Metabolism and hepatic toxicity of flutamide in cytochrome P450 1A2 knockout SV129 mice.
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.
Matsuzaki
Yasushi
Y
Department of Gastroenterology and Hepatology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan.
Nagai
Daichi
D
Ichimura
Eiji
E
Goda
Rika
R
Tomura
Arihiro
A
Doi
Mikio
M
Nishikawa
Kiyohiro
K
D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000596:Amino Acids / Q000008:administration & dosage / Q000172:deficiency; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005485:Flutamide / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D005978:Glutathione / Q000097:blood / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D000596:Amino Acids; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D011944:Receptors, Androgen; D005485:Flutamide; D019388:Cytochrome P-450 CYP1A2; D000410:Alanine Transaminase; D005978:Glutathione