EFFECTS OF MORPHINE TREATMENT AND STARVATION ON THE SUBSTRATE INTERACTION WITH P-450 IN THE OXIDATION OF DRUGS BY LIVER MICROSOMES

Abstract

In previous papers (1, 2), it has been reported that in male rats the administration of morphine and also starvation caused a marked decrease in the activities of drug-metabolizing enzymes of liver microsomes for hexobarbital hydroxylation and aminopyrine N-demethylation, but this was not the case in female rats. On the other hand, the activities of drugmetabolizing enzymes for aniline hydroxylation and zoxazolamine hydroxylation were not significantly altered in both sexes or even increased by the same treatments. The castration of male rats markedly decreased the activities of hexobarbital hydroxylation and aminopyrine N-demethylation, while the activities were not altered by the castration of female rats (1, 2). The administration of methyltestosterone to the castrated male and female rats increased the activities of hexobarbital hydroxylation and aminopyrine N-demethylation in liver microsomes and these activities again decreased by the administration of morphine and by starvation in the androgen-treated rats (1, 2). These results indicate that both morphine and starvation decrease the activities of drug-metabolizing enzymes which are stimulated by androgens, probably through the impairment of an androgen-dependent stimulating mechanism (1-4). Recent studies have established that an unique hemoprotein clled P-450 (5) is involved as the oxygen activating component in a number of NADPH-dependent monooxygenase reactions, such as hydroxylations of drugs and steroid hormones (6-10). Imai and Sato (11) and Schenkman et al. (12) have recently reported that a number of drugs, substrates of hepatic microsomal hydroxylases, react with the microsomal cytochrome to give two characteristic types of spectral change. These results suggest that the spectral changes observed are indicative of substrate interaction with cytochrome P-450 presumably representing the primary binding of substrate for enzymic hydroxylation (13, 14). Moreover, Schenkman et al. (15) demonstrated that the magnitude of the hexobarbital-induced spectral change was greater in liver microsomes isolated from male rats than in those from female rats and castration of male rats abolished this sex difference. These observations suggested that the sex difference in the hydroxylation of hexobarbital may be due to the difference in the substrate interaction with P-450. The purpose of the present communication is to investigate whether the decrease in the hexobarbital hydroxylation and aminopyrine N-demethylation in liver microsomes from morphine-treated and fasted male rats is related to an impairment of androgeninduced stimulation of the substrate-P-450 interaction.