Coenzyme Q10 Reduction with Statins: Another Pleiotropic Effect

Hiroshi      Mabuchi; Atsusi      Nohara; Junji      Kobayashi; Masa-aki      Kawashiri; Akihiro      Inazu

Abstract

Hypercholesterolemia is a major coronary risk factor, and extensive epidemiological data have shown that the higher the serum cholesterol level the higher the incidence of coronary heart disease (CHD). Over the past decade, 3- hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have emerged as one of the most effective means of reducing risk for CHD. A number of clinical trials have demonstrated that statins are not only safe and well tolerated but also significantly decrease CHD morbidity and mortality in hyper- and normo-cholesterolemic patients in both primary and secondary prevention studies. These findings support “the lower the cholesterol, the better” concept. HMG-CoA reductase converts HMG-CoA to mevalonate, and inhibition of this enzyme results in decreased synthesis of cholesterol and other products downstream of mevalonate. Sometimes clinical results from treatment with statins are not fully explained by reduction in serum cholesterol levels. These effects of the statins that go beyond the clinical effects brought about by cholesterol reduction are called “pleiotropic effects”. Many of these so-called pleiotropic effects have been shown to be secondary to inhibition of the synthesis of isoprenoid intermediates of the mevalonate pathway, and, thus, are completely independent of intracellular cholesterol biosynthesis. Although statins have been known to be safe, fatal cases of rhabdomyolysis in connection with this drug has raised major concerns about the possibility that certain pleiotropic effects of statins could also be harmful. Mevalonate is a precursor of coenzyme Q10 (CoQ10) which is a central compound of the mitochondrial respiratory chain, and is a potent lipophilic antioxidant present in nearly all human tissues and plasma lipoproteins. Decreased content of CoQ10 found in the patients plasma could therefore increase its potential to oxidize. Supplementation of CoQ10 may restore tissue and plasma CoQ10 concentrations in patients treated with statins. Inhibitors of cholesterol biosynthesis beyond mevalonate may reduce cholesterol synthesis without inhibiting the biosynthesis of CoQ10 and dolichol. Here, we have reviewed CoQ10 metabolism in patients treated with statins, and the correlation with the possible side effects of statins.

Keywords: CoQ10, statin, mevalonate pathway, squalene synthase inhibitor, pleiotropic effect, rhabdomyolysis

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