Metabolic map of the antiviral drug podophyllotoxin provides insights into hepatotoxicity.
Xenobiotica
; 51(9): 1047-1059, 2021 Sep.
Article
em En
| MEDLINE
| ID: mdl-34319859
ABSTRACT
Podophyllotoxin (POD) is a natural compound with antiviral and anticancer activities. The purpose of the present study was to determine the metabolic map of POD in vitro and in vivo.Mouse and human liver microsomes were employed to identify POD metabolites in vitro and recombinant drug-metabolizing enzymes were used to identify the mono-oxygenase enzymes involved in POD metabolism. All in vitro incubation mixtures and bile samples from mice treated with POD were analysed with ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry.A total of 38metabolites, including six phase-I metabolites and 32 phase-II metabolites, of POD were identified from bile and faeces samples after oral administration, and their structures were elucidated through interpreting MS/MS fragmentation patterns.Nine metabolites, including two phase-I metabolites, five glucuronide conjugates, and two GSH conjugates were detected in both human and mouse liver microsome incubation systems and the generation of all metabolites were NADPH-dependent. The main phase-I enzymes involved in metabolism of POD in vitro include CYP2C9, CYP2C19, CYP3A4, and CYP3A5.POD administration to mice caused hepatic and intestinal toxicity, and the cellular damage was exacerbated when 1-aminobenzotriazole, a broad-spectrum inhibitor of CYPs, was administered with POD, indicating that POD, but not its metabolites, induced hepatic and intestinal toxicities.This study elucidated the metabolic map and provides important reference basis for the safety evaluation and rational for the clinical application of POD.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Espectrometria de Massas em Tandem
/
Doença Hepática Induzida por Substâncias e Drogas
Limite:
Animals
Idioma:
En
Revista:
Xenobiotica
Ano de publicação:
2021
Tipo de documento:
Article