Effects of ethinyl estradiol on hepatic microsomal proteins and the turnover of cytochrome P-450.

The effect of ethinyl estradiol, a steroid commonly used in birth control pills and possibly associated with impaired drug metabolism in humans, on the activity of and turnover of components of the hepatic microsomal mixed-function oxidase system was studied in male rats. After 5 days of ethinyl estradiol, 5 mg/kg/day, there was a significant decrease in the activity of ethylmorphine-N-demethylase and in cytochrome P-450, cytochrome b2, and NADPH cytochrome c reductase. Cytochrome P-450 apoproteins were identified within an SDS-polyacrylamide gel system, and the rate of turnover of cytochrome P-450 apoproteins was studied by double-isotope labeling techniques. After 5 days of ethinyl estradiol administration, the rate of degradation of cytochrome P-450 apoprotein was reduced (half-life of 50 hr compared to 24 hr in control), and their relative rate of synthesis was likewise reduced, indicating that a new steady state of protein turnover associated with reduced synthesis rate had been reached. This was confirmed by studies of the effect of ethinyl estradiol on the level of microsomal cytochrome P-450 over a 10-day period.