SPECIES DIFFERENCE IN DRUG METABOLISM BY LIVER MICROSOMES IN ALLOXAN DIABETIC OR FASTED ANIMALS (II) THE SUBSTRATE INTERACTION WITH CYTOCHROME P-450 IN DRUG OXIDATION

Abstract

Imai and Sato (1), and Schenkman et al. (2) showed that a number of drugs which are substrates of hepatic microsomal monooxygenase react with a microsomal cytochrome called cytochrome P-450 to give characteristic types of spectral change. These results have suggested that the spectral changes observed are indicative of substrate interaction for enzymic hydroxylation (2) and that the magnitude of the substrate binding with cytochrome P-450 is one of important factors controlling the rate of the over-all hydroxylation of drugs by liver microsomes (3-6). In the preceding paper (7), it was demonstrated that, in contrast to the results obtained with male rats, the hexobarbital hydroxylation by liver microsomes was not decreased in alloxan diabetic or fasted male mice and rabbits. These results supported the hypothesis that the decrease in the hexobarbital hydroxylation in alloxan diabetic or fasted rats is due to an impairment of the androgen-dependent stimulating mechanism for drug-metabolizing enzymes (8, 9). It has been reported that the magnitude of hexobarbital-induced spectral change was greater in male rats than in the females, and that androgen administration increased the magnitude of the spectral change (3, 6). On the other hand, there was no clear sex difference in the magnitude of hexobarbital-induced spectral change in liver microsomes from mice and rabbits and the administration of androgen did not stimulate the magnitude of the spectral change (6, 10). In the present studies, therefore, the effect of alloxan diabetes or starvation on the binding of cytochrome P-450 with substrate in liver microsomes of both sexes of rats, mice and rabbits was investigated in relation to the effect on the hydroxylating activity for hexobarbital and aniline.