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Specificity of the in vitro destruction of adrenal and hepatic microsomal steroid hydroxylases by thio steroids






Molecular Pharmacology 16(3): 997-1010

Specificity of the in vitro destruction of adrenal and hepatic microsomal steroid hydroxylases by thio steroids

Studies are presented to show that thiosteroids such as deacetylspironolactone or 7.alpha.-thiotestosterone may be used as biochemical probes to correlate the amount of cytochrome P-450 associated with specific steriod hydroxylases. The ability of the thiosteroids to destroy cytochrome P-450 differed markedly among microsomes prepared from [rat] liver, [guinea pig] adrenal and testicular tissues, and seemed proportional to the magnitude of the spectral interactions of the thiosteroids with cytochrome P-450. At low concentrations (1.0 .mu.M), 7.alpha.-thiotestosterone caused a NADPH-dependent destruction of hepatic cytochrome P-450 which was associated with a preferential decrease in the activity of testosterone 7.alpha.-hydroxylase. At 4.5 .mu.M, it caused a NADPH-dependent decrease in 2.beta., 6.beta. and 16.alpha.-testosterone hydroxylase, but no NADPH-dependent decrease in benzo(a)pyrene hydroxylation. The destruction of adrenal cytochrome P-450 by deacetylspironolactone in guinea pig microsomes was concurrent with a decrease in the activity of progesterone 17.alpha.-hydroxylase, but not of progesterone 21-hydroxylase. Studies with radiolabeled deacetylspironolactone suggest that during the loss of cytochrome P-450 by thiosteroids the S atom of the thio group after activation by cytochrome P-450 is eliminated from the steroid moiety and binds covalently to the cytochrome P-450-apoenzymes, thereby resulting in the concomitant loss of the activity and the heme of the cytochrome P-450-dependent steroid hydroxylase.


Accession: 006459080

PMID: 119158



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