Sex differences in the steroidogenic and respiratory electron transport chains in the rat adrenal cortex

Abstract

Both steroid 11β-hydroxylation and cholesterol side chain cleavage occur in the mitochondria of adrenocortical cells and they require reducing power in the form of NADPH. There are direct sources of NADPH in rat adrenal mitochondria but another potential source of NADPH is the energy-linked transhydrogenase reaction. This suggests that there is a relationship between the steroidogenic and respiratory chains. We have elaborated upon this relationship by exploring the expression of cytochrome c oxidase (CO) and cytochrome P-45011β. We have studied the regulation of one mitochondrial-encoded (COII) and one nuclear-encoded (COIV) subunit. Normal, untreated male rats had higher basal levels of activity of CO in adrenal (255%) and liver (144%) mitochondria, compared to normal, untreated female rats. They also had increased COII (300% and 138%) and COIV (300% and 135%). Cytochrome P-45011β levels, however, were lower (48%) in adrenal mitochondria of male rats than those of female rats. Androgen treatment of male rats caused an increase in the activity of CO in the mitochondria of the adrenal gland with the levels being 171% of the corresponding controls. This increase in activity paralleled an increase in the levels of COII and COIV in the adrenal as measured by Western analysis. In contrast, adrenal cytochrome P-45011β levels were lower (68%). Androgen treatment caused no significant change in the levels of mRNA's for COII and COIV whereas cytochrome P-45011β mRNA was significantly lower than normal. Treatment of rats with the anti-androgen, flutamide, caused a decrease in the activity of CO and the levels of COII and COIV in the mitochondria of the adrenal gland and liver in both sexes. The activity of CO in adrenal and liver mitochondria of flutamide-treated male rats was comparable to that in untreated female rats. Other evidence, supporting the mediation of the androgen effect by an interaction with adrenal androgen receptors are findings from androgen-resistant (tfm) rats showing that activity of CO and levels of COII and COIV in the adrenal are low and cytochrome P-45011β high. These changes in the levels and expression of key adrenal mitochondrial enzymes could help to explain the well known sex differences in adrenal cortical function in rats.