title: Cyclosporine A and palmitic acid treatment synergistically induce cytotoxicity in HepG2 cells.
abstract: Immunosuppressant cyclosporine A (CsA) treatment can cause severe side effects. Patients taking immunosuppressant after organ transplantation often display hyperlipidemia and obesity. Elevated levels of free fatty acids have been linked to the etiology of metabolic syndromes, nonalcoholic fatty liver and steatohepatitis. The contribution of free fatty acids to CsA-induced toxicity is not known. In this study we explored the effect of palmitic acid on CsA-induced toxicity in HepG2 cells. CsA by itself at therapeutic exposure levels did not induce detectible cytotoxicity in HepG2 cells. Co-treatment of palmitic acid and CsA resulted in a dose dependent increase in cytotoxicity, suggesting that fatty acid could sensitize cells to CsA-induced cytotoxicity at the therapeutic doses of CsA. A synergized induction of caspase-3/7 activity was also observed, indicating that apoptosis may contribute to the cytotoxicity. We demonstrated that CsA reduced cellular oxygen consumption which was further exacerbated by palmitic acid, implicating that impaired mitochondrial respiration might be an underlying mechanism for the enhanced toxicity. Inhibition of c-Jun N-terminal kinase (JNK) attenuated palmitic acid and CsA induced toxicity, suggesting that JNK activation plays an important role in mediating the enhanced palmitic acid/CsA-induced toxicity. Our data suggest that elevated FFA levels, especially saturated FFA such as palmitic acid, may be predisposing factors for CsA toxicity, and patients with underlying diseases that would elevate free fatty acids may be susceptible to CsA-induced toxicity. Furthermore, hyperlipidemia/obesity resulting from immunosuppressive therapy may aggravate CsA-induced toxicity and worsen the outcome in transplant patients.
authors.affiliation: Compound Safety Prediction Group, Pfizer Global Research & Development, Groton, CT 06340, USA. yi.luo@pfizer.com
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Payal
authors.initials: P
authors.lastname: Rana
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Will
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D056945:Hep G2 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008928:Mitochondria / Q000187:drug effects; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000633:toxicity*
chemical_list: D007166:Immunosuppressive Agents; D019308:Palmitic Acid; D016572:Cyclosporine; D048031:JNK Mitogen-Activated Protein Kinases