Selective inhibition of cytochrome P-450 in rat testicular microsomes: Effect of cobalt-protoporphyrin on progesterone metabolism

Abstract

Cobalt-protoporphyrin (CoPP) administration to adult male rats results in a profound reduction in hepatic cytochrome P-450 concentration and activity, and decreased plasma concentrations of testosterone and luteinizing hormone (LH). The metabolism of progesterone by rat testicular microsomes isolated 48 h after treatment in vivo with CoPP was compared to that in microsomes from control rats. The conversion of progesterone to 17 alpha-hydroxyprogesterone and 4-androstenedione, which is NADPH-dependent, was reduced by approximately 40% in testicular microsomes following treatment with CoPP (50 mumol/kg body weight) and this inhibition was dose-dependent. The concentration of cytochrome P-450 in testicular microsomes and the activity of 7-ethoxycoumarin de-ethylase (a cytochrome P-450 dependent function) were also reduced following treatment with CoPP in contrast to two other functional assays of cytochrome P-450, aryl hydrocarbon hydroxylase and ethylmorphine demethylase, which were unaffected by treatment with CoPP. Thus, the profound effect of CoPP on androgen homeostasis has been extended to include decreased testicular synthesis of 4-androstenedione in addition to increased hepatic metabolism of testosterone, attenuated pituitary LH release in response to luteinizing hormone-releasing hormone, and failure of testicular response to LH.