Oxidative metabolism of spironolactone: Evidence for the involvement of electrophilic thiosteroid species in drug-mediated destruction of rat hepatic cytochrome P450
- Univ. of California, San Francisco (USA)
In a preliminary paper, the authors have shown that the antimineralocorticoid spironolactone (SPL) preferentially inactivates dexamethasone (DEX) inducible rat hepatic cytochrome P450p isozymes in a suicidal manner. These findings are now confirmed, and the kinetic characteristics of such a process are detailed. In an effort to elucidate the mechanism of SPL-mediated inactivation of cytochrome P450, they have examined the metabolism of SPL in vitro. Incubation of ({sup 14}C)SPL and NADPH with liver microsomes prepared from DEX-pretreated rats results in the formation of several polar metabolites separable by HPLC with UV detection. This process is found to be dependent on NADPH, O{sub 2}, SPL, and enzyme concentration, as well as temperature. Furthermore, metabolite formation was significantly attenuated by P450 inhibitors CO and n-octylamine. Mass metabolites indicated that these compounds had molecular weights that corresponded to the sulfinic and sulfonic acid derivatives of deacetyl-SPL (SPL-SH). These finding document the formation of previously unreported polar metabolites of SPL by rat liver microsomes enriched in cytochrome P450p and implicate a role for this isozyme in the oxidation of the thiol moiety of deacetyl-SPL. The detection of such metabolites also implicates a catalytic trajectory that includes the thiyl radical and/or sulfenic acid species as a plausible protagonist in drug-mediated inactivation of cytochrome P450p.
- OSTI ID:
- 5443427
- Journal Information:
- Biochemistry; (USA), Vol. 28:12; ISSN 0006-2960
- Country of Publication:
- United States
- Language:
- English
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CARBON 14 COMPOUNDS
METABOLISM
CYTOCHROMES
INACTIVATION
LACTONES
CORTICOSTEROIDS
ISOENZYMES
LIVER
METABOLITES
MICROSOMES
OXIDATION
RATS
THIOLS
ADRENAL HORMONES
ANIMALS
BODY
CELL CONSTITUENTS
CHEMICAL REACTIONS
DIGESTIVE SYSTEM
ESTERS
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
KETONES
LABELLED COMPOUNDS
MAMMALS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANOIDS
ORGANS
PIGMENTS
PREGNANES
PROTEINS
RIBOSOMES
RODENTS
STEROIDS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques