Alterations of heme, cytochrome P-450, and steroid metabolism by mercury in rat adrenal

Abstract

The treatment of male rats with Hg 2+ resulted in significant alterations in heme and hemoprotein metabolism in the adrenal gland which, in turn, were reflected in abnormal steroidogenic activities and steroid output. Twenty-four hours after the administration of 30 μmol of HgCl 2/kg (sc) the mitochondrial heme and cytochrome P-450 concentrations increased by approximately 50%. Also, Hg 2+ treatment stimulated a porphyrinogenic response which included an 11-fold increase in the activity of δ-aminolevulinate synthetase. The increase in mitochondrial cytochrome P-450 content was reflected in elevated steroid 11β-hydroxylase and cholesterol side-chain cleavage activities. In contrast, Hg 2+ treatment resulted in decreased concentrations of microsomal cytochrome P-450 (−75%) and heme (−45%). Similarly, the reduction in the microsomal cytochrome P-450 content was accompanied by reduced steroid 21α-hydroxylase and benzo[ a]pyrene hydroxylase activities. The mechanisms responsible for the loss of the microsomal cytochrome P-450 content appeared to involve a selective impairment of formation of the holocytochrome as well as an enhanced rate of heme degradation. This suggestion is made on the basis of findings that (a) the decrease in the microsomal cytochrome P-450 content was accompanied by a sevenfold increase in the activity of adrenal heme oxygenase, (b) no decrease in apocytochrome P-450 could be detected in sodium dodecyl sulfate-gel electrophoresis of the solubilized microsomal fractions stained for heme, and (c) the concentration of adrenal microsomal cytochrome b 5 was significantly increased in the Hg 2+-treated animals. It is suggested that Hg 2+ directly caused a defect in adrenal steroid biosynthesis by inhibiting the activity of 21α-hydroxylase. The apparent physiological consequences of this effect included lowered plasma levels of corticosterone and elevated concentrations of progesterone and dehydroepiandrosterone. This abnormal plasma steroid profile is indicative of a 21α-hydroxylase impairment.