Cholesterol sulfate inhibits adrenal mitochondrial cholesterol side chain cleavage at a site distinct from cytochrome P-450scc. Evidence for an intramitochondrial cholesterol translocator.
Cholesterol sulfate inhibits (K1/2, 6 microM) the side chain cleavage of exogenous cholesterol in intact rat adrenal mitochondria. Inhibition is at a site other than cytochrome P-450scc: the spin state of the hemoprotein is not perturbed, and its activity is unaffected as judged by the failure to inhibit the metabolism both of 25-hydroxycholesterol and of endogenous cholesterol in a mitochondrial "steroidogenic pool." In contrast, 25-hydroxycholesterol, known to interact with the cytochrome, prevented the cleavage of both endogenous and exogenous cholesterol and produced the expected optical changes in the hemoprotein. Inhibition was specific, since a variety of related compounds including pregnenolone sulfate were not effective. Metabolic conversion to other species was insufficient to account for inhibition, indicating that cholesterol sulfate is the effective molecule. A hallmark of an inhibitor of a transport system is that disruption of the barrier to transport eliminates inhibition. Sonic disruption of mitochondria abated by 70% the effect of cholesterol sulfate, but did not affect inhibition by 25-hydroxycholesterol. Thus, the cholesterol sulfate appears to inhibit an intramitochondrial cholesterol translocation system that functions to move cholesterol into a steroidogenic pool. The high content of cholesterol sulfate in adrenal cortex (Drayer, N.M., Roberts, K.D., Bandi, L., and Lieberman, S. (1964) J. Biol. Chem. 239, 3112-3114) suggests a possible regulatory role for this molecule.
D000311:Adrenal Glands / Q000201:enzymology / Q000648:ultrastructure*; D000616:Aminoglutethimide / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000494:pharmacology*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006888:Hydroxycholesterols / Q000494:pharmacology; D008928:Mitochondria / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011284:Pregnenolone / Q000096:biosynthesis; D013010:Sonication
D002788:Cholesterol Esters; D006888:Hydroxycholesterols; D000616:Aminoglutethimide; D011284:Pregnenolone; C007997:25-hydroxycholesterol; D002784:Cholesterol; D010088:Oxidoreductases; D002786:Cholesterol Side-Chain Cleavage Enzyme; C007045:cholesteryl sulfate