It has been reported that the bioactive intermediate metabolites of trazodone might cause hepatotoxicity. This study was designed to investigate the exact mechanism of hepatocellular injury induced by trazodone as well as the protective effects of taurine and/or melatonin against this toxicity. Freshly isolated rat hepatocytes were used. Trazodone was cytotoxic and caused cell death with LC50 of 300 µm within 2 h. Trazodone caused an increase in reactive oxygen species (ROS) formation, malondialdehyde accumulation, depletion of intracellular reduced glutathione (GSH), rise of oxidized glutathione disulfide (GSSG), and a decrease in mitochondrial membrane potential, which confirms the role of oxidative stress in trazodone-induced cytotoxicity. Preincubation of hepatocytes with taurine prevented ROS formation, lipid peroxidation, depletion of intracellular reduced GSH, and increase of oxidized GSSG. Taurine could also protect mitochondria against trazodone-induced toxicity. Administration of melatonin reduced the toxic effects of trazodone in isolated rat hepatocytes.

Phenytoin is a widely used antiepileptic drug. However, hepatotoxicity is one of its adverse effects reported in some patients. The mechanism(s) by which phenytoin causes hepatotoxicity is not clear yet. This study was designed to evaluate the cytotoxic mechanism(s) of phenytoin toward rat hepatocytes (whose cytochrome P450 enzymes had been induced by Phenobarbital). Furthermore, the effect of taurine and/or melatonin on this toxicity was investigated. Cell death, reactive oxygen species (ROS) formation, lipid peroxidation (LPO), and mitochondrial depolarization were monitored as toxicity markers. Results showed that phenytoin caused an elevation in ROS formation, depletion of intracellular reduced glutathione, increase in cellular oxidized glutathione, enhancement of LPO, and mitochondrial damage. Taurine (1 mM) and/or melatonin (1 mM) administration decreased the intensity of cellular injury caused by phenytoin. This study suggests the protective role of taurine and/or melatonin against phenytoin-induced cellular damage probably through their reactive radical scavenging properties and their effects on mitochondria.

SUMMARY:Carbamazepine is widely used in a broad spectrum of psychiatric and neurological disorders. Idiosyncratic hepatotoxicity is a well-known adverse reaction associated with carbamazepine. Hepatotoxicity is rare, but a real concern when initiating therapy. It was found that oxidative stress is a potential mechanism for carbamazepine-induced hepatotoxicity. Present study evaluated the hepato protective role of taurine and melatonin against carbamazepine-induced hepatotoxicity. Hepatocytes were prepared by the method of collagenase enzyme perfusion via portal vein. Cells were treated with 400 µM carbamazepine, 1mM taurine, and 1mM melatonin. Cell death, reactive oxygen species formation, lipid peroxidation, and mitochondrial membrane depolarization were assessed as toxicity markers and the effects of taurine and melatonin administration on them were investigated. Our results showed that carbamazepine induced oxidative stress; increased ROS formation and lipid peroxidation products and also decreased mitochondrial membrane potential (∆Ψ m ). Carbamazepine caused a decrease in cellular glutathione content and an elevation in oxidized glutathione levels. Our investigation showed that preincubation of hepatocytes with taurine (1 mM) could alleviate oxidative damages induced by carbamazepine; melatonin was also a good antioxidant to protect hepatocytes against cytotoxicity induced by carbamazepine. It may be concluded that taurine and melatonin are effective antioxidants to prevent carbamazepine-induced hepatotoxicity. Following our findings, further studies are suggested on the antioxidant effects of taurine and melatonin in patients receiving carbamazepine.