Interaction of oxygen and aromatic amines with hepatic microsomal mixed-function oxidase

Abstract

A biphasic effect of carbon monoxide on N-oxide formation from N, N-dimethylaniline has been observed, such that CO stimulates N-oxide formation at low oxygen concentrations and inhibits product formation at high oxygen concentrations. Inhibition is discussed in terms of the involvement of cytochrome P-450 in the N-oxidation process. Furtheremore, carbon monoxide abolishes the sigmoidal character of the oxygen saturation curve, found for N-oxide formation, and reduces K m the apparent Michaelis constant for oxygen. It is suggested that CO influences oxidase activity by affecting the equilibrium between two allosteric forms of cytochrome P-450 , shifting the equilibrium toward the form with the higher affinity for carbon monoxide and oxygen, and with n for oxygen activation near 1.0. N, N-Dimethylaniline has been found to accelerate the reduction of cytochrome P-450 by NADPH. The rate of binding of aniline and N, N-dimethylaniline to the hemoprotein is differentially affected by NADPH. It is proposed that there might exist a regulatory cycle in the binding of both compounds to cytochrome P-450.