ABSTRACT
Background: Trazodone is an antidepressant agent widely administered for the treatment of depressive disorders. On the other hand, several cases of hepatic injury have been reported after Trazodone administration. Although the precise mechanism(s) of trazodone-induced liver injury is not known, some investigations proposed the role of reactive intermediates in this complication. This study was designed to investigate the role of reactive metabolites in hepatocytes injury induced by trazodone. Methods: Isolated rat hepatocytes were prepared by the method of collagenase enzyme perfusion via the portal vein. Cells were treated with trazodone, its cytotoxic metabolite, and different enzyme inhibitors and cytoprotective agents. Results: It was found that trazodone was toxic towards hepatocytes and caused 50% cell death after 2 h of incubation at a dose of 450 µM. The trazodone postulated reactive metabolite; m-chlorophenyl piperazine (m-CPP) was less toxic and caused 50% cell death at a dose of 750 µM at a similar time period. Cellular glutathione (GSH) depletion and lipid peroxidation were detected when hepatocytes were treated with trazodone and/or m-CPP. Depleting hepatocytes GSH beforehand, increased cytotoxicity of both trazodone and m-CPP. Troleandomycin as the CYP3A4 inhibitor prevented cytotoxicity of trazodone but slightly affected m-CPP-induced cell injury. Inhibition of CYP2D6 by quinidine and cimetidine increased the cytotoxicity of both trazodone and m-CPP. Antioxidants and ATP suppliers slightly prevented cytotoxicity of trazodone and m-CPP. Conclusion: As inhibitors of CYP3A4 and 2D6 affected trazodone cytotoxicity, it is suggested that trazodone -induced cytotoxicity, at least in part, is mediated by its reactive metabolites.
Subject(s)
Chemical and Drug Induced Liver Injury/metabolism , Hepatocytes/drug effects , Inactivation, Metabolic/drug effects , Trazodone/metabolism , Trazodone/pharmacology , Animals , Antioxidants/metabolism , Cell Death/drug effects , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP3A/metabolism , Enzyme Inhibitors/pharmacology , Glutathione/metabolism , Hepatocytes/metabolism , Lipid Peroxidation/drug effects , Liver/drug effects , Liver/metabolism , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolismABSTRACT
BACKGROUND: Hydrogen sulfide (H2S) exhibits both physiological and toxicological roles in the biological systems. Acute exposure to high levels of H2S is life threatening while long-term exposure to ambient levels of H2S elicits human health effects. OBJECTIVE: To study the harmful effects of long-term exposure to low levels of H2S on human blood cells. METHODS: 110 adult workers from Iran who were occupationally exposed to 0-90 ppb H2S for 1-30 years were studied. The participants aged between 18 and 60 years and were exposed directly or indirectly to sulfur compounds (exposed group). The origin of H2S was natural gas processing plants. A control group consisting of 110 males who were not in contact with H2S was also studied. For all participants, hematological profile including total hemoglobin and red blood cell count and sulfhemoglobin, methemoglobin levels were measured. RESULTS: Among all parameters evaluated in this study the mean methemoglobin and sulfhemoglobin levels were significantly higher among workers who were exposed to sulfur compounds than the control group. Major differences throughout the study period for sulfhemoglobinemia among exposed groups were observed. CONCLUSION: Long-term exposure to even low levels of H2S in workplaces may have potential harmful effects on human health.
