title: Dose-dependent actions of spironolactone on the inner and outer zones of the guinea pig adrenal cortex.
abstract: The results of prior in vitro studies indicated that spironolactone (SL) caused far greater degradation of cytochromes P-450 in the outer (zona glomerulosa plus zona fasciculata) than inner (zona reticularis) zone of the guinea pig adrenal cortex and selectively decreased microsomal 17 alpha-hydroxylase activity. Studies were done to determine if the effects of SL in vivo were similarly zone and/or enzyme selective. Administration of high doses of SL (100 mg/kg) to guinea pigs altered the gross appearance of the adrenal glands and caused declines in 17 alpha- and 21-hydroxylase activities in both inner and outer zone microsomal preparations. The losses in enzyme activities were accompanied by decreases in microsomal cytochrome P-450, cytochrome b5 and heme concentrations, and in mitochondrial P-450 levels in both zones. Microsomal P-450(17 alpha) apoprotein levels were also decreased in both zones. A lower dose (25 mg/kg) of SL did not affect adrenal morphology, but decreased microsomal P-450 levels in both zones. Neither mitochondrial P-450 nor microsomal b5 concentrations were affected in either zone. 17 alpha-Hydroxylase activities and P-450(17 alpha) apoprotein concentrations in both zones were decreased by the lower dose of SL, but 21-hydroxylase activity declined in the inner zone only. The results indicate that very high doses of SL have a variety of nonspecific effects on the adrenals which may be the consequence of drug toxicity. Nontoxic doses exert more selective effects on microsomal cytochromes P-450 in both adrenal zones, more closely mimicking the in vitro actions of the drug.
authors.affiliation: Department of Pharmacology and Toxicology, Philadelphia College of Pharmacy and Science, Pa. 19104.
authors.forename: D C
authors.initials: DC
authors.lastname: Kossor
authors.forename: H D
authors.initials: HD
authors.lastname: Colby
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015786:Cytochromes b5 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007274:Injections, Intraperitoneal; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008928:Mitochondria / Q000201:enzymology; D013148:Spironolactone / Q000494:pharmacology*; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000378:metabolism; D015383:Zona Fasciculata / Q000187:drug effects / Q000378:metabolism; D015384:Zona Glomerulosa / Q000187:drug effects / Q000378:metabolism; D015385:Zona Reticularis / Q000187:drug effects / Q000378:metabolism
chemical_list: D013148:Spironolactone; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D013255:Steroid 21-Hydroxylase; D013254:Steroid 17-alpha-Hydroxylase