Metabolic Activation and Inflammation Reactions Involved in Carbamazepine-Induced Liver Injury

Abstract

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.

Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats

“…This result is consistent with a previous study that KTZ significantly reduced the metabolism-dependent irreversible binding of radiolabeled CBZ to human liver microsomes (Pirmohamed et al, 1992b). In contrast, our previous study reported that cotreatment with TAO or KTZ exacerbated the CBZ-induced liver injury in mice (Higuchi et al, 2012). This controversial result may be attributed to the species differences in the P450-mediated metabolism of CBZ between the mouse and rat.…”

“…The administration method was determined by reference to our previous mouse study of CBZ-induced liver injury (Higuchi et al, 2012). Rats were orally administered CBZ at a dose of 400 mg/kg once daily for 4 days, then 400, 600, or 800 mg/kg on the 5th day.…”

“…Previously, we established the mouse model of CBZ-induced liver injury and suggested the relationship between 3-hydroxy-CBZ and hepatotoxicity (Higuchi et al, 2012). In the present study, to expand our knowledge about the role of CBZ metabolism on liver injury, we attempted to develop a novel rat model of CBZ-induced liver injury.…”

“…Previously, we developed a mouse model of CBZ-induced liver injury without BSO treatment as follows: Mice were administered CBZ at a dose of 400 mg/kg once daily for 4 days and 800 mg/kg on the 5th day (Higuchi et al, 2012). Although we applied this dosing regimen, only slight changes in the plasma ALT levels were observed (Fig.…”

Oral hygiene in children with epilepsy: Effect of interleukin-1β and VEGF levels in gingival crevicular fluid

“…The authors reported that valproic acid prevented an inflammation, and carbamazepine could cause an inflammation and hepatic injury as a result of this. 23,24 We couldn't find any information about possible anti-inflammatory effects of phenobarbital. But, in our study, when patients were classified according to the use of the drug, no differences were found in IL-1β and VEGF levels of GCF among the drug groups.…”