Coenzyme Q10

Coenzyme Q10
Names
IUPAC name
2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-Decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.005.590
UNII
Properties
C59H90O4
Molar mass 863.37 g·mol−1
Appearance yellow or orange solid
Melting point 48–52 °C (118–126 °F; 321–325 K)
insoluble
Pharmacology
C01EB09 (WHO)
Related compounds
Related quinones
 1,4-Benzoquinone
Plastoquinone
Ubiquinol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Coenzyme Q10, also known as ubiquinone, ubidecarenone, coenzyme Q, and abbreviated at times to CoQ10 /ˌkoʊˌkjuːˈtɛn/, CoQ, or Q10 is a coenzyme that is ubiquitous in animals and most bacteria (hence the name ubiquinone). It is a 1,4-benzoquinone, where Q refers to the quinone chemical group and 10 refers to the number of isoprenyl chemical subunits in its tail.

This fat-soluble substance, which resembles a vitamin, is present in all respiring eukaryotic cells, primarily in the mitochondria. It is a component of the electron transport chain and participates in aerobic cellular respiration, which generates energy in the form of ATP. Ninety-five percent of the human body's energy is generated this way.[1][2] Therefore, those organs with the highest energy requirements—such as the heart, liver, and kidney—have the highest CoQ10 concentrations.[3][4][5]

There are three redox states of CoQ10: fully oxidized (ubiquinone), semiquinone (ubisemiquinone), and fully reduced (ubiquinol). The capacity of this molecule to act as a two-electron carrier (moving between the quinone and quinol form) and a one-electron carrier (moving between the semiquinone and one of these other forms) is central to its role in the electron transport chain due to the iron–sulfur clusters that can only accept one electron at a time, and as a free-radical–scavenging antioxidant.

Deficiency and toxicity

There are two major factors that lead to deficiency of CoQ10 in humans: reduced biosynthesis, and increased use by the body. Biosynthesis is the major source of CoQ10. Biosynthesis requires at least 12 genes, and mutations in many of them cause CoQ deficiency. CoQ10 levels also may be affected by other genetic defects (such as mutations of mitochondrial DNA, ETFDH, APTX, FXN, and BRAF, genes that are not directly related to the CoQ10 biosynthetic process). The role of statins in deficiencies is controversial.[6] Some chronic disease conditions (cancer, heart disease, etc.) also are thought to reduce the biosynthesis of and increase the demand for CoQ10 in the body, but there are no definite data to support these claims.

Usually, toxicity is not observed with high doses of CoQ10. A daily dosage up to 3,600 mg was found to be tolerated by healthy as well as unhealthy persons.[7] Some adverse effects, however, largely gastrointestinal, are reported with very high intakes. The observed safe level (OSL) risk assessment method indicated that the evidence of safety is strong at intakes up to 1200 mg/day, and this level is identified as the OSL.[8]

Clinical assessment

Although CoQ10 may be measured in blood plasma, these measurements reflect dietary intake rather than tissue status. Currently, most clinical centers measure CoQ10 levels in cultured skin fibroblasts, muscle biopsies, and blood mononuclear cells.[6] Culture fibroblasts can be used also to evaluate the rate of endogenous CoQ10 biosynthesis, by measuring the uptake of 14C-labelled p-hydroxybenzoate.[9]

Inhibition by statins and beta blockers

CoQ10 shares a biosynthetic pathway with cholesterol. The synthesis of an intermediary precursor of CoQ10, mevalonate, is inhibited by some beta blockers, blood pressure-lowering medication,[10] and statins, a class of cholesterol-lowering drugs.[11] Statins can reduce serum levels of CoQ10 by up to 40%.[12]

Supplementation

CoQ10 is not approved by the U.S. Food and Drug Administration (FDA) for the treatment of any medical condition.[13] It is sold as a dietary supplement. In the U.S., supplements are not regulated as drugs, but as foods. How CoQ10 is manufactured is not regulated and different batches and brands may vary significantly.[13]

A 2004 laboratory analysis by ConsumerLab.com of CoQ10 supplements on the market found that some did not contain the quantity identified on the product label. Amounts varied from "no detectable CoQ10", to 75% of stated dose, and up to a 75% excess.[14]

Generally, CoQ10 is well tolerated. The most common side effects are gastrointestinal symptoms (nausea, vomiting, appetite suppression, and stomachaches), rashes, and headaches.[15]

While there is no established ideal dosage of CoQ10, a typical daily dose is 100–200 milligrams. Note that different supplement brands may have varying ingredients and strengths [16]

Heart disease

A 2014 Cochrane Collaboration meta-analysis found "no convincing evidence to support or refute" the use of CoQ10 for the treatment of heart failure.[17] However, a 2013 meta-analysis showed that "supplementation with CoQ10 resulted in a pooled mean net change of 3.67% (95% CI: 1.60%, 5.75%) in the ejection fraction, and -0.30 (95% CI: -0.66, 0.06) in the New York Heart Association functional class".[18] Evidence with respect to preventing heart disease in those who are otherwise healthy is also poor.[19]

Another 2014 study of 420 patients in 17 patient centers over 7 years found that it "improves symptoms, and reduces major adverse cardiovascular events" after 106 weeks.[20]

A 2016 Cochrane review concluded that studies looking at the effects of CoQ10 on blood pressure provided moderate-quality evidence that coenzyme Q10 does not lower blood pressure.[21]

Huntington's disease

Available evidence suggests that "CoQ10 is likely ineffective in moderately improving" the chorea associated with Huntington's disease.[22]

Male infertility

While CoQ10 can improve some measurements regarding sperm quality, there is no evidence that CoQ10 increases live births or pregnancy rates.[23]

Migraine headaches

Supplementation of CoQ10 has been found to have a beneficial effect on the condition of some sufferers of migraine. An explanation for this is the theory that migraines are a mitochondrial disorder,[24] and that mitochondrial dysfunction can be improved with CoQ10.[25] The Canadian Headache Society guideline for migraine prophylaxis recommends, based on low-quality evidence, that 300 mg of CoQ10 be offered as a choice for prophylaxis.[26]

Statin myopathy

CoQ10 has been routinely used to treat muscle breakdown associated as a side effect of use of statin medications. However, evidence from randomized controlled trials does not appear to support the idea that CoQ10 is an effective treatment for statin myopathy.[27]

Cancer

No large well-designed clinical trials of CoQ10 in cancer treatment have been done.[13] The National Cancer Institute identified issues with the few, small studies that have been done stating, "the way the studies were done and the amount of information reported made it unclear if benefits were caused by the CoQ10 or by something else".[13] The American Cancer Society has concluded, "CoQ10 may reduce the effectiveness of chemo and radiation therapy, so most oncologists would recommend avoiding it during cancer treatment."[28]

Dental disease

A 1995 review study found that there is no clinical benefit to the use of CoQ10 in the treatment of periodontal disease.[29] Most of the studies suggesting otherwise were outdated, focused on in vitro tests,[30][31][32] had too few test subjects and/or erroneous statistical methodology and trial setup,[33][34] or were sponsored by a manufacturer of the product.[35]

Drug interactions

Coenzyme Q10 has potential to inhibit the effects of warfarin (Coumadin), a potent anticoagulant, by reducing the INR, a measure of blood clotting. The structure of coenzyme Q10 is very much similar to the structure of vitamin K, which competes with and counteracts warfarin's anticoagulation effects. Coenzyme Q10 should be avoided in patients currently taking warfarin due to the increased risk of clotting.[15]

Chemical properties

The oxidized structure of CoQ10 is shown on the top-right. The various kinds of Coenzyme Q may be distinguished by the number of isoprenoid subunits in their side-chains. The most common Coenzyme Q in human mitochondria is CoQ10. Q refers to the quinone head and 10 refers to the number of isoprene repeats in the tail. The molecule below has three isoprenoid units and would be called Q3.

Coenzyme Q3

Biosynthesis

Biosynthesis occurs in most human tissue. There are three major steps:

  1. Creation of the benzoquinone structure (using phenylalanine or tyrosine)
  2. Creation of the isoprene side chain (using acetyl-CoA)
  3. The joining or condensation of the above two structures

The initial two reactions occur in mitochondria, the endoplasmic reticulum, and peroxisomes, indicating multiple sites of synthesis in animal cells.[36]

An important enzyme in this pathway is HMG-CoA reductase, usually a target for intervention in cardiovascular complications. The "statin" family of cholesterol-reducing medications inhibits HMG-CoA reductase. One possible side effect of statins is decreased production of CoQ10, which may be connected to the development of myopathy and rhabdomyolysis.

Genes involved include PDSS1, PDSS2, COQ2, and ADCK3 (COQ8, CABC1).[37]

Increasing the endogenous biosynthesis of CoQ10 has gained attention in recent years as a strategy to fight CoQ10 deficiency.

Absorption and metabolism

Absorption

CoQ10 is a crystalline powder insoluble in water. Absorption follows the same process as that of lipids; the uptake mechanism appears to be similar to that of vitamin E, another lipid-soluble nutrient. This process in the human body involves secretion into the small intestine of pancreatic enzymes and bile, which facilitates emulsification and micelle formation required for absorption of lipophilic substances.[38] Food intake (and the presence of lipids) stimulates bodily biliary excretion of bile acids and greatly enhances absorption of CoQ10. Exogenous CoQ10 is absorbed from the small intestine and is best absorbed if taken with a meal. Serum concentration of CoQ10 in fed condition is higher than in fasting conditions.[39][40]

Metabolism

Data on the metabolism of CoQ10 in animals and humans are limited.[41] A study with 14C-labeled CoQ10 in rats showed most of the radioactivity in the liver two hours after oral administration when the peak plasma radioactivity was observed, but CoQ9 (with only 9 isoprenyl units) is the predominant form of coenzyme Q in rats.[42] It appears that CoQ10 is metabolised in all tissues, while a major route for its elimination is biliary and fecal excretion. After the withdrawal of CoQ10 supplementation, the levels return to normal within a few days, irrespective of the type of formulation used.[43]

Pharmacokinetics

Some reports have been published on the pharmacokinetics of CoQ10. The plasma peak can be observed 2–6 hours after oral administration, depending mainly on the design of the study. In some studies, a second plasma peak also was observed at approximately 24 hours after administration, probably due to both enterohepatic recycling and redistribution from the liver to circulation.[38] Tomono et al. used deuterium-labeled crystalline CoQ10 to investigate pharmacokinetics in humans and determined an elimination half-time of 33 hours.[44]

Improving the bioavailability of CoQ10

The importance of how drugs are formulated for bioavailability is well known. In order to find a principle to boost the bioavailability of CoQ10 after oral administration, several new approaches have been taken; different formulations and forms have been developed and tested on animals and humans.[41]

Reduction of particle size

Nanoparticles have been explored as a delivery system for various drugs, such as improving the oral bioavailability of drugs with poor absorption characteristics.[45] However, this protocol has not proved successful with CoQ10, although reports have differed widely.[46][47] The use of aqueous suspension of finely powdered CoQ10 in pure water also reveals only a minor effect.[43]

Soft-gel capsules with CoQ10 in oil suspension

A successful approach was to use the emulsion system to facilitate absorption from the gastrointestinal tract and to improve bioavailability. Emulsions of soybean oil (lipid microspheres) could be stabilised very effectively by lecithin and were used in the preparation of soft gelatin capsules. In one of the first such attempts, Ozawa et al. performed a pharmacokinetic study on beagles in which the emulsion of CoQ10 in soybean oil was investigated; about twice the plasma CoQ10 level than that of the control tablet preparation was determined during administration of a lipid microsphere.[43] Although an almost negligible improvement of bioavailability was observed by Kommuru et al. with oil-based softgel capsules in a later study on dogs,[48] the significantly increased bioavailability of CoQ10 was confirmed for several oil-based formulations in most other studies.[49]

Novel forms of CoQ10 with increased water-solubility

Facilitating drug absorption by increasing its solubility in water is a common pharmaceutical strategy and also has been shown to be successful for CoQ10. Various approaches have been developed to achieve this goal, with many of them producing significantly better results over oil-based softgel capsules in spite of the many attempts to optimize their composition.[41] Examples of such approaches are use of the aqueous dispersion of solid CoQ10 with the polymer tyloxapol,[50] formulations based on various solubilising agents, such as hydrogenated lecithin,[51] and complexation with cyclodextrins; among the latter, the complex with β-cyclodextrin has been found to have highly increased bioavailability.[52][53] and also is used in pharmaceutical and food industries for CoQ10-fortification.[41] Also some other novel carrier systems, such as liposomes, nanoparticles or dendrimers, may be used to increase the bioavailability of CoQ10.

History

CoQ10 was first discovered by Fredrick L. Crane and colleagues at the University of Wisconsin–Madison Enzyme Institute in 1957.[54][55] In 1958, its chemical structure was reported by Karl Folkers and coworkers at Merck. In the early 1970s Gian Paolo Littarru and Karl Folkers observed that a deficiency of CoQ10 was associated with human heart disease.[56][57][58] The 1980s witnessed a steep rise in the number of clinical trials due to the availability of large quantities of pure CoQ10 and methods to measure plasma and blood CoQ10 concentrations. The redox functions of CoQ in cellular energy production and antioxidant protection are based on the ability to exchange two electrons in a redox cycle between ubiquinol (reduced CoQ) and ubiquinone (oxidized CoQ).[59][60] The antioxidant role of the molecule as a free-radical scavenger was widely studied by Lars Ernster. Numerous scientists around the globe started studies on this molecule since then in relation to various diseases including cardiovascular diseases and cancer.

Dietary concentrations

Detailed reviews on occurrence of CoQ10 and dietary intake were published in 2010.[61] Besides the endogenous synthesis within organisms, CoQ10 also is supplied to the organism by various foods. Despite the scientific community's great interest in this compound, however, a very limited number of studies have been performed to determine the contents of CoQ10 in dietary components. The first reports on this aspect were published in 1959, but the sensitivity and selectivity of the analytical methods at that time did not allow reliable analyses, especially for products with low concentrations.[61] Since then, developments in analytical chemistry have enabled a more reliable determination of CoQ10 concentrations in various foods:

CoQ10 levels in selected foods[61]
FoodCoQ10 concentration (mg/kg)
Beef heart113
liver39–50
muscle26–40
Pork heart12–128
liver23–54
muscle14–45
Chicken breast8–17
thigh 24–25
wing 11
Fish sardine5–64
mackerel:
- red flesh43–67
- white flesh11–16
salmon4–8
tuna5
Oils soybean54–280
olive4–160
grapeseed64–73
sunflower4–15
canola64–73
Nuts peanut27
walnut19
sesame seed18–23
pistachio20
hazelnut17
almond5–14
Vegetables parsley8–26
broccoli6–9
cauliflower2–7
spinachup to 10
Chinese cabbage2–5
Fruit avocado10
blackcurrant3
grape6–7
strawberry1
orange1–2
grapefruit1
apple1
banana1

Meat and fish are the richest sources of dietary CoQ10; levels over 50 mg/kg may be found in beef, pork, chicken heart, and chicken liver. Dairy products are much poorer sources of CoQ10 compared to animal tissues. Vegetable oils also are quite rich in CoQ10. Within vegetables, parsley and perilla are the richest CoQ10 sources, but significant differences in their CoQ10 levels may be found in the literature. Broccoli, grapes, and cauliflower are modest sources of CoQ10. Most fruit and berries represent a poor to very poor source of CoQ10, with the exception of avocados, which have a relatively high CoQ10 content.[61]

Intake

In the developed world, the estimated daily intake of CoQ10 has been determined at 3–6 mg per day, derived primarily from meat.[61]

Effect of heat and processing

Cooking by frying reduces CoQ10 content by 14–32%.[62]

See also

  • Idebenone – synthetic analog with reduced oxidant generating properties
  • MitoQ – mitochondrion-targeted version of CoQ10 with increased bioavailability and efficacy

References

  1. ↑ Ernster, L.; Dallner, G. (1995). "Biochemical, physiological and medical aspects of ubiquinone function". Biochimica et Biophysica Acta. 1271 (1): 195–204. doi:10.1016/0925-4439(95)00028-3. PMID 7599208.
  2. ↑ Dutton, P. L.; Ohnishi, T.; Darrouzet, E.; Leonard, M. A.; Sharp, R. E.; Cibney, B. R.; Daldal, F.; Moser, C. C. (2000). "4 Coenzyme Q oxidation reduction reactions in mitochondrial electron transport". In Kagan, V. E.; Quinn, P. J. Coenzyme Q: Molecular mechanisms in health and disease. Boca Raton: CRC Press. pp. 65–82.
  3. ↑ Okamoto, T.; Matsuya, T.; Fukunaga, Y.; Kishi, T.; Yamagami, T. (1989). "Human serum ubiquinol-10 levels and relationship to serum lipids". International Journal for Vitamin and Nutrition Research. 59 (3): 288–292. PMID 2599795.
  4. ↑ Aberg, F.; Appelkvist, E. L.; Dallner, G.; Ernster, L. (1992). "Distribution and redox state of ubiquinones in rat and human tissues". Archives of Biochemistry and Biophysics. 295 (2): 230–234. doi:10.1016/0003-9861(92)90511-T. PMID 1586151.
  5. ↑ Shindo, Y.; Witt, E.; Han, D.; Epstein, W.; Packer, L. (1994). "Enzymic and non-enzymic antioxidants in epidermis and dermis of human skin". Journal of Investigative Dermatology. 102 (1): 122–124. doi:10.1111/1523-1747.ep12371744. PMID 8288904.
  6. 1 2 Trevisson, E.; Dimauro, S.; Navas, P.; Salviati, L. (Oct 2011). "Coenzyme Q deficiency in muscle". Current Opinion in Neurology. 24 (5): 449–456. doi:10.1097/WCO.0b013e32834ab528. PMID 21844807.
  7. ↑ Hyson, H. C.; Kieburtz, K.; Shoulson, I.; et al. (Sep 2010). "Safety and tolerability of high-dosage coenzyme Q10 in Huntington's disease and healthy subjects". Movement Disorders. 25 (12): 1924–1928. doi:10.1002/mds.22408. PMID 20669312.
  8. ↑ Hathcock, J. N.; Shao, A. (Aug 2006). "Risk assessment for coenzyme Q10 (Ubiquinone)". Regulatory Toxicology and Pharmacology. 45 (3): 282–288. doi:10.1016/j.yrtph.2006.05.006. PMID 16814438.
  9. ↑ Montero, R.; Sánchez Alcázar, J. A.; Briones, P.; et al. (Jun 2008). "Analysis of coenzyme Q10 in muscle and fibroblasts for the diagnosis of CoQ10 deficiency syndromes". Clinical Biochemistry. 41 (9): 697–700. doi:10.1016/j.clinbiochem.2008.03.007. PMID 18387363.
  10. ↑ Kishi, T.; Watanabe, T.; Folkers, K. (1977). "Bioenergetics in clinical medicine XV. Inhibition of coenzyme Q10-enzymes by clinically used adrenergic blockers of beta-receptors". Research Communications in Chemical Pathology and Pharmacology. 17 (1): 157–164. PMID 17892.
  11. ↑ Mortensen, S. A.; Leth, A.; Agner, E.; Rohde, M. (1997). "Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors". Molecular Aspects of Medicine. 18 (Suppl.): S137–S144. doi:10.1016/S0098-2997(97)00014-9. PMID 9266515.
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  20. ↑ Mortensen, Svend A.; Rosenfeldt, Franklin; Kumar, Adarsh; Dolliner, Peter; Filipiak, Krzysztof J.; Pella, Daniel; Alehagen, Urban; Steurer, Günter; Littarru, Gian P. (Dec 2014). "The Effect of Coenzyme Q10 on Morbidity and Mortality in Chronic Heart Failure". Heart Failure. American College of Cardiology Foundation (6): 641–649.
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  25. ↑ Yorns, W. R.; Hardison, H. H. (Sep 2013). "Mitochondrial dysfunction in migraine". Seminars in Pediatric Neurology. 20 (3): 188–193. doi:10.1016/j.spen.2013.09.002. PMID 24331360.
  26. ↑ Pringsheim, T.; Davenport, W.; Mackie, G.; et al. (Mar 2012). "Canadian Headache Society guideline for migraine prophylaxis". Canadian Journal of Neurological Science. 39 (2 Suppl. 2): S1–S59. PMID 22683887.
  27. ↑ Banach, M.; Serban, C.; Sahebkar, A.; Ursoniu, S.; Rysz, J.; Muntner, P.; Toth, P. P.; Jones, S. R.; Rizzo, M.; Glasser, S. P.; Lip, G. Y.; Dragan, S; Mikhailidis, D. P. (Jan 2015). "Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials". Mayo Clinic Proceedings (Systematic Review and Meta-Analysis). Lipid and Blood Pressure Meta-analysis Collaboration Group. 90 (1): 24–34. doi:10.1016/j.mayocp.2014.08.021. PMID 25440725.
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  29. ↑ Watts, T. L. P. (1995). "Coënzyme Q10 and periodontal treatment: is there any beneficial effect?". British Dental Journal. Department of Periodontology and Preventive Dentistry, UMDS, Guy's Hospital London. 178 (6): 209–213. doi:10.1038/sj.bdj.4808715. PMID 7718355.
  30. ↑ Folkers, K.; Hanioka, T.; Xia, L.; McRee, J., Jr; Langsjoen, P. (1991). "Coenzyme Q10 increases T4/T8 ratios of lymphocytes in ordinary subjects and relevance to patients having the aids related complex". Biochemical and Biophysical Research Communications. 176 (2): 786–791. doi:10.1016/S0006-291X(05)80254-2. PMID 1673841.
  31. ↑ Littarru, G. P.; Nakamura, R.; Ho, L.; Folkers, K.; Kuzell, W. C. (Oct 1971). "Deficiency of Coenzyme Q10 in Gingival Tissue from Patients with Periodontal Disease". Proceedings of the National Academy of Sciences. 68 (10): 2332–2335. doi:10.1073/pnas.68.10.2332. PMC 389415. PMID 5289867.
  32. ↑ Nakamura, R.; Littarru, G. P.; Folkers, K.; Wilkinson, E. G. (Apr 1974). "Study of CoQ10-Enzymes in Gingiva from Patients with Periodontal Disease and Evidence for a Deficiency of Coenzyme Q10". Proceedings of the National Academy of Sciences. 71 (4): 1456–1460. doi:10.1073/pnas.71.4.1456. PMC 388248. PMID 4151519.
  33. ↑ McRee, J. T.; Hanioka, T.; Shizukuishi, S.; Folkers, K. (1993). "Therapy with coenzyme Q10 for patients with periodontal disease". Journal of Dental Health. 43 (5): 659–666. doi:10.5834/jdh.43.659.
  34. ↑ Hanioka, T.; Tanaka, M.; Ojima, M.; Shizukuishi, S.; Folkers, K. (1994). "Effect of topical application of coenzyme Q10 on adult periodontitis". Molecular Aspects of Medicine. 15 (Suppl.): S241–S248. doi:10.1016/0098-2997(94)90034-5. PMID 7752836.
  35. ↑ Wilkinson, E. G.; Arnold, R. M.; Folkers, K. (1976). "Bioenergetics in clinical medicine. VI. adjunctive treatment of periodontal disease with coenzyme Q10". Research communications in chemical pathology and pharmacology. 14 (4): 715–719. PMID 785563.
  36. ↑ Bentinger, M.; Tekle, M.; Dallner, G. (May 2010). "Coenzyme Q—biosynthesis and functions". Biochemical and Biophysical Research Communications. 396 (1): 74–79. doi:10.1016/j.bbrc.2010.02.147. PMID 20494114.
  37. ↑ Espinós, Carmen; Felipo, Vicente; Palau, Francesc (2009). Inherited Neuromuscular Diseases: Translation from Pathomechanisms to Therapies. Springer. pp. 122ff. ISBN 978-90-481-2812-9. Retrieved 4 Jan 2011.
  38. 1 2 Bhagavan, Hemmi N.; Chopra, Raj K. (2006). "Coenzyme Q10: Absorption, tissue uptake, metabolism and pharmacokinetics". Free Radical Research. 40 (5): 445–453. doi:10.1080/10715760600617843. PMID 16551570.
  39. ↑ Bogentoft 1991
  40. ↑ Ochiai, A.; Itagaki, S.; Kurokawa, T.; Kobayashi, M.; Hirano, T.; Iseki, K. (Aug 2007). "Improvement in intestinal coenzyme Q10 absorption by food intake". Yakugaku Zasshi. 127 (8): 1251–1254. doi:10.1248/yakushi.127.1251. PMID 17666877.
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  42. ↑ Kishi, H.; Kanamori, N.; Nisii, S.; Hiraoka, E.; Okamoto, T.; Kishi, T. (1964). "Metabolism and Exogenous Coenzyme Q10 in vivo and Bioavailability of Coenzyme Q10 Preparations in Japan". Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam: Elsevier. pp. 131–142.
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