April 17, 2008
Ubiquitous in nature—found in every living organism—ubiquinone, also known as coenzyme Q10 (CoQ10), plays a number of important roles in the body. The lipid-soluble enzymatic cofactor plays a key role in cellular energy production, and its reduced form in the body, ubiquinol, is a potent lipophilic antioxidant that can both protect against oxidative damage and help regenerate other antioxidants. Perhaps the only thing more ubiquitous than its appearance is the ongoing controversy surrounding its health effects, bioavailability and quality.
CoQ10 was discovered by Frederick L. Crane, Ph.D., at the University of Wisconsin in the late 1950s during his research on the biochemistry of the mitochondrial electron transport chain. Crane isolated the pure substance from beef heart mitochondria, and sent it to Karl Folkers, Ph.D., at Merck for identification and elucidation of its structure. It was designated coenzyme Q10 because of its quinone structure and the ten isoprene unit side chain. During the same time period, English scientists isolated the same substance from mitochondria and named it ubiquinone because of its widespread occurrence in nature.
From its discovery, scientists looked into its role in cellular energy, longevity and the health of such organs as the heart, kidneys and liver. In fact, CoQ10 is responsible for 95 percent of energy expenditure in some areas of cells. Unfortunately, the body’s production of CoQ10 diminishes with age. Young and healthy individuals produce about 300 mg/d of CoQ10, but production levels decline rapidly after age 30.
At the metabolic level, CoQ10 plays an important role in the production of adenosine triphosphate (ATP), the form of energy used by the cells, from carbohydrates and fats. Information from the Linus Pauling Institute (LPI) at Oregon State University noted CoQ10 works as part of the mitochondrial electron transport chain, shuttling fatty acids, glucose molecules and protons across the mitochondrial membrane to release energy to produce ATP. In addition, CoQ10 as ubiquinol is an important cellular antioxidant. LPI’s team stated ubiquinol may inhibit lipid peroxidation, neutralize free radicals and regenerate alpha-tocopherol.
“The CoQ10 molecule has the ability to cycle easily back and forth between the oxidized and reduced forms, and it is this cycling that is essential in enabling the compound to function as an electron carrier,” said Robin Koon, senior vice president, Best Formulations. “Within the cell, CoQ10 (as a redox pair) exists in a 50/50 state between ubiquinone and ubiquinol, in its primary role of making energy. However, when CoQ10 is in blood circulation, waiting to be taken up by individual cells, it exists mostly in the reduced state and is attached to low-density lipoprotein (LDL). In this circulating state, it also acts as an antioxidant.”
Animal products such as beef, pork and chicken are relatively good dietary sources of CoQ10. Organ meats such as heart and muscle are the best sources. As a general rule, tissues with high energy demands contain relatively high amounts of CoQ10. Among foods of plant origin, broccoli and spinach contain significant amounts of CoQ10. Unrefined vegetable oils, such as soybean oil and palm oil, are also good sources of CoQ10. However, it would be impractical to produce industrial quantities of CoQ10 from beef hearts, for example. Instead, CoQ10 is produced by bacterial fermentation or a combination of partial fermentation and synthesis using a chemical called solanesol.
One of the most active areas of research for CoQ10 is in the area of heart health. Because CoQ10 works to prevent oxidation of cholesterol, particularly LDL cholesterol, it may help prevent the onset of atherosclerosis. Indian researchers noted administration of 3 mg/kg/d of CoQ10 (Q-Gel®, from Tishcon) in rabbits with high trans fat levels helped limit oxidative damage and atherosclerosis development.1 Supplementing with a combination of CoQ10 and alpha-tocopherol has been shown to increase plasma levels of vitamin E and beneficial high-density lipoprotein (HDL) cholesterol,2 and reduce atherosclerosis at the aortic root and descending thoracic aorta.3
In addition, reviews suggest CoQ10 may help lower systolic and diastolic blood pressure in hypertension.4,5 In fact, the Natural Standard Patient Monograph on CoQ10 noted there is good scientific evidence for the use of CoQ10 for lowering blood pressure, and that low blood levels of CoQ10 are found in people with hypertension, though there may not be a causal link.
However, the pharmaceutical treatment of high cholesterol may adversely affect the body’s CoQ10 levels. The enzyme hydroxymethylglutaryl (HMG)-CoA reductase plays an important role in regulating cholesterol synthesis; inhibiting this activity is the goal of the statin class of cholesterol-reducing pharmaceuticals. Unfortunately, the same HMG-CoA reductase pathway also regulates CoQ10 synthesis. Italian researchers noted statin treatment generally results in lower plasma levels of CoQ10, possibly related to the fact that the drugs lower levels of LDL, the primary transport molecule for CoQ10; however, there is also a decrease of CoQ10 seen in the platelets and lymphocytes, suggesting CoQ10 synthesis itself may be inhibited.6
Intervention studies with statins have examined the impact of the drugs on CoQ10 levels. A new Japanese open study examined the impact of pitavastatin or atorvastatin on plasma levels of CoQ10 in patients with hypercholesterolemia, and found the drugs did significantly reduce total and LDL cholesterol and increase HDL cholesterol.7 However, treatment with atorvastatin also significantly reduced (-26.1 percent) plasma levels of CoQ10, more so than pitavastatin (-7.7 percent). Similarly, Italian researchers reported three months of statin therapy dose dependently reduced total cholesterol, as well as levels of ubiquinol and ubiquinone in plasma.8 The researchers concluded: “The concomitant administration of ubiquinone with statins, leading to its increase in plasma, lymphocytes and liver may cooperate in counteracting the adverse effects of statins.”
Interestingly, there is a growing interest in the use of statins as an adjunct treatment for heart failure (HF); however, reviewers out of Norway noted low concentrations of cholesterol are generally associated with a worse prognosis in HF patients, possibly because of reduced CoQ10 levels.9
CoQ10 may also be an important neuroprotective agent. Because CoQ10 levels decline with age,10 accelerating precursors of beta-amyloid deposition, CoQ10 supplementation may be preventive against Alzheimer’s disease (AD), Parkinson’s disease (PD) and other neurodegenerative disorders.11 In one study, CoQ10 therapy attenuated amyloid beta-peptide toxicity in brain mitochondria isolated from elderly rats.12 Hong Kong researchers similarly found in a group of 48 mice (four genotypes), those treated with CoQ10 (1,200 mg/d) after ischemic injury for 28 days had amyloid precursor protein mutations and smaller infarct volumes, while the volumes of hemisphere and hippocampus on the infarcted side were larger than those treated with placebo, suggesting CoQ10 could protect the brain from ischemic-related atrophy in aged and susceptible transgenic mice.13
A recent study out of Weill Medical College of Cornell University, New York, found administration of CoQ10 via the diet could protect against the loss of dopamine, exerting neuroprotective effects in a model of PD.14 Japanese researchers also found a link between oxidized CoQ10 levels in cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS), suggesting mitochondrial oxidative damage may play a role in pathogenesis of ALS.15
Researchers are also examining CoQ10’s effects on energy production and athletic performance. Japanese researchers recently reported providing oral CoQ10 (100 or 300 mg/d) to healthy adults for one week prior to a workload trial found CoQ10 could improve subjective fatigue and physical performance.16 Another study out of Japan found CoQ10 supplementation (300 mg/d) reduced exercise-induced muscular injury, possibly due to its antioxidant effects.17 And a trial in 22 aerobically trained and 19 untrained male and female adults who received a placebo or fast-melt CoQ10 supplement for 14 days reported supplementation increased muscle CoQ10 concentration and lowered serum superoxide dismutase (SOD) oxidative stress, while also increasing plasma CoQ10 concentrations and time to exercise exhaustion.18
There are many evolving areas of research as well. There is currently an ongoing FDA- and NIH-funded clinical trial using Tishcon’s liquid ubiquinol (LiQNOL®) in mito-patients. In fact, Tishcon holds orphan drug designation for CoQ10 in the treatment of mitochondrial cytopathies, conditions characterized by defects in the mitochondria often related to DNA mutations.
Further, Scott Steinford, ZMC-USA, reported on new research presented at the International CoQ10 association’s symposium in 2007. “One particularly interesting discovery from scientists at the University of Kiel in Germany showed that CoQ10 protects against an in-vitro model of inflammation,” he said. “Furthermore, through proteomics, these researchers showed a wide area of impact of CoQ10, such as affecting genes that are involved in metabolism of lipids, heme metabolism, and the synthesis of bone tissue.” Steinford added there are 12 federally-funded studies underway researching the effects of CoQ10 relating to issues such as muscular dystrophy, mitochondrial disease and preeclampsia.
Given its health-promoting effects, it is no wonder the market for CoQ10 is on the rise. ZMC-USA estimated there are approximately 6 million U.S. consumers supplementing with CoQ10 daily, and added retail sales data from IRI indicated there was a 19 percent increase in dollar sales volume and a 9 percent increase in unit sales of CoQ10 in 2007.
However, there are several considerations, including absorption, bioavailability, formulation and quality control. “Since CoQ10 is a rather large lipid molecule, it is not easily absorbed,” Koon noted. “CoQ10 is absorbed intestinally via a process known as passive facilitated diffusion. Absorption occurs on a molecular level, which means only single molecules can be absorbed at a time. But the CoQ10 material exists in a crystalline state, meaning it must be dissolved into single molecules in order to be absorbed.”
And the melting point of CoQ10 is almost 20-degrees higher than body temperature; therefore, the standard crystalline (powder) form of CoQ10 has always been poorly absorbed, with absorption of about 1 percent—for every 100 mg of CoQ10 capsule/tablet ingested, the body only absorbs 1 mg.
Raj Chopra, CEO, Tishcon, noted CoQ10’s lipophilic form presents absorption challenges, because it is almost insoluble in aqueous media. “The lack of adequate oral bioavailability of CoQ10 has led to the search for delivery technologies that would render it more water-friendly,” he said. Tishcon, for example, developed the patented BioSolv® process, which involves the use of a nonionic surfactant and a polyhydric alcohol to facilitate the hydrosolubility of CoQ10 (U.S. Patent No. 6,056,971). Other patented systems include the complexation of CoQ10 with cyclodextrins (U.S. Patent No. 6,861,447); the formulation of liposomal dispersions of CoQ10 (U.S. Patent No. 6,445,072); the formulation of self-emulsifying CoQ10 complexes; and numerous other processes.
Soft Gel Technologies Inc. (SGTI) developed its CoQsol® and CoQsol-CF™ formulations, using a lipid-based soft gel delivery system, to increase absorption. In a randomized, placebo-controlled study, researchers determined the differences in steady state absorption over a 30-day period (60 mg/d) and five-hour peak absorption characteristics (30 mg) between CoQsol and dry CoQ10 powder in a two-piece hard shell capsule. After 30 days supplementation, the average basal blood CoQ10 levels for the CoQsol group increased by 165 percent, compared to an 80 percent increase in the dry powder group. Further, in the five hour trial portion, 30 mg of CoQsol increased peak absolute CoQ10 levels by 0.48 µg/ml blood compared to an increase of 0.19 µg/ml for the subjects taking 30 mg dry CoQ10 powder. CoQsol-CF was the subject of a pilot clinical trial, in which supplementation with 60 mg/d increased mean CoQ10 plasma levels by 200 percent over 28 days.
Best Formulations created a proprietary, patent-pending, lipid tri-blend formulation to produce Q-BEST™, a 100-percent crystal-free form of CoQ10; the proprietary treatment of the lipid tri-blend keeps the CoQ10 solubilized and enhances absorption. The formula underwent an IRB-registered human clinical trial on absorption. Results of the 36 hour peak absorption study showed Q-BEST had a total absorption of 11.65 percent, compared to dry powder with an absorption of 1.32 percent. In addition, results of a 28-day steady state study showed at the end of the intervention, there were 8,989 mcg of Q-BEST available for use by the cells, compared to 1,623 mcg of dry powder.
Kaneka has also supported research on the safety and bioavailability of its CoQ10 ingredients. In one study, conducted out of Haradoi Hospital, researchers assessed the safety of Kaneka Q10 in a double blind, placebo-controlled, randomized study in 88 healthy adults.19 Kaneka Q10 in capsule form was taken for four weeks at doses of 300, 600 and 900 mg/d; no serious adverse events were reported, and adverse events were even across the placebo and intervention groups and judged to have no relationship to Kaneka Q10. Plasma CoQ10 concentration after eight-month withdrawal was almost the same as before administration.
In a second study, Kaneka researchers evaluated the safety and bioavailability of ubiquinol (as Kaneka QH™) in a single blind, placebo-controlled study; healthy volunteers received a single oral dose of 150 or 300 mg, and then oral administration of 90, 150 or 300 mg/d for four weeks.20 There were no clinically relevant changes in standard lab tests, while mean plasma ubiquinol concentration-time curves increased non-linearly after single administration. There was also significant absorption seen, in non-linear dose fashion, over the four week study.
In addition to testing bioavailability, companies are also committing to studying the safety of their CoQ10 ingredients in a variety of matrices. Several firms are now offering GRAS (generally recognized as safe) CoQ10 ingredients for use in food and beverage products. Robert Berman, senior marketing manager, DSM, noted the company’s ALL-Q® is both self-affirmed GRAS and certified OU Kosher. Kaneka’s Q10 is also self-affirmed GRAS, as are offerings from Blue California and Asahi Kasei Pharma Corp.
Whether they’re putting CoQ10 into foods or supplements, manufacturers must be mindful of certain processing limitations when working with CoQ10. “Ubiquinone is susceptible to degradation when exposed to elevated temperatures and to light for prolonged periods,” Chopra said. “In the case of ubiquinol, the situation is very critical because the least bit of exposure of ubiquinol to atmospheric oxygen can lead to its oxidation to ubiquinone. One needs to operate in an inert (nitrogen) atmosphere and employ suitable formulation technologies, such as our patented technology that employs ascorbyl palmitate as an antioxidant.”
Finally, there is the issue of quality control. “When there was a shortage of CoQ10, many sellers of raw materials were selling other forms (e.g., CoQ9, etc.) or adulterated material,” Koon recalled. “Testing is the only way to be sure of the purity and quality of the material. CoQ10 also occurs in two isomeric forms. The material called natural CoQ10 is in the trans form, whereas the synthetic CoQ10 contains a mixture of both trans and cis isomers. USP limits the presence of other CoQ10 analogs and the cis-isomer and related impurities to less than 1.5 percent. The cis isomer can only be created in a synthetic process in the laboratory or as a by-product of manufacturing.”
Chopra added companies seeking exclusively natural CoQ10 should test for the absence of the synthetic cis isomer, while also assessing the material’s quality via testing. “The quality of CoQ10 ingredients can be verified by subjecting it to U.S. Pharmacopoeia (USP) monograph testing,” he said. “If the raw material passes all the tests, it can be considered a good quality material.”
Rising consumer interest, combined with greater raw material availability and stable pricing, will yield continued growth for CoQ10. Steinford noted, “CoQ10 remains a dynamic ingredient with a promising future. While CoQ10 is currently considered one of the most clinically studied ingredients on the market, the reality of new studies indicates the likelihood of more positive news and support of CoQ10.”
Editor's Note: A full list of references begins on the next page.
1. Singh RB et al. "Effect of coenzyme Q10 on experimental atherosclerosis and chemical composition and quality of atheroma in rabbits." Atherosclerosis. 2000;148(2):275-82.
2.Singh RB et al. "Effect of coenzyme Q10 on risk of atherosclerosis in patients with recent myocardial infarction." Mol Cell Biochem. 2003;246(1-2):75-82.
3. Thomas SR et al. "Dietary cosupplementation with vitamin E and coenzyme Q(10) inhibits atherosclerosis in apolipoprotein E gene knockout mice." Arterioscler Thromb Vasc Biol. 2001;21(4):585-93.
4. Rosenfeldt F et al. "Systematic review of effect of coenzyme Q10 in physical exercise, hypertension and heart failure." Biofactors. 2003;18(1-4):91-100.
5. Houston MC. "The role of vascular biology, nutrition and nutraceuticals in the prevention and treatment of hypertension." JANA. S1:5-71, 2002.
6. Littarru GP, Langsjoen P. “Coenzyme Q10 and statins: biochemical and clinical implications.” Mitochondrion. 2007 Jun;7 Suppl:S168-74.
7. Kawashiri MA et al. “Comparison of Effects of Pitavastatin and Atorvastatin on Plasma Coenzyme Q10 in Heterozygous Familial Hypercholesterolemia: Results from a Crossover Study.” Clin Pharmacol Ther. 2007 Oct 24; ePub ahead of print.
8. Passi S et al. “Statins lower plasma and lymphocyte ubiquinol/ubiquinone without affecting other antioxidants and PUFA.” Biofactors. 2003;18(1-4):113-24.
9. Gullestad L et al. “The role of statins in heart failure.” Fundam Clin Pharmacol. 2007 Nov;21 Suppl 2:35-40.
10. Willis R et al. "Clinical implications of the correlation between coenzyme Q10 and vitamin B6 status." Biofactors. 1999;9(2-4):359-63.
11. Joseph JA, et al “Reversals of Age-Related Declines in Neuronal Signal Transduction, Cognitive, and Motor Behavioral Deficits with Blueberry, Spinach, or Strawberry Dietary Supplementation.” J Neurosci. 1999;19:8114-8121.
12. Moreira PI et al. "CoQ10 therapy attenuates amyloid beta-peptide toxicity in brain mitochondria isolated from aged diabetic rats." Exp Neurol. 2005;196(1):112-9.
13.Li G, Zou L, “Neuroprotective effect of Coenzyme Q10 on ischemic hemisphere in aged mice with mutations in the amyloid precursor protein” Neurobiol Aging. 2007;28(6):877-82.
14. Cleren C et al. “Therapeuticl effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of Parkinsonism.” J Neurochem. 2008 Mar;104(6):1613-21.
15. Murata T, Ohtsuka C, Terayama Y. “Increased mitochondrial oxidative damage and oxidative DNA damage contributes to the neurodegenerative process in sporadic amyotrophic lateral sclerosis.” Free Radic Res. 2008 Mar;42(3):221-5.
16. Mizuno K et al. “Antifatigue effects of coenzyme Q10 during physical fatigue.” Nutrition. 2008 Apr;24(4):293-299.
17. Kon M et al. “Reducing exercise-induced muscular injury in kendo athletes with supplementation of coenzyme Q10.” Br J Nutr. 2008 Feb 20;1-7.
18. Cooke M et al. “Effects of acute and 14-day coenzyme Q10 supplementation on exercise performance in both trained and untrained individuals.” J Int Soc Sports Nutr. 2008 Mar 4;5(1):8.
19. Ikematsu H et al. “Safety assessment of coenzyme Q10 (Kaneka Q10) in healthy subjects: A double-blind, randomized, placebo-controlled trial.” Regul Toxicol Pharmacol. 2006;44:21218.
20. Hosoe K et al. “Study on safety and bioavailability of ubiquinol (Kaneka QH™) after single and 4-week multiple oral administration to healthy volunteers.” Regul Toxicol Pharmacol. 2007;47:19-28.
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