Metabolic activation and inflammation reactions involved in carbamazepine-induced liver injury.
Drug-induced liver injury is a major safety concern in drug development and clinical pharmacotherapy; however, advances in the understanding of the mechanisms of drug-induced liver injury are hampered by the lack of animal models. Carbamazepine (CBZ) is a widely used antiepileptic agent. Although the drug is generally well tolerated, only a small number of patients prescribed CBZ develop severe hepatitis. In the present study, we developed a mouse model of CBZ-induced liver injury and elucidated the mechanisms accounting for the hepatotoxicity of CBZ. Male BALB/c mice were orally administered CBZ for 5 days. The plasma levels of alanine aminotransferase and aspartate aminotransferase were prominently increased, and severe liver damage was observed via histological evaluation. The analysis of the plasma concentration of CBZ and its metabolites demonstrated that 3-hydroxy CBZ may be relevant in CBZ-induced liver injury. The hepatic glutathione levels were significantly decreased, and oxidative stress markers were significantly altered. Mechanistic investigations found that hepatic mRNA levels of toll-like receptor 4, receptor for advanced glycation end products, and their ligands were significantly increased. Moreover, the plasma concentrations of proinflammatory cytokines were also increased. Prostaglandin E(1) administration ameliorated the hepatic injury caused by CBZ. In conclusion, metabolic activation followed by the stimulation of immune responses was demonstrated to be involved in CBZ-induced liver injury in mice.
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
Satonori
S
Higuchi
Azusa
A
Yano
Shohei
S
Takai
Koichi
K
Tsuneyama
Tatsuki
T
Fukami
Miki
M
Nakajima
Tsuyoshi
T
Yokoi
D000410:Alanine Transaminase / Q000097:blood; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000378:metabolism; D001711:Biotransformation; D002220:Carbamazepine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006505:Hepatitis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects
D000927:Anticonvulsants; D015415:Biomarkers; D016207:Cytokines; D005343:Fibrinolytic Agents; D002220:Carbamazepine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000527:Alprostadil; D005978:Glutathione