Mechanistic Study of Xanthotoxin-Mediated Inactivation of CYP1A2 and Related Drug-Drug Interaction with Tacrine.
Chem Res Toxicol
; 36(3): 420-429, 2023 03 20.
Article
em En
| MEDLINE
| ID: mdl-36892569
ABSTRACT
Xanthotoxin (XTT) is a biologically active furanocoumarin widely present in foods and plants. The present study is designed to systematically investigate the enzymatic interaction of XTT with CYP1A2, along with pharmacokinetic alteration of tacrine resulting from the co-administration of XTT. The results showed that XTT induced a time-, concentration-, and NADPH-dependent inhibition of CYP1A2, and the inhibition was irreversible. Co-incubation of glutathione (GSH) and catalase/superoxide dismutase was unable to prevent enzyme inactivation. Nevertheless, competitive inhibitor fluvoxamine exhibited a concentration-dependent protective effect against the XTT-induced CYP1A2 inactivation. A GSH trapping experiment provided strong evidence for the production of epoxide or/and γ-ketoenal intermediates resulting from the metabolic activation of XTT. Furthermore, pretreatment of rats with XTT was found to significantly increase the Cmax and area under the curve of plasma tacrine relative to those of tacrine administration alone.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tacrina
/
Citocromo P-450 CYP1A2
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Chem Res Toxicol
Assunto da revista:
TOXICOLOGIA
Ano de publicação:
2023
Tipo de documento:
Article