Oxidative metabolism of spironolactone: Evidence for the involvement of electrophilic thiosteroid species in drug-mediated destruction of rat hepatic cytochrome P450

Journal Article · Tue Jun 13 04:00:00 EDT 1989 · Biochemistry; (USA)

DOI:https://doi.org/10.1021/bi00438a033· OSTI ID:5443427

Decker, C J; Rashed, M S; Baillie, T A; Maltby, D; Correia, M A ^[1]

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1. 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), Journal Name: Biochemistry; (USA) Vol. 28:12; ISSN 0006-2960; ISSN BICHA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ADRENAL HORMONES
ANIMALS
BODY
CARBON 14 COMPOUNDS
CELL CONSTITUENTS
CHEMICAL REACTIONS
CORTICOSTEROIDS
CYTOCHROMES
DIGESTIVE SYSTEM
ESTERS
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
INACTIVATION
ISOENZYMES
KETONES
LABELLED COMPOUNDS
LACTONES
LIVER
MAMMALS
METABOLISM
METABOLITES
MICROSOMES
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANOIDS
ORGANS
OXIDATION
PIGMENTS
PREGNANES
PROTEINS
RATS
RIBOSOMES
RODENTS
STEROIDS
THIOLS
VERTEBRATES