Effects of morphine treatment and starvation on the substrate interaction with P-450 in the oxidation of drugs by liver microsomes.

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-demethyl ation, but this was not the case in female rats. On the other hand, the activities of drug metabolizing 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 hydroxy lation and aminopyrine N-demethylation, while the activities were not altered by the cast ration 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 administ ration 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