Efficiency of hepatocyte pretreatment with coenzyme Q10 against statin toxicity

Eghbal, Mohammad Ali; Abdoli, Narges; Azarmi, Yadollah

doi:10.2478/10004-1254-65-2014-2398

Cited by 16 publications

(18 citation statements)

References 32 publications

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“…We also saw that pretreatment with CoQ10 could block the release of Cyt c, inhibit the activation of caspase-3 and caspase-9, and regulate the expression of Bcl-2/Bax to reach equilibrium and prevent subsequent apoptosis in L-02 hepatocytes. These results are compatible with the findings of other studies using CoQ10 against iron-induced neuronal toxicity [28], statin toxicity in hepatocytes [50], or ethanol-induced apoptosis in corneal fibroblasts [51]. …”

Section: Discussionsupporting

confidence: 92%

CoQ10 Deficiency May Indicate Mitochondrial Dysfunction in Cr(VI) Toxicity

Zhong

Sá

et al. 2017

IJMS

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To investigate the toxic mechanism of hexavalent chromium Cr(VI) and search for an antidote for Cr(VI)-induced cytotoxicity, a study of mitochondrial dysfunction induced by Cr(VI) and cell survival by recovering mitochondrial function was performed. In the present study, we found that the gene expression of electron transfer flavoprotein dehydrogenase (ETFDH) was strongly downregulated by Cr(VI) exposure. The levels of coenzyme 10 (CoQ10) and mitochondrial biogenesis presented by mitochondrial mass and mitochondrial DNA copy number were also significantly reduced after Cr(VI) exposure. The subsequent, Cr(VI)-induced mitochondrial damage and apoptosis were characterized by reactive oxygen species (ROS) accumulation, caspase-3 and caspase-9 activation, decreased superoxide dismutase (SOD) and ATP production, increased methane dicarboxylic aldehyde (MDA) content, mitochondrial membrane depolarization and mitochondrial permeability transition pore (MPTP) opening, increased Ca2+ levels, Cyt c release, decreased Bcl-2 expression, and significantly elevated Bax expression. The Cr(VI)-induced deleterious changes were attenuated by pretreatment with CoQ10 in L-02 hepatocytes. These data suggest that Cr(VI) induces CoQ10 deficiency in L-02 hepatocytes, indicating that this deficiency may be a biomarker of mitochondrial dysfunction in Cr(VI) poisoning and that exogenous administration of CoQ10 may restore mitochondrial function and protect the liver from Cr(VI) exposure.

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Section: Discussionsupporting

confidence: 92%

CoQ10 Deficiency May Indicate Mitochondrial Dysfunction in Cr(VI) Toxicity

Zhong

Sá

et al. 2017

IJMS

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“…Even if coenzyme Q 10 administration does not relieve myalgia, it may be beneficial due to the fact that CoQ 10 enhances adenosine-5′-triphosphate production, exerts antioxidant activity, influences the expression of multiple genes, has membrane stabilizing properties, protects against LDL oxidation and inhibits proinflammatory cytokines and other factors [ 35 , 80 , 84 , 85 ]. Moreover, it has been suggested that the addition of CoQ 10 to statin therapy may protect hepatocytes from statin-induced injuries and reduce their adverse effects [ 45 , 80 , 86 ].…”

Section: Mechanisms Of Statin Intolerancementioning

confidence: 99%

Molecular mechanisms of statin intolerance

Gluba-Brzózka¹,

Franczyk²,

Tóth³

et al. 2016

aoms

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Statins reduce cardiovascular morbidity and mortality in primary and secondary prevention. Despite their efficacy, many persons are unable to tolerate statins due to adverse events such as hepatotoxicity and myalgia/myopathy. In the case of most patients, it seems that mild-to-moderate abnormalities in liver and muscle enzymes are not serious adverse effects and do not outweigh the benefits of coronary heart disease risk reduction. The risk for mortality or permanent organ damage ascribed to statin use is very small and limited to cases of myopathy and rhabdomyolysis. Statin-induced muscle-related adverse events comprise a highly heterogeneous clinical disorder with numerous, complex etiologies and a variety of genetic backgrounds. Every patient who presents with statin-related side effects cannot undergo the type of exhaustive molecular characterization that would include all of these mechanisms. Frequently the only solution is to either discontinue statin therapy/reduce the dose or attempt intermittent dosing strategies at a low dose.

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“…In fact, the depletion of this coenzyme was observed in the liver of our experimental model (Lorza-Gil et al, unpublished data ) as well as in skeletal muscle, heart, brain, plasma, HepG2 and insulin-secreting INS-1 cells after statins treatments ( Tavintharan et al, 2007 ; La Guardia et al, 2013 ; Urbano et al, 2017 ). The second point is that CoQ10 effects are mediated mostly by its free radical scavenger action ( Tavintharan et al, 2007 ; Eghbal et al, 2014 ) rather than by its electron transfer function, since under the present conditions, pravastatin did not inhibit mitochondria respiration. This mechanism was previously proposed by our group ( La Guardia et al, 2013 ; Busanello et al, 2017 ).…”

Section: Discussionmentioning

confidence: 71%

Coenzyme Q10 or Creatine Counteract Pravastatin-Induced Liver Redox Changes in Hypercholesterolemic Mice

et al. 2018

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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.

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Efficiency of hepatocyte pretreatment with coenzyme Q10 against statin toxicity

Cited by 16 publications

References 32 publications

CoQ10 Deficiency May Indicate Mitochondrial Dysfunction in Cr(VI) Toxicity

CoQ10 Deficiency May Indicate Mitochondrial Dysfunction in Cr(VI) Toxicity

Molecular mechanisms of statin intolerance

Coenzyme Q10 or Creatine Counteract Pravastatin-Induced Liver Redox Changes in Hypercholesterolemic Mice

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