Statins are the preferred
therapy to treat
hypercholesterolemia. Their main action consists of inhibiting the
cholesterol biosynthesis pathway. Previous studies report mitochondrial oxidative stress and membrane permeability transition (MPT) of several experimental models submitted to diverse
statins treatments. The aim of the present study was to investigate whether chronic treatment with the hydrophilic
pravastatin induces hepatotoxicity in
LDL receptor knockout mice (LDLr-/-), a model for human
familial hypercholesterolemia. We evaluated respiration and reactive
oxygen production rates,
cyclosporine-A sensitive mitochondrial
calcium release,
antioxidant enzyme activities in liver mitochondria or homogenates obtained from LDLr-/- mice treated with
pravastatin for 3 months. We observed that
pravastatin induced higher H2O2 production rate (40%), decreased activity of
aconitase (28%), a
superoxide-sensitive Krebs cycle
enzyme, and increased susceptibility to Ca2+-induced MPT (32%) in liver mitochondria. Among several
antioxidant enzymes, only
glucose-6-phosphate dehydrogenase (G6PD) activity was increased (44%) in the liver of treated mice.
Reduced glutathione content and reduced to
oxidized glutathione ratio were increased in livers of
pravastatin treated mice (1.5- and 2-fold, respectively). The presence of oxidized
lipid species were detected in
pravastatin group but
protein oxidation markers (carbonyl and SH- groups) were not altered. Diet supplementation with the
antioxidants CoQ10 or
creatine fully reversed all
pravastatin effects (reduced H2O2 generation, susceptibility to MPT and normalized
aconitase and G6PD activity). Taken together, these results suggest that 1-
pravastatin induces liver mitochondrial redox imbalance that may explain the hepatic side effects reported in a small number of patients, and 2- the co-treatment with safe
antioxidants neutralize these side effects.