Species differences in the effect of morphine administration or adrenalectomy on the substrate interactions with cytochrome P-450 and drug oxidations by liver microsomes

The hexobarbital hydroxylation and the magnitude of hexobarbital interaction with cytochrome P-450 were markedly decreased in liver microsomes from morphine-treated male rats, whereas they were not decreased in liver microsomes from morphine-treated female rats, male and female mice and rabbits. The binding capacity of cytochrome P-450 for hexobarbital calculated from the magnitude of hexobarbital interaction with cytochrome P-450 in liver microsomes was also decreased only in the morphine-treated male rats. Similarly, the hexobarbital hydroxylation, the magnitude of hexobarbital interaction with cytochrome P-450 and the binding capacity of cytochrome P-450 in liver microsomes were decreased only in adrenalectomized male rats, but not in adrenalectomized female rats, male and female mice. In contrast to the results obtained with hexobarbital, the aniline hydroxylation, the magnitude of aniline interaction with cytochrome P-450 and the binding capacity of cytochrome P-450 for aniline were not decreased in liver microsomes from male and female rats, mice and rabbits by the morphine treatment or adrenalectomy. These results therefore support the previous suggestion that the decrease in the hexobarbital hydroxylation and in the magnitude of hexobarbital interaction with cytochrome P-450 is mainly due to the decrease in the binding capacity of cytochrome P-450 for hexobarbital, probably through an impairment of the action of androgen to increase the binding capacity of cytochrome P-450 for hexobarbital.