Cholesterol sulfate is a naturally occurring compound which is widely distributed among various tissues including the adrenal cortex. When added to adrenal mitochondria from ether-stressed rats, it inhibits pregnenolone synthesis from exogenous but not endogenous cholesterol. Evidence supports a locus of action at the level of an intramitochondrial cholesterol translocation system with no effect on the side-chain cleavage enzymatic system (cytochrome P-450scc). Levels of endogenous cholesterol sulfate in the adrenal are similar to the Ki for inhibition by this compound, suggesting a possible physiological role. Moreover, quantities of cholesterol sulfate present in isolated mitochondria from ether-stressed animals are variable, and levels correlate inversely with rates of pregnenolone production by these preparations. In the presence of malate, mitochondrial cholesterol sulfate is metabolized slowly to pregnenolone sulfate, and its removal correlates with activation of cholesterol side-chain cleavage. Cholesterol sulfate levels are not regulated acutely by stress, but can be decreased significantly after several weeks of daily injection of ACTH (a model of chronic stress). Such treatments result in an increased capacity of isolated adrenal mitochondria to synthesize pregnenolone, and increased activity correlates with increased levels of circulating corticosterone. Thus, we propose that cholesterol sulfate is a new physiological regulator of steroid hormone biosynthesis which may function to regulate the magnitude of the steroidogenic response of the adrenal cortex to ACTH.
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