Cytochrome P-450-linked monooxygenase system and drug-induced spectral interactions in human liver microsomes

Summary Human liver microsomes isolated from operation biopsy samples from patients with cholelithiasis or a malignant disease, were studied with respect to a drug-oxidizing monooxygenase system. The human liver contained about 30-40 mg of microsomal protein per gram of wet weight and about 50% of that was recovered in the microsomal fraction. The mean levels of cytochrome P-450, NADPH-cytochrome c reductase and cytochrome b5 in the livers of cholelithiatic patients were essentially similar to those in the livers of rat and guinea pig and only slightly lower than those in the rabbit liver. The cytochrome P-450-carbon monoxide difference spectrum exhibited a peak at 450 nm and, in microsomes from several smokers, no peak shift to 448 nm was evident. Studies with ethyl isocyanide as a ligand revealed a typical difference spectrum with a peak ratio at pH 7.4 of 455/430 nm of 0.46 and a pH intercept of at about 7.9. There was no correlation between cigarette smoking and a peak ratio. Drug-induced interactions of type I (SKF 525A, bromobenzene), type II (aniline, n-octylamine, KCN) and reverse type I (phenacetin, n-butanol) variety were detected in liver samples studied. Hexobarbital and aminopyrine gave either type I or reverse type I spectral changes. The spectral dissociation constant for aniline was of the same order of magnitude as in rat liver microsomes. These studies seem to indicate that although qualitative differences between hepatic monooxygenase systems in man and laboratory animals may exist, available evidence suggests that many essential differences are only quantitative in nature.