6533b85ffe1ef96bd12c13b8

RESEARCH PRODUCT

NADPH-cytochrome P-450 reductase: Preferential inhibition by ellipticine and other type II compounds having little effect on NADPH-cytochrome c reductase

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Abstract Ellipticine (5,11-dimethyl-[6H]-pyrido[4,3b]carbazole) binds with an affinity greater than most other compounds known to interact with P-450. Control and 3-methylcholanthrene-induced aryl hydrocarbon (benzo[ a ]pyrene) hydroxylase (EC 1.14.14.2) and acetanilide 4-hydroxylase and control and phenobarbital-induced ethylmorphine N -demethylase activities are all markedly inhibited by ellipticine to about the same extent. Ellipticine and other Type II compounds (metyrapone, octylamine-1, pyridine and aniline) preferentially inhibit NADPH-cytochrome P-450 reductase activity, while affecting NADPH-cytochrome c reductase activity very little. Butanol-1, a compound having pure Reverse Type I character, does not block P-450 reductase activity like these Type II compounds. These data suggest that Type II compounds bind to P-450 ferric iron in the sixth coordinate position in such a way as to impede transfer of the first electron from the hydrophobic binding site of the reductase to the P-450-substrate complex, while leaving unencumbered any transfer of electrons from the hydrophilic binding site of the reductase to soluble electron acceptors such as cytochrome c . These data indicate that ellipticine may be very useful in attempting to understand the mechanism by which electrons are transferred from the reductase to the cytochrome(s) P-450.