Toxicity of statins on rat skeletal muscle mitochondria.
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.
Kaufmann
P
P
Division of Clinical Pharmacology and Toxicology and Department of Research, University Hospital, 4031, Basel, Switzerland.
Török
M
M
Zahno
A
A
Waldhauser
K M
KM
Brecht
K
K
Krähenbühl
S
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D000069059:Atorvastatin; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000633:toxicity; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000633:toxicity; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D007211:Indoles / Q000633:toxicity; D008564:Membrane Potentials / Q000187:drug effects; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000648:ultrastructure; D010100:Oxygen / Q000378:metabolism; D017035:Pravastatin / Q000633:toxicity; D011725:Pyridines / Q000633:toxicity; D011758:Pyrroles / Q000633:toxicity; D051381:Rats; D019821:Simvastatin / Q000633:toxicity
D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011725:Pyridines; D011758:Pyrroles; D000077340:Fluvastatin; D045304:Cytochromes c; D000069059:Atorvastatin; D019821:Simvastatin; C086276:cerivastatin; D017035:Pravastatin; D010100:Oxygen