The involvement of ryanodine receptors in halothane-induced liver injury in mice

抄録

[Purpose] Drug-induced liver injury is a major problem in drug development and clinical drug therapy. Halothane (HAL), an inhaled anesthetic, induces severe and idiosyncratic liver injury. It has been known that disordered hepatic calcium homeostasis is an early feature of HAL-induced liver injury in guinea pigs. Even though some underlying mechanisms in HAL-induced hepatotoxicity have been understood, there are no reports of the involvement of ryanodine receptors (RYR) in HAL-induced liver injury.

[Methods] Female BALB/cCrSlc mice were treated with 50μg/kg of ryanodine (RYA, a RYR agonist, i.p.) 1 h before HAL (15 mmol/kg, i.p.) treatment. Dantrolene sodium (DAN, an inhibitor of RYR) was orally given at a dose of 80 mg/kg 2 h after HAL (20 mmol/kg, i.p) treatment. The mice were dissected to collect plasma and livers, and then the parameters were determined.

[Results and Discussion] RYA co-treated with HAL significantly elevated plasma ALT and AST levels, while resulted in severe hepatic inflammation, necrosis and neutrophil infiltration. In contrast, DAN treatment showed a dose-dependent manner to suppress the liver injury induced by HAL. The hepatic mRNA levels of RYR1/2/3 were increased at different time points in HAL-induced hepatotoxicity. Among the hepatic expression levels of inflammatory and apoptosis factors , RYA showed an enhanced effect and DAN showed a protective effect on HAL-induced liver injury.

[Conclusions] We found a new insight into the effect of RYR which might be as a novel factor involved in the analysis of the mechanism on HAL-induced liver injury.