibition were tested in a rat brain constitutive NOS (cNOS) assay. It was found that all four compounds inhibit rat brain cNOS in a comp etitive 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 i nteract differently to NOS compared with cytochrome P-450, indicating that there is a functional difference in the molecular mechanism of bo th enzymes in contrast to what has been suggested. (C) 1997 Published by Elsevier Science Ltd.