Abstract:
Statins are competitive inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis pathway, which converts HMG-CoA to mevalonate. Statins lower plasma Low Density Lipoprotein (LDL)-bound cholesterol by causing intracellular cholesterol depletion and upregulating the expression of LDL receptors. Apart from cholesterol, mevalonate is also used as the substrate for the synthesis of nonsteroid isoprenoids including farnesylpyrophosphate, geranylgeranylpyrophosphate (both attached to small GTP-binding proteins by protein prenyltransferases), coenzyme Q, dolichol, isopentenylpyrophosphate, etc. Inhibiting the synthesis of these nonsteroid isoprenoids results in so called "pleiotropic" effects of statins which are independent of cholesterol lowering. Although statins are generally well-tolerated, adverse effects may occur in some patients. Myopathy is the most frequent side effect of statins. Other less common include peripheral neuropathy, hepatotoxicity, increased risk of cataract and, according to some studies, increased risk of breast cancer. Some studies suggest that under specific experimental conditions statins may exert detrimental effects also on processes which are generally believed to be favorably modified by these drugs, e.g. vascular reactivity, myocardial performance or atherogenesis. In this review currently recognized mechanisms through which statins could induce side effects are discussed.
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