Inactivation of rat hepatic cytochrome P-450 by spironolactone.
Administration of antimineralocorticoid spironolactone (SPL) to rats results in modest destruction of hepatic cytochrome P-450 with parallel loss of heme. This process is accentuated by pretreatment with dexamethasone (DEX), an inducer of cytochrome P-450p and is associated with marked functional loss of cytochrome P-450p-dependent hydroxylases. Cytochrome P-450 destruction may be replicated in vitro when microsomes from DEX-pretreated rats are incubated with SPL and NADPH and is impaired when these rats are given triacetyloleandomycin, an inhibitor of cytochrome P-450p. In vitro SPL-mediated cytochrome P-450 destruction is accompanied by a loss of heme, which appears to be converted to reactive intermediates which covalently bind to microsomes or are converted to polar metabolites.
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D006418:Heme / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009249:NADP / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013148:Spironolactone / Q000494:pharmacology*; D013997:Time Factors; D014217:Troleandomycin / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D013148:Spironolactone; D006418:Heme; D009249:NADP; D003907:Dexamethasone; D014217:Troleandomycin