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

Abstract

Carbamazepine (CBZ) is widely used as an antiepileptic agent and causes rare but severe liver injury in humans. It has been generally recognized that reactive metabolites formed via the metabolic activation reaction contribute to the onset of liver injuries by several drugs. However, the role of CBZ metabolism in the development of liver injury is not fully understood. In this study, we developed a novel rat model of CBZ-induced liver injury and attempted to elucidate the associated mechanisms by focusing on the metabolism of CBZ. The repeated administration of CBZ for 5 days in combination with L-buthionine sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, resulted in increases in the plasma alanine aminotransferase (ALT) levels and centrilobular necrosis in the liver that were observed in various degrees. The CBZ and 2-hydroxy-CBZ concentrations in the plasma after the last CBZ administration were lower in the rats with high plasma ALT levels compared with those with normal plasma ALT levels, showing the possibility that the further metabolism of CBZ and/ or 2-hydroxy-CBZ is associated with the liver injury. Although a single administration of CBZ did not affect the plasma ALT levels, even when cotreated with BSO, pretreatment with dexamethasone, a CYP3A inducer, increased the plasma ALT levels. In addition, the rats cotreated with troleandomycin or ketoconazole, CYP3A inhibitors, suppressed the increased plasma ALT levels. In conclusion, reactive metabolite(s) of CBZ produced by CYP3A under the GSH-depleted condition might be involved in the development of liver injury in rats.

Role of cytochrome P450-mediated metabolism and involvement of reactive metabolite formations on antiepileptic drug-induced liver injuries

“…The involvement of drug metabolism in the development of CBZ-induced liver injury has been indicated. In the rat model, repeated administration of CBZ caused severe liver injury, yet single administration failed to produce liver injury even under GSH-depleted conditions (Iida et al, 2015). Similar to the rat model, repeated administration is required for developing liver injury in a mouse model .…”

“…The hepatic CYP3A contents and its enzyme activ-ities were increased in parallel with the administration period. In addition, CYP3A inhibitor-treatment strongly suppressed the development of liver injury in rats (Iida et al, 2015), whereas in the mouse model, Cyp3a inhibitor co-treatment exacerbated liver injury accompanied by acceleration of the metabolic pathway toward 2-hydroxy and 3-hydroxy CBZ formations . Thus, CYP3A-mediated metabolism and the metabolic pathways toward 2-hydroxy and 3-hydroxy CBZ formations are critical factors for liver injury development.…”

“…In the first half of 2010, animal models of CBZ-induced liver injury were reported in mice and rats (Iida et al, 2015). The involvement of drug metabolism in the development of CBZ-induced liver injury has been indicated.…”

“…In reports from both rat and mouse models, electrophilic metabolite(s) formation is considered to be a crucial step in the development of liver injury because hepatic GSH is reduced by repeated administration of CBZ and treatment with the GSH depletor BSO exacerbates the CBZ-induced liver injury in the rat model (Iida et al, 2015). In the rat model, reducing the 2-hydroxy CBZ concentration in plasma is associated with the degree of liver injury.…”

“…From this fact, decreases in mEH activity would be an unlikely direct cause for DPH-or CBZ-induced liver injury. GSH has been shown to be a crucial factor implicated in the detoxification of electrophilic reactive metabolites as typified by acetaminophen Mitchell et al, 1973;Dahlin et al, 1984), ticlopidine (Shimizu et al, 2009(Shimizu et al, , 2011, tienilic acid (Nishiya et al, 2008), and DPH , and CBZ (Ju and Uetrecht, 1999;Pearce et al, 2005;Iida et al, 2015). Most soft electrophilic metabolites can react with GSH or NAC by forming stable GSH-or NAC-conjugates.…”