Influence of peroxisome proliferator-activated receptor-alpha (PPARα) activity on adverse effects associated with amiodarone exposure in mice

Pharmacological Research : the Official Journal of the Italian Pharmacological Society
Matthew C ErnstP Timothy Pollak

Abstract

Although amiodarone is the most effective antiarrhythmic agent currently available, concerns regarding adverse effects, including liver, lung and thyroid toxicity, often limit its use. Previously, we reported that amiodarone-induced hepatic steatosis in mice was associated with an upregulation of target genes modulated by peroxisome proliferator-activated receptor-alpha (PPARα). Because amiodarone does not directly stimulate PPARα, target gene induction may reflect a compensatory reaction countering some adverse effects of amiodarone. To test this, we examined co-treatment with the PPARα agonist, fenofibrate, and amiodarone in both PPARα(+/+) and PPARα(-/-) mice. Amiodarone treated PPARα(-/-) mice exhibited significantly greater weight loss and higher serum aspartate aminotransferase (AST) compared to PPARα(+/+) mice. Fenofibrate co-treatment reduced weight loss in amiodarone treated PPARα(-/-) mice, but not PPARα(+/+) mice. Fenofibrate stimulation of PPARα reduced serum amiodarone concentrations in normal mice. Serum amiodarone concentrations were higher in mice without PPARα expression given at 40-80 mg/kg amiodarone doses. These results are consistent with a protective influence of PPARα in reducing amiodarone-induced hepati...Continue Reading

Citations

Nov 15, 2014·Archives of Toxicology·Paul JenningsJeffrey S Wiseman
Oct 1, 2017·Toxicological Sciences : an Official Journal of the Society of Toxicology·Noam ErezOren Shibolet
Feb 25, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yuan HongHailin Ma

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