Coenzyme Q10
A Review of Essential Functions and Clinical Trials
Caroline Fuke, Pharm.D.
Pharmacist, Long s Pharmacy,
Honolulu, HI
Susan A. Krikorian, M.S., R.Ph.
Associate Professor of Clinical Pharmacy,
Massachusetts College of Pharmacy and Health Sciences
Clinical Pharmacy Specialist in Nephrology,
Beth Israel Deaconess Medical Center, Boston, MA
R. Rebecca Couris, Ph.D., R.Ph.
Associate Professor of Nutrition Science and Pharmacy,
Massachusetts College of Pharmacy and Health Sciences
Research Scientist,
Marino Center for Progressive Health, Cambridge, MA
Research suggests a role for CoQ10 in conditions related to oxidative stress.
Coenzyme Q10 (CoQ10), a vitamin-like substance found in every cell, hence the name ubiquinone, is vital in the production of energy. It was first isolated from the mitochondria of bovine hearts in 1957 at the University of Wisconsin.[1] Identification of the chemical structure and synthesis was completed by 1958.[2] Research conducted in the 1960s and 1970s demonstrated that CoQ10 acts as an antioxidant and plays a central role in mitochondrial oxidative phosphorylation. Therefore, in 1974, the Japanese government approved CoQ10 for the treatment of cardiovascular disease, leading to its use by more than 12 million Japanese adults today.[3] In addition, the use of CoQ10 has been widely advocated by health care professionals throughout the United States and Europe.
Pharmacology
CoQ10 (2,3-dimethoxy-5-methylbenzoquinone) is chemically classified as a fat-soluble quinone ring attached to 10 isoprene side units, structurally similar to vitamin K.4 In humans, CoQ10 is found in relatively higher concentrations in cells with high energy requirements such as heart, liver, muscle, and pancreas. The total body content of CoQ10 has been estimated to be 0.5 1.5 g, its active form protein bound. Normal blood levels range from 0.7 1.0 µg/mL. Human cells synthesize CoQ10 from the amino acid tyrosine, in an eight-step aromatic pathway, requiring adequate levels of vitamins such as folic acid, niacin, riboflavin, and pyridoxine.[5] A deficiency in any of these nutrients would result in a deficiency in CoQ10.
Pharmacokinetics
CoQ10 is absorbed slowly. Peak plasma levels are attained within 5 10 hours following oral administration. Absorption is dependent on the presence of fat in the gastrointestinal tract. After absorption, CoQ10 is initially sequestered by chylomicrons and then distributed to the liver to be incorporated into very low density lipoproteins (VLDL). The metabolic fate of CoQ10 has not been fully elucidated. The elimination half-life of the parent compound is approximately 34 hours; excretion is primarily through the biliary tract and over 60% of the oral dose is recovered in the feces.[4]
Mechanism of Action
Electron Transport Chain to Produce ATP: CoQ10, found in the inner mitochondrial membrane, is the cofactor for at least three mitochondrial enzymes (complexes I, II and III) that play a vital role in oxidative phosphorylation. It functions as the only non-protein component of the electron transport chain (ETC) in addition to not being attached to a protein itself. This unique characteristic enables CoQ10 to move and transfer electrons between flavoproteins and cytochromes. Each pair of electrons processed by the ETC must first interact with CoQ10, which is considered the central rate-limiting constituent of the mitochondrial respiratory chain. Therefore, CoQ10 plays an essential role in adenosine triphosphate (ATP), or biological energy, production.[6-8]
Antioxidant:In addition to serving as an electron and proton carrier in the mitochondrial respiratory chain, CoQ10 also functions as an antioxidant.[9,10] It acts to inhibit lipid and protein peroxidation and scavenges free radicals. CoQ10 constantly undergoes oxidation-reduction recycling.11 The reduced form readily gives up electrons to neutralize oxidants and displays its strongest antioxidant activity.[12,13] Some investigators have documented that CoQ10 prevents lipid peroxidation at nearly the same rate as vitamin E.[14]Other investigators have found CoQ10 to be more efficient in preventing LDL oxidation than vitamin E, lycopene, or -carotene.[15] In addition, CoQ10 can work synergistically with vitamin E, regenerating its active form, tocopherol, in the same synergistic mechanism as with vitamin C. CoQ10 is the only known naturally occurring lipid-soluble antioxidant that can be regenerated to its active form in the body.
Membrane Stabilization and Fluidity:
The membrane stabilizing property of CoQ10 has been postulated to involve the phospholipid-protein interaction that increases prostaglandin (especially prostacyclin) metabolism. It is thought that CoQ10 stabilizes myocardial calcium-dependent ion channels and prevents the depletion of metabolites essential for ATP synthesis.4 CoQ10 also decreases blood viscosity, and improves blood flow to cardiac muscle in patients with ischemic heart disease.[16]
Overview of Clinical Uses
Research has documented an age-dependent decrease in CoQ10; peak serum concentrations occur at 19 21 years of age and drop 65% by age 80.[17] Other factors leading to CoQ10 deficiency include inadequate dietary intake, environmental stress, strenuous exercise, and selected drugs. Deficiencies have also been reported in various disease processes, including congestive heart failure (CHF), cardiomyopathy, chronic obstructive pulmonary disease (COPD), acquired immunodeficiency syndrome (AIDS), cancer, hypertension, and periodontal disease.
Several clinical trials and case series have provided evidence, supporting the use of CoQ10 in the prevention and treatment of various disorders related to oxidative stress. It has been shown that CoQ10 s antioxidant properties and central role in mitochondrial oxidative phosphorylation make it useful as adjunct therapy for cardiovascular diseases such as CHF, hypertension, stable angina, drug-induced cardiotoxicity, and ventricular arrhythmia, and non-cardiac conditions including cancer, periodontal disease, compromised immune systems, COPD, and muscular dystrophy. Therefore, healthcare professionals are advocating its use as a supplement.
Cardiovascular Studies
Congestive Heart Failure (CHF): Several open and controlled studies have examined the efficacy of CoQ10 as adjunctive therapy for treating CHF. The presence of increasing symptoms associated with CHF has been correlated to the severity of CoQ10 deficiency. In one study, the mean myocardial tissue level (µg/dry weight) of CoQ10 from endomyocardial biopsies obtained during catheterization in control subjects, New York Heart Association (NYHA) Class I with normal hemodynamic findings and normal biopsy morphology, were compared to that of NYHA Functional Class III or IV patients; these levels were reported as 0.42 and 0.28, respectively.[18,19] The authors concluded that CoQ10 myocardial tissue levels in CHF patients are on average 33% lower than in control patients. The degree of CoQ10 deficiency correlated with the severity of symptoms and presence of dilated cardiomyopathy in NYHA Class III and IV patients. In addition, reported mean serum CoQ10 levels were 0.6 µg/mL and reached as low as 0.3 µg/mL in some patients.
|
Table 1 |
|
|
Cardiovascular Disease |
Arteriosclerosis/Ischemic Chronic Heart Failure Toxin-Induced Hypertension |
| Neurodegenerative Disease |
Neurogenic Atrophic Muscular Dystrophy |
| Cancer |
Breast Lung Prostate Pancreatic Colon |
| Periodontal Disease |
Inflamed Gingiva |
| Immune Deficiency Disease |
AIDS |
A cross-sectional study by Jameson et al.[20] analyzed serum CoQ10, alpha-tocopherol, and free cholesterol levels in 94 consecutive hospitalized patients over 50 years of age. Patients exhibiting a significantly lower serum free cholesterol-related CoQ10 value (CoQ10 levels expressed per milligram of free cholesterol) had an increased risk of CHF, severe myalgia, concomitant use of cytostatic and lipid-lowering drug therapy, and/or death within a six-month follow-up.
These findings led to several clinical trials that examined the efficacy of CoQ10 as adjunctive therapy for treating CHF. A multicenter, randomized, double-blind, placebo-controlled study by Morisco et al.[21] evaluated the effect of CoQ10 in patients with NYHA Class III and IV HF receiving conventional treatment for heart failure. All enrolled patients had symptoms of dyspnea and/or fatigue with signs of fluid retention and no evidence of pulmonary disease. Subjects were randomized to receive adjunctive therapy of either placebo (n=322) or CoQ10 2 mg/kg/day (n=319) up to a maximum daily dose of 150 mg for one year. Assessment parameters at 3, 6, and 12 months included the incidence of hospitalization, pulmonary edema, cardiac asthma, ventricular arrhythmias, or mortality. Conventional drug regimens, adjusted to maintain hemodynamic stability, and patient demographics were similar in both groups. The incidence of one or more hospitalizations for symptomatic CHF in both the CoQ10 and placebo groups were 20% and 40% (p<0.01), respectively. The number of deaths in each group was not statistically significant. The authors concluded that the incidence of pulmonary edema, cardiac asthma, and arrhythmia was significantly lower in the CoQ10 group vs. the placebo group and that treating 1000 patients for one year with study doses of CoQ10 may prevent 200 hospitalizations due to worsening CHF symptoms.
Baggio et al.[22] studied the efficacy of CoQ10 as adjunctive therapy in an open, prospective, noncomparative, multicenter study of 2,359 evaluable patients with heart failure in NYHA Class II (n=1,715) or III (n=644) stabilized on conventional therapy. Patients received 50 150 mg/day of CoQ10. At the end of the three-month study period, the proportions of patients with improvements in clinical and functional assessment from baseline were documented. The results indicated improvements in cyanosis (78.1%), edema (78.6%), pulmonary rales (77.8%), hepatomegaly (49.3%), jugular reflux (71.8%), dyspnea (52.7%), palpitations (75.4%), sweating (79.8%), vertigo (73.1%), subjective arrhythmia (63.4%), insomnia (62.8%) and nocturia (53.6%). Fifty-four percent of patients had improvements of at least three symptoms. Moreover, 28.8% of patients entered as NYHA Class III improved in score to Class II and 89.7% of patients entered as NYHA Class II improved in score to Class I. The authors concluded that patients receiving CoQ10 improved functionally and that patients in NYHA Class II showed better improvement rates than did patients in NYHA Class III.
In an open controlled trial, the efficacy of CoQ10 as adjunctive treatment in chronic heart failure of various origins was evaluated in 35 patients who were symptomatic on conventional drug therapy. Patients received CoQ10 in adjunctive doses of 100 mg/day for two months. Two thirds of the patients responded with an improvement in functional class by one or two scores; the most pronounced response was in the dilated cardiomyopathy group and the least beneficial effects were in the ischemic heart disease group.[19]
An open-label study by Langsjoen et al.[23] evaluated the long-term efficacy and safety of CoQ10 therapy for idiopathic dilated cardiomyopathy in NYHA Classes II, III, and IV. One hundred twenty-six symptomatic patients ranging in age from 19 80 received 33.3 mg of CoQ10 three times daily over six years in addition to conventional therapy for heart failure. Baseline and periodic assessments evaluated ejection fraction calculated from systolic time intervals, CoQ10 serum concentrations and survival rate. Baseline mean ejection fractions improved from 41% to 59% in six months (p<0.001) and remained stable thereafter. The mean baseline serum CoQ10 level increased from 0.85 µg/mL to approximately 2 µg/mL in three months (p<0.001) and remained stable thereafter. Survival rates at 1, 2, 3, 4, and 5 years were 97%, 84%, 79%, 70%, and 57%, respectively. The majority of patients in all groups improved in functional NYHA Class by one or two scores. All patients in NYHA Class II became asymptomatic; the majority of patient deaths occurred in NYHA Class IV.
In a recently reported randomized, double-blind, placebo-controlled trial conducted by Khatta et al.24 in 55 patients receiving standard medical treatment for CHF with NYHA Class III and IV symptoms, the effects of CoQ10 in doses of 200 mg/day were compared to placebo on functional parameters including ejection fraction assessed by nuclear ventriculography, changes in peak oxygen consumption, and exercise duration. Although serum levels of CoQ10 increased during supplemental treatment, ejection fraction, peak oxygen consumption, and exercise duration did not change in the CoQ10 and placebo groups. The results contradict previously published reports and warrant further investigation of CoQ10 in heart failure.
CoQ10 s proposed mechanism on benefiting CHF is through positive inotropic action.[4] Such action increases the contractile force of the heart to improve cardiac output. Many drugs of conventional CHF therapy also possess this positive inotropic property, yet the increased contractility requires an adequate supply of ATP. Failed hearts are believed to lack ATP, thus this bioenergetic process is the reasoning behind supplementing CHF therapy with CoQ10.
Despite its lack of effect on survival, CoQ10 may improve cardiac function and quality of life in patients with severe CHF. Fewer hospitalizations could reduce the cost of managing patients with NYHA Class III or IV heart failure. Further prospective trials need to be conducted to determine the significance of these findings.
Ischemic Heart Disease/Stable Angina: In a double-blind, randomized, placebo-controlled crossover trial of 12 adults with stable angina on conventional therapy, supplements of 150 mg/day of CoQ10 for four weeks showed a decrease in both anginal frequency and use of nitroglycerin (p>0.05).[25] However, a significant increase in exercise duration and delay in exercise-induced ischemic segment changes assessed by treadmill EKG parameters were reported.
It has been postulated that the mechanism for improved exercise tolerance may be attributed to the ability of CoQ10 to maintain oxidative phosphorylation, thereby acting as a direct membrane protectant via the production of ATP.
