Metabolism and hepatic toxicity of flutamide in cytochrome P450 1A2 knockout SV129 mice.
J Gastroenterol
; 41(3): 231-9, 2006 Mar.
Article
em En
| MEDLINE
| ID: mdl-16699857
ABSTRACT
BACKGROUND:
Flutamide, a nonsteroidal antiandrogen used for treatment of prostate cancer, causes a temporary increase in transaminase and in some cases severe liver dysfunction. It is dominantly metabolized by cytochrome P450 (CYP) 1A2 into 2-hydroxyflutamide (OH-flutamide), which has stronger antiandrogenic activity without obvious cytotoxicity to cultured hepatocytes. We hypothesized that another subsidiary metabolite might be responsible for induction of hepatotoxicity.METHODS:
Flutamide was administered daily to CYP1A2 knockout mice and parental SV129 mice to compare pharmacokinetics and appearance of hepatic toxicity.RESULTS:
In the CYP1A2 knockout mice, the plasma concentration of flutamide maintained at a high level and OH-flutamide stayed low; a higher amount of FLU-1, an alternative metabolite of flutamide, was detected in urine. Simple repetitive administration of 800 mg/kg of flutamide for 28 days to CYP1A2 knockout mice did not show abnormal elevation of plasma alanine aminotransferase (ALT). However, after the knockout mice were fed with an amino acid-deficient diet for 2 weeks, which reduced the glutathione (GSH) content to 27% of the initial, administration of 400 mg/kg of flutamide increased ALT to over 200 IU/l and histopathologically moderate hepatitis developed. Since FLU-1 itself did not show cytotoxicity or reduce GSH content in vitro, a further metabolized molecule must cause the hepatotoxicity.CONCLUSIONS:
Blockade of CYP1A2 produced an unknown potential hepatotoxic molecule through FLU-1, and GSH might play an important role in diminishing the reactive hepatotoxic metabolite.
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Base de dados:
MEDLINE
Assunto principal:
Antineoplásicos Hormonais
/
Citocromo P-450 CYP1A2
/
Flutamida
/
Antagonistas de Androgênios
/
Hepatopatias
Limite:
Animals
Idioma:
En
Revista:
J Gastroenterol
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Japão