Abstract

The metabolism of aminopyrine, p-nitroanisole, hexobarbital and 4-dimethylaminoazobenzene (4-DAB) by 9000 X g supernatant fractions from male rats was shown to follow a circadian rhythm with maxima at 0200 hours and minima at 1400 hours. A similar rhythm was noted in the female rat. A circadian rhythm in the metabolism of aminopyrine and p-nitroanisole was also found in the male mouse. Fasting for 24 hr prior to sacrifice did not modify the rhythm in the rat. Adrenalectomy abolished the circadian rhythm in the oxidative metabolism of aminopyrine, p-nitroanisole and hexobarbital but had no effect on the reduction of 4-DAB. Experiments with mixed 9000 X g supernatant and washed microsomal fractions showed that the variation in drug metabolism is due to an alteration in the activity of the microsomal component; this suggested that the amount of enzyme present is the major determinant of the rhythm. Plasma corticosterone levels in the male rat were found to follow a circadian rhythm with maxima and minima exactly 12 hr removed from those observed in enzyme activity. Maintenance of elevated plasma corticosterone levels by administration of the steroid resulted in the abolition of the circadian rhythm in drug metabolism. The rhythm in enzyme activity was likewise absent in rats which had been pretreated with phenobarbital for 4 days prior to sacrifice, although the circadian rhythm in plasma corticosterone leveLs was not affected. These studies suggest that the adrenal glands may be involved in the short-term regulation of hepatic drug-metabolizing enzyme activity.