DRUG INDUCED MITOCHONDRIAL TOXICITY: MECHANISTIC DIVERSITY AND DELETERIOUS CONSEQUENCES FOR THE LIVER
Mechanisms of Atorvastatin - induced impairment of mitochondrial permeability and Co enzyme Q level.
Statins are potent lipid-lowering drugs which reduce the concentrations of low density lipoprotein (LDL) cholesterol. Statins are competitive inhibitors of 3-hydroxy-3- methylglutarylcoenzyme A (HMG-CoA) reductase - a rate limiting enzyme in cholesterol biosynthesis - which converts HMG-CoA to mevalonate.43Mevalonate is a precursor of cholesterol but also of a whole class of other important substances, such as ubiquinone, dolichols and other isoprenoids44. Statins are not free from side effects despite being considered as safe drugs.45Although infrequent, hepatotoxicity and myopathy are two of the most common complications associated with this class of drugs, especially when used at maximum doses, or when combined with other lipid lowering drugs such as fibrates, or combined with drugs that use the same enzymatic pathway as cytochrome P450 (CYP450) in its metabolic pathway, or in the elderly, or in subjects having considerable hepatic and/or renal dysfunction.45
Many studies have demonstrated that statins decrease CoQ concentration in plasma and various tissues of experimental animals. Atorvastatin administered for only 14 days decreased plasma CoQ by about 50% in patients with hypercholesterolemia43. Ubiquinone depletion induced by statin therapy may be accompanied by impaired mitochondrial function, as evidenced by reduced oxygen consumption and reduced capacity of the respiratory chain and rate of ATP synthesis in the liver mitochondria.
Thus, both CoQ levels (and thus antioxidant defence) and membrane lipid composition, which might depress oxygen consumption and energy production in the mitochondria.46
In physiological conditions mitochondrial function are an index of uptake of oxygen, calcium handling, production of ATP, and regulation of respiratory chain function. Mitochondrial lipid peroxidation alters membrane integrity and permeability of mitochondria. Thus alteration of Atorvastatin result in modulation of mitochondrial function leads to irreversible liver injury.44
Mitochondrial functions are an index of uptake of oxygen, calcium handling, and production of ATP and regulation of respiratory chain function in physiological conditions. Mitochondrial lipid peroxidation alters membrane integrity and permeability of mitochondria. Thus modulation of mitochondrial function owing to Atorvastatin leads to irreversible liver injury.
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