Lipid‐lowering drugs and mitochondrial function: effects of HMG‐CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio

Abstract

1 Statins inhibit synthesis of mevalonate, a precursor of ubiquinone that is a central compound of the mitochondrial respiratory chain. The main adverse effect of statins is a toxic myopathy possibly related to mitochondrial dysfunction. 2 This study was designed to evaluate the effect of lipid-lowering drugs on ubiquinone (coenzyme Q10 ) serum level and on mitochondrial function assessed by blood lactate/pyruvate ratio. 3 Eighty hypercholesterolaemic patients (40 treated by statins, 20 treated by fibrates, and 20 untreated patients, all 80 having total cholesterol levels >6.0 mmol l−1) and 20 healthy controls were included. Ubiquinone serum level and blood lactate/pyruvate ratio used as a test for mitochondrial dysfunction were evaluated in all subjects. 4 Lactate/pyruvate ratios were significantly higher in patients treated by statins than in untreated hypercholesterolaemic patients or in healthy controls (P<0.05 and P<0.001). The difference was not significant between fibratetreated patients and untreated patients. 5 Ubiquinone serum levels were lower in statin-treated patients (0.75 mg l−1±0.04) than in untreated hypercholesterolaemic patients ( 0.95 mg l−1±0.09; P<0.05). 6 We conclude that statin therapy can be associated with high blood lactate/ pyruvate ratio suggestive of mitochondrial dysfunction. It is uncertain to what extent low serum levels of ubiquinone could explain the mitochondrial dysfunction.

Statin and fibrate associed myopathy: study of eight patients

“…Statins inhibit the HMG-CoA-reductase resulting in lower intracellular cholesterol levels.This later is an important component of cell membranes modulating their fluidity [1][2][3][4][5] . Myotoxicity associated to the use of statin is complex, involving mechanisms on the structure and function of the cellular membrane, mitochondrial dysfunction, and changes in the duplication of the myocyte [1][2][3][4][5][6][7][8][13][14][15] . A reduction in plasmatic and intracellular cholesterol can result in reduced levels of the membrane cholesterol leading to physical changes in this and a decrease in cell proliferation.…”

“…The most severe risk of these drugs is myositis with rhabdomyolysis. Rapid remission of symptoms after discontinuation of therapy has frequently been reported [1][2][3][4][5][6][7][8][9] .…”

Ubiquinone does not rescue acute myeloid leukemia cells from growth inhibition by statins

“…1,2 Serum concentrations of ubiquinone, a coenzyme involved in mitochondrial respiratory metabolism, are decreased in patients taking statin drugs. 3 Oral supplementation with ubiquinone may allow patients to tolerate higher doses of statins as may be required for the treatment of AML and other malignancies. 4 Therefore, prior to considering a therapeutic trial of statins for the treatment of leukemia, we wished to determine whether ubiquinone would rescue AML cells from the cytotoxic effects of statins.…”

Is There an Answer?

“…In humans, statin-induced CoQ 10 depletion was associated with a fall in left ventricular function, elevation of the lactate to pyruvate ratio, and an enhancement of LDL cholesterol oxidation. However, there was no correlation between blood lactate/pyruvate ratios and serum CoQ 10 concentrations, and patients with untreated hypercholesterolemia had higher levels of CoQ 10 than normocholesterolemic subjects (8).…”

“…Is the effect of statins on muscle due to lack of CoQ 10 ? An effect on muscle mitochondria may be suspected since treatment with statins, but not fibrates, was associated with low CoQ 10 concentrations (8). Myotoxicity may also be due to interaction with the cytochrome P 450 system (CYP-450).…”