Role of mitochondrial complex I and protective effect of CoQ10 supplementation in propofol induced cytotoxicity.

Propofol (2,6-diisopropylphenol) is an anaesthetic widely used for human sedation. Due to its intrinsic antioxidant properties, rapid induction of anaesthesia and fast recovery, it is employed in paediatric anaesthesia and in the intensive care of premature infants. Recent studies have pointed out that exposure to anaesthesia in the early stage of life might be responsible of long-lasting cognitive impairment. The apoptotic neurodegeneration induced by general anaesthetics (GA) involves mitochondrial impairment due to the inhibition of the OXPHOS machinery. In the present work, we aim to identify the main mitochondrial respiratory chain target of propofol toxicity and to evaluate the possible protective effect of CoQ10 supplementation. The propofol effect on the mitochondrial functionality was assayed in isolated mitochondria and in two cell lines (HeLa and T67) by measuring oxygen consumption rate. The protective effect of CoQ10 was assessed by measuring cells viability, NADH-oxidase activity and ATP/ADP ratio in cells treated with propofol. Our results show that propofol reduces cellular oxygen consumption rate acting mainly on mitochondrial Complex I. The kinetic analysis of Complex I inhibition indicates that propofol interferes with the Q module acting as a non-competitive inhibitor with higher affinity for the free form of the enzyme. Cells supplemented with CoQ10 are more resistant to propofol toxicity. Propofol exposure induces cellular damages due to mitochondrial impairment. The site of propofol inhibition on Complex I is the Q module. CoQ10 supplementation protects cells against the loss of energy suggesting its possible therapeutic role to minimizing the detrimental effects of general anaesthesia.

Effect of carni Q-gel (ubiquinol and carnitine) on cytokines in patients with heart failure in the Tishcon study.

INTRODUCTION: There is evidence that both carnitine and coenzyme Q 10 (Co Q), which are important for the functioning of myocardial mitochondria, are deficient in patients with congestive heart failure, in association with increased pro-inflammatory cytokines. It is possible that supplementation with ubiquinol and L-carnitine may protect these patients by decreasing inflammation. SUBJECTS AND METHODS: In a randomized, double-blind, placebo-controlled trial, the effects of carni Q-gel (2250 mg/d L-carnitine and 270 mg/d hydrosoluble ubiquinol) were examined for 12 weeks. Thirty-one patients with heart failure received intervention (group A) and another 31 patients served as controls (group B). Serum levels of interleukin (IL)-6, tumour necrosis factor (TNF)-alpha and IL-10 could be studied among 29 patients in each group. Statistical analysis was conducted by analysis of variance and chi square test. RESULTS: Echocardiographic ejection fractions were lower at baseline (38.8 + 7.6 vs. 39.3 + 6.7% in the intervention and control groups, respectively) among both group of patients, indicating class II-IV heart failure. Serum concentration of interleukin-6 (IL-6), a pro-inflammatory cytokine, was high (18.7 +/- 5.8 vs. 15.0 +/- 3.3 pg/ml, normal 0.0-3.9) and IL-10 (anti-inflammatory) was normal (3.4 +/- 1.5 vs. 2.9 +/- 1.0 pg/ml, the normal range is 1.5-3.1 pg/ml) in both groups at baseline. After 12 weeks, there was a marked reduction in IL-6 in the intervention group without such changes in the control group (7.6 +/- 1.5 vs. 11.4 +/- 2.5 pg/ml, P < 0.01. IL-10 showed only the non-significant decrease in both groups from the baseline levels (3.2 +/- 1.0 vs. 2.8 +/- 0.9 pg/ml). TNF-alpha, which was comparable at baseline (17.6 +/- 4.3 vs. 20.0 +/- 5.3 pg/ml), also showed a greater decline in the carni Q-gel group compared to the placebo group (12.5 +/- 3.3 vs. 17.2 +/- 3.2 pg/ml, P < 0.05). Baseline serum CoQ levels (0.21 +/- 0.11 vs. 0.19 +/- 0.10 microg/ml) were low; however, after 12 weeks, serum CoQ showed a significant increase in the carni Q-gel group as compared to the control group (2.7 +/- 1.2 and 0.76 +/- 0.14 microg/ml, respectively). After 12 weeks of treatment, the quality of life visual analogous scale revealed that dyspnoea, palpitation and fatigue, (NYHA class II-III-IV), which were present at rest in all patients at baseline, showed beneficial effects in the intervention group compared to the placebo group. The six-minute walk test showed that there was a significant greater benefit in walking, from the baseline distance in the intervention group (208 +/- 15.8 vs. 281 +/- 20.6 metres, P < 0.02) compared to the placebo group (218.4 +/- 17.6 vs. 260.7 +/- 19.3 metres, P < 0.05). The symptom scale indicated that the majority of patients showed improvement in the intervention group compared to the control group (28 vs. 16 patients, respectively, P < 0.05). Three patients in the intervention group had nausea and vomiting, which were controlled with symptomatic treatment. CONCLUSIONS: These findings indicate that treatment with ubiquinol + L-carnitine can cause a significant reduction in the pro-inflammatory cytokines that are neurohumoural precursors related to sympathetic and parasympathetic activity, which is impaired in patients with heart failure. There was no adverse effect on IL-10. There was a significant improvement in quality of life as well as decrease in NYHA-defined heart failure.

Effects of CoQ10 supplementation on plasma lipoprotein lipid, CoQ10 and liver and muscle enzyme levels in hypercholesterolemic patients treated with atorvastatin: a randomized double-blind study.

The long-term efficacy and safety of HMG-CoA reductase inhibitors (statins) have been established in large multicenter trials. Inhibition of this enzyme, however, results in decreased synthesis of cholesterol and other products downstream of mevalonate, such as CoQ10 or dolichol. This was a randomized double-blind, placebo-controlled study that examined the effects of CoQ10 and placebo in hypercholesterolemic patients treated by atorvastatin. Eligible patients were given 10mg/day of atorvastatin for 16 weeks. Half of the patients (n=24) were supplemented with 100mg/day of CoQ10, while the other half (n=25) were given the placebo. Serum LDL-C levels in the CoQ10 group decreased by 43%, while in the placebo group by 49%. The HDL-C increment was more striking in the CoQ10 group than in the placebo group. All patients showed definite reductions of plasma CoQ10 levels in the placebo group, by 42%. All patients supplemented with CoQ10 showed striking increases in plasma CoQ10 by 127%. In conclusion atorvastatin definitely decreased plasma CoQ10 levels and supplementation with CoQ10 increased their levels. These changes in plasma CoQ10 levels showed no relation to the changes in serum AST, ALT and CK levels. Further studies are needed, however, for the evaluation of CoQ10 supplementation in statin therapy.

The role of coenzyme Q10 in statin-associated myopathy: a systematic review.

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are currently the most effective medications for reducing low-density lipoprotein cholesterol concentrations. Although generally safe, they have been associated with a variety of myopathic complaints. Statins block production of farnesyl pyrophosphate, an intermediate in the synthesis of ubiquinone or coenzyme Q10 (CoQ10). This fact, plus the role of CoQ10 in mitochondrial energy production, has prompted the hypothesis that statin-induced CoQ10 deficiency is involved in the pathogenesis of statin myopathy. We identified English language articles relating statin treatment and CoQ10 levels via a PubMed search through August 2006. Abstracts were reviewed and articles addressing the relationship between statin treatment and CoQ10 levels were examined in detail. Statin treatment reduces circulating levels of CoQ10. The effect of statin therapy on intramuscular levels of CoQ10 is not clear, and data on intramuscular CoQ10 levels in symptomatic patients with statin-associated myopathy are scarce. Mitochondrial function may be impaired by statin therapy, and this effect may be exacerbated by exercise. Supplementation can raise the circulating levels of CoQ10, but data on the effect of CoQ10 supplementation on myopathic symptoms are scarce and contradictory. We conclude that there is insufficient evidence to prove the etiologic role of CoQ10 deficiency in statin-associated myopathy and that large, well-designed clinical trials are required to address this issue. The routine use of CoQ10 cannot be recommended in statin-treated patients. Nevertheless, there are no known risks to this supplement and there is some anecdotal and preliminary trial evidence of its effectiveness. Consequently, CoQ10 can be tested in patients requiring statin treatment, who develop statin myalgia, and who cannot be satisfactorily treated with other agents. Some patients may respond, if only via a placebo effect.

Effect of coenzyme q10 on myopathic symptoms in patients treated with statins.

Treatment of hypercholesterolemia with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) is effective in the primary and secondary prevention of cardiovascular disease. However, statin use is often associated with a variety of muscle-related symptoms or myopathies. Myopathy may be related in part to statin inhibition of the endogenous synthesis of coenzyme Q10, an essential cofactor for mitochondrial energy production. The aim of this study is to determine whether coenzyme Q10 supplementation would reduce the degree of muscle pain associated with statin treatment. Patients with myopathic symptoms were randomly assigned in a double-blinded protocol to treatment with coenzyme Q10 (100 mg/day, n = 18) or vitamin E (400 IU/day, n = 14) for 30 days. Muscle pain and pain interference with daily activities were assessed before and after treatment. After a 30-day intervention, pain severity decreased by 40% (p <0.001) and pain interference with daily activities decreased by 38% (p <0.02) in the group treated with coenzyme Q10. In contrast, no changes in pain severity (+9%, p = NS) or pain interference with daily activities (-11%, p = NS) was observed in the group treated with vitamin E. In conclusion, results suggest that coenzyme Q10 supplementation may decrease muscle pain associated with statin treatment. Thus, coenzyme Q10 supplementation may offer an alternative to stopping treatment with these vital drugs.

Acute administration of red yeast rice (Monascus purpureus) depletes tissue coenzyme Q(10) levels in ICR mice.

In this study, we attempted to evaluate the effect of administration of a high quantity of red yeast rice on coenzyme Q10 (CoQ10) synthesis in the tissues of ICR mice. Eighty-eight adult male ICR mice were housed and divided into control and experimental groups for red yeast rice treatment. Animals were gavaged with a low (1 g/kg body weight) or a high dose (5 g/kg body weight, approximately five times the typical recommended human dose) of red yeast rice dissolved in soyabean oil. After gavagement, animals of the control group were immediately killed; mice of the experimental groups (eight for each subgroup) were killed at different time intervals of 0.5, 1, 1.5, 4 and 24 h. The liver, heart and kidney were taken for analysis of monacolin K (liver only) and CoQ10 analysis. Liver and heart CoQ10 levels declined dramatically in both groups administered red yeast rice, especially in the high-dose group, within 30 min. After 24 h, the levels of hepatic and cardiac CoQ10 were still reduced. A similar trend was also observed in the heart, but the inhibitory effect began after 90 min. The higher dose of red yeast rice presented a greater suppressive effect than did the lower dose on tissue CoQ10 levels. In conclusion, acute red yeast rice gavage suppressed hepatic and cardiac CoQ10 levels in rodents; furthermore, the inhibitory effect was responsive to the doses administered.

Short-term and long-term vitamin C supplementation in humans dose-dependently increases the resistance of plasma to ex vivo lipid peroxidation.

To assess the effects of short-term and long-term vitamin C supplementation in humans on plasma antioxidant status and resistance to oxidative stress, plasma was obtained from 20 individuals before and 2h after oral administration of 2g of vitamin C, or from eight subjects enrolled in a vitamin C depletion-repletion study using increasing daily doses of vitamin C from 30 to 2500 mg. Plasma concentrations of ascorbate, but not other physiological antioxidants, increased significantly after short-term supplementation, and increased progressively in the long-term study with increasing vitamin C doses of up to 1000 mg/day. Upon incubation of plasma with a free radical initiator, ascorbate concentrations were positively correlated with the lag phase preceding detectable lipid peroxidation. We conclude that vitamin C supplementation in humans dose-dependently increases plasma ascorbate concentrations and, thus, the resistance of plasma to lipid peroxidation ex vivo. Plasma and body saturation with vitamin C in humans appears desirable to maximize antioxidant protection and lower risk of oxidative damage.

Evaluation of ubiquinone concentration and mitochondrial function relative to cerivastatin-induced skeletal myopathy in rats.

As a class, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors can potentially cause skeletal myopathy. One statin, cerivastatin, has recently been withdrawn from the market due to an unacceptably high incidence of rhabdomyolysis. The mechanism underlying statin-induced myopathy is unknown. This paper sought to investigate the relationship among statin-induced myopathy, mitochondrial function, and muscle ubiquinone levels. Rats were administered cerivastatin at 0.1, 0.5, and 1.0 (mg/kg)/day or dose vehicle (controls) by oral gavage for 15 days. Samples of type I-predominant skeletal muscle (soleus) and type II-predominant skeletal muscle [quadriceps and extensor digitorum longus (EDL)], and blood were collected on study days 5, 10, and 15 for morphological evaluation, clinical chemistry, mitochondrial function tests, and analysis of ubiquinone levels. No histological changes were observed in any of the animals on study days 5 or 10, but on study day 15, mid- and high-dose animals had necrosis and inflammation in type II skeletal muscle. Elevated creatine kinase (CK) levels in blood (a clinical marker of myopathy) correlated with the histopathological diagnosis of myopathy. Ultrastructural characterization of skeletal muscle revealed disruption of the sarcomere and altered mitochondria only in myofibers with degeneration, while adjacent myofibers were unaffected and had normal mitochondria. Thus, mitochondrial effects appeared not to precede myofiber degeneration. Mean coenzyme Q9 (CoQ9) levels in all dose groups were slightly decreased relative to controls in type II skeletal muscle, although the difference was not significantly different in most cases. Mitochondrial function in skeletal muscle was not affected by the changes in ubiquinone levels. The ubiquinone levels in high-dose-treated animals exhibiting myopathy were not significantly different from low-dose animals with no observable toxic effects. Furthermore, ubiquinone levels did not correlate with circulating CK levels in treated animals. The results of this study suggest that neither mitochondrial injury, nor a decrease in muscle ubiquinone levels, is the primary cause of skeletal myopathy in cerivastatin-dosed rats.

The effect of pravastatin and atorvastatin on coenzyme Q10.

BACKGROUND: Coenzyme Q10 (CoQ10) is an antioxidant and plays an important role in the synthesis of adenosine triphosphate. Studies suggest that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors reduce CoQ10 levels; however, no studies have directly compared HMG-CoA reductase inhibitors in a randomized crossover fashion. METHODS: Twelve healthy volunteers received either 20 mg pravastatin (P) or 10 mg atorvastatin (A) for 4 weeks in a randomized crossover fashion. There was a 4- to 8-week washout period between the 2 phases. CoQ10 levels and a lipid profile were obtained. RESULTS: There was no difference in CoQ10 levels from baseline to post-drug therapy for either P or A (0.61 +/- 0.14 vs 0.62 +/- 0.2 microg/mL and 0.65 +/- 0.22 vs 0.6 +/- 0.12 microg/mL, respectively; P >.05). There was a significant difference in low-density lipoprotein (LDL) levels from baseline to post-drug therapy for both P and A (97 +/- 21 vs 66 +/- 19 mg/dL and 102 +/- 21 vs 52 +/- 14 mg/dL, respectively; P <.01). There was no significant correlation between LDL and CoQ10. CONCLUSIONS: P and A did not decrease CoQ10 despite a significant decrease in LDL levels. These findings suggest that HMG-CoA reductase inhibitors do not significantly decrease the synthesis of circulating CoQ10 in healthy subjects. Routine supplementation of CoQ10 may not be necessary when HMG-CoA reductase inhibitor therapy is administered.