Toxicity of statins on rat skeletal muscle mitochondria

Abstract

We investigated mitochondrial toxicity of four lipophilic stains (cerivastatin, fluvastatin, atorvastatin, simvastatin) and one hydrophilic statin (pravastatin). In L6 cells (rat skeletal muscle cell line), the four lipophilic statins (100 micromol/l) induced death in 27-49% of the cells. Pravastatin was not toxic up to 1 mmol/l. Cerivastatin, fluvastatin and atorvastatin (100 micromol/l) decreased the mitochondrial membrane potential by 49-65%, whereas simvastatin and pravastatin were less toxic. In isolated rat skeletal muscle mitochondria, all statins, except pravastatin, decreased glutamate-driven state 3 respiration and respiratory control ratio. Beta-oxidation was decreased by 88-96% in the presence of 100 micromol/l of the lipophilic statins, but only at higher concentrations by pravastatin. Mitochondrial swelling, cytochrome c release and DNA fragmentation was induced in L6 cells by the four lipophilic statins, but not by pravastatin. Lipophilic statins impair the function of skeletal muscle mitochondria, whereas the hydrophilic pravastatin is significantly less toxic.

Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity

“…47 Oxidative stress can activate aged rodents 55 and in other models of mitochondrial injury, 56 and is considered a marker of mitochondrial toxicity. 57,58 Furthermore, AMA decreased cell viability and activated apoptotic markers, as well as inhibited cellular respiration in cardiomyocytes, further increasing cytotoxicity (Fig. 8).…”

Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: A systematic review

“…34 With statin cessation, liver chemistry elevations resolved within 2-8 weeks. Reactive metabolite 32 20-160 mg 26 Atorvastatin, simvastatin, lovastatin (n ¼ 10) 34 30% 34 Decreases mitochondrial membrane potential; inhibits fatty acid beta-oxidation 36 ; uncouples electron transport from phosphorylation 37 Atorvastatin electrophilic acyl glucuronide metabolite 35 20-80 mg 26 Isoniazid, rifampin, pyrazinamide (n ¼ 220) 6 Statin injury is predominantly hepatocellular. 33 The formation of electrophilic metabolites covalently binding to proteins is frequently implicated in immunebased hepatotoxicity; an electrophilic acyl glucuronide metabolite has been reported for atorvastatin.…”

“…35 When tested in vitro, lipophilic statins (e.g., atorvastatin, simvastatin, cerivastatin, fluvastatin) decrease mitochondrial membrane potential and beta-oxidation and increase mitochondrial swelling, cytochrome c release, and DNA disruption. 36 In isolated rat hepatic mitochondria, simvastatin uncouples electron transport from phosphorylation. 37 Statin-induced mitochondrial impairment and/or reactive metabolite formation contributes to rechallenge injury.…”

Is immunity a mechanism contributing to statin-induced diabetes?

“…Increased production of mitochondrial reactive oxygen species (mtROS), altered mitochondrial membrane potential and decreased intracellular ATP levels have been observed with concentrations of statin as low as 1 mM. [68][69][70][71][72] Statins have also been shown to promote a modest increase in cellular ROS and an increase of ATP release in THP-1 monocytes. 56 Statininduced IL-1b production was also shown to be dependent on P2X purinoceptor 7 (P2X7) activation.…”