Inhibition of the conversion of cholesterol to pregnenolone in bovine adrenocortical preparations.
The inhibition of the conversion of [4-14C] cholesterol to [4-14C] pregnenolone by a number of steroids has been studied in bovine adrenocortical mitochondrial acetonedried preparations. At equimolar substrate and inhibitor concentrations (3.3 muM) the most potent inhibitors were cholesterol derivatives containing a nitrogen function at c-22, followed by derivatives containing oxygen functions at c-22 or c-20 or both. The presence of a hydroxyl group at c-17 or the replacement of the 3beta-hydroxyl group by fluorine reduced the inhibitory efficacy. In the presence of inhibitors that were also relatively good substrates of the cholesterol side-chain cleavage system, such as some cholesterol derivatives hydroxylated in the side-chain,the rate of [4-14C] pregnenolone formation increased with time as the inhibitor was consumed. (20S)-20,21-Dihydroxycholesterol exerted such an effect on the kinetics of [4-14C]pregnenolone formation, and yielded 21-hydroxypregnenolone which was identified by gas chromatography-mass spectrometry. The synthesis of (20R)-22-ketocholesterol, of (20R,22R)-22hydroxycholesterol, (20R,22S)-hydroxycholesterol, and of (20S)-desmosterol is described.
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism*; D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006888:Hydroxycholesterols / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D013058:Mass Spectrometry; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D011284:Pregnenolone / Q000096:biosynthesis*; D013329:Structure-Activity Relationship
D006888:Hydroxycholesterols; D010091:Oximes; D011284:Pregnenolone; D002784:Cholesterol