Sex steroids and drug metabolism: A sex-related difference in hepatic microsomal ethoxyresorufin- o-deethylation in Sprague-Dawley rats

Abstract

The effect of sex steroids and pregnenolone-16α-carbonitrile (PCN) on hepatic microsomal monooxygenase activity was examined in male and female Sprague-Dawley rats. Male rats had a greater cytochrome(s) P-450 content and ethoxycoumarin- O-deethylase (ECOD) and NADPH-cytochrome c reductase (CcR) activities than females. Ethoxyresorufin- O-deethylation (EROD) in hepatic microsomes from females, however, was greater than from males, suggesting that the female rats possessed inherently higher cytochrome P-448-mediated monooxygenase activity. Testosterone propionate and PCN administration resulted in stimulation of ECOD and CcR activities in female rats, and PCN also increased the cytochrome(s) P-450 content. Estradiol benzoate decreased ECOD and CcR in male rats but enhanced EROD in both sexes. Neither testosterone nor PCN had an effect on EROD activity. In castrated male rats, testosterone increased, and estradiol decreased, ECOD activity without affecting cytochrome(s) P-450 content. Estradiol pretreatment of castrated males resulted in an increase in EROD activity, with testosterone having no effect. Thus, testosterone and estradiol may be, in part, responsible for the inherently higher and lower cytochrome(s) P-450-related activities in male and female rats, respectively, and estradiol may be responsible for the elevated cytochrome P-448-type activity observed in the females.