Protective mechanisms of atorvastatin against doxorubicin-induced hepato-renal toxicity.

To investigate the mechanisms by which the anticancer drug doxorubicin (DOX)-induced hepato-renal damage could be prevented by the cholesterol-lowering statin, atorvastatin (Ator), Ator (10 mg/kg) was administered orally for 10 days, and, in independent rat groups, DOX hepato-renal toxicity was induced via a single i.p. dose of 15 mg/kg at day 5 of experiment, with or without Ator. DOX caused deterioration in hepato-renal function, as it significantly increased blood urea nitrogen (BUN), creatinine, alanine transaminase (ALT) and aspartate transaminase (AST) compared to control, with distortion in normal renal and hepatic histology. Pretreatment with Ator preserved kidney and liver function and histology. DOX caused oxidative stress as indicated by significant decrease in reduced glutathione (GSH) level and catalase activity with increase in malondialdehyde (MDA) compared to control. Combined DOX/Ator significantly reversed these values compared to DOX in both kidney and liver. DOX caused nitrosative stress, as it increased tissue nitric oxide compared to control. Concomitant DOX/Ator treatment decreased NO in kidney and liver. Furthermore, DOX caused inflammatory effects indicated by up-regulation of hepato-renal nuclear factor-κB (NF-κB) expression and increment of tumor necrosis factor-α (TNF-α) tissue concentration, with down-regulation of endothelial nitric oxide synthase (eNOS). DOX also caused apoptotic effect, as it up-regulated the apoptotic marker, Bcl-2-associated X protein (Bax), expression in liver and kidney. Using Ator with DOX reversed hepato-renal inflammatory and apoptotic marker expression. These findings suggest Ator as a protective adjuvant against DOX toxicity, via antioxidant, anti-nitrosative, anti-inflammatory and anti-apoptotic mechanisms.