Ubiquinol, the “Other CoQ10” May Help When Standard Forms Don’t

Over the last decade, many clinicians have embraced Coenzyme Q10 as a key component in their treatment of patients with cardiovascular disease, especially those with congestive heart failure.

As researchers continue to study CoQ10, they are making significant new discoveries suggesting that this vitamin-like substance may also have a role in improving the health of obese individuals, lowering blood pressure, and potentially countering amyloid-beta toxicity in the brain—a key driver of age-related neurodegeneration.

Researchers are also shedding light on the chemistry of CoQ10, which really is two compounds, not one. CoQ10 dynamically cycles between two useful states as either oxidized ubiquinone (the most common form in dietary supplements) or reduced ubiquinol.  This cycle has profound consequences in human metabolism, because the two forms differ greatly in their absorbability and their physiological behavior at the cellular level. Choosing the right form of CoQ10 for a given patient can greatly improve clinical results of supplementation.

Vitamin-like Catalyst

CoQ10 is generally referred to as “ubiquinone” because it is so widely present in plant and animal cells. It has a chemical structure related to that of vitamins E and K. This similarity was noted by Karl Folkers, who in 1958 first described the structure of CoQ10 a year after it was first isolated from beef heart muscle by Prof. Frederick Crane. Folkers demonstrated that CoQ10 possesses vitamin-like catalytic functions, and later documented deficiency of CoQ10 in the myocardium of humans with heart disease.

CoQ10 is part of the mitochondrial electron transport system, and is essential for production of adenosine triphosphate (ATP). It is synthesized in all cells, but holds special importance in the heart, which is spectacularly endowed with mitochondria. Heart muscle has the body’s highest concentration of CoQ10. In descending order of tissue concentration, CoQ10 is also found in the liver, kidney, spleen and pancreas. 

Since the mid-1960’s, Japanese doctors have used CoQ10 as standard therapy in cardiac disorders and dysfunctions. With the now widespread prescription of statin drugs, which inhibit endogenous CoQ10 production, the need for supplementation has grown, especially in people at risk for CHF.  This issue was examined at length in “Metabolic Cardiology:  Solving the Heart’s Energy Crisis” in the Summer 2008 edition of Holistic Primary Care (join www.holisticprimarycare.net for access to this and other archived content).

Ubiquinol vs Ubiquinone

It is only recently that investigators and clinicians have begun to recognize that the reduction status of supplemental CoQ10 is an important determinant of its effect in CHF. The oxidized ubiquinone form is not as easily assimilated as the reduced ubiquinol form, and often fails to deliver the expected clinical benefits. Disproportionate results between the two forms have been observed in exercise-induced fatigue and certain measures of aging in an animal model.

Ubiquinol, the reduced form, is the dominant form of endogenous CoQ10 in the blood, representing some 80% of total circulating CoQ10 (Kontush A., et al. Biofactors. 1999;9:225-9.). Yet until quite recently, virtually all research on oral CoQ10 supplementation utilized ubiquinone, the oxidized form, which suffers from notoriously poor uptake. The body must first reduce ubiquinone to ubiquinol in order for it to work effectively. Much of this reduction takes place in the enterocytes in the gastrointestinal tract during absorption. (Xia S, et al. J Agric Food Chem. 2009 Sept 9;57(17):7989-96.)

The importance of the ubiquinol:ubiquinone ratio shows up clearly in diabetes. Japanese researchers looked at the effects of diabetes on oxidative stress throughout the day. Over the course of the day, levels of oxidative stress increased and the ubiquinol:ubiquinone ratio declined (Hasegaqa G., et al. Acta Diabetol. 2005 Dec;42(4):179-81.), meaning that the relative amount of the reduced form is declining while the oxidized form is increasing.

Research from Singapore indicates that the blood of diabetics may exhibit on the order of 75% lower ubiquinol:ubiquinone ratios compared with non-diabetics.  Similarly, in a recent US study, comparison of minimal risk and high-risk metabolic syndrome groups indicated an increased CoQ redox ratio in the high-risk group (Miles MV, et al. Clin Chim Acta. 2004 Jun;344(1-2):173-9).

Reduced Form Reduces CHF

For clinicians, perhaps the most significant findings regarding ubiquinol involve its efficacy in conditions in which supplemental ubiquinone has not given benefit. 
Dr. Peter Langsjoen, a cardiologist in Tyler, TX, and one of the world’s foremost CoQ10 researchers, studied advanced CHF patients already taking CoQ10 at doses up to 900 mg/day but who failed to increase blood levels above 2 mcg/mL and exhibited very little improvement in ejection fraction. Generally, plasma levels need to reach 4 mcg/mL or more before one can expect benefit in advanced CHF. Dr. Langsjoen’s hypothesis was that impaired absorption of CoQ10 prevented improvements.

To test this, he switched a set of seven patients already taking an average dose of 450 mg/day ubiquinone and who showed a mean serum CoQ10 level of 1.6 mcg/mL to 450 mg/day of ubiquinol with resulting mean plasma levels climbing to 6.5 mcg/mL. The increased plasma concentration correlated with both clinical improvement  and left ventricular function. (Langsjoen PH, Langsjoen AM. Biofactors. 2008;32(1-4):119-28.)  Langsjoen’s findings represent extreme cases, but even under normal circumstances it appears that supplemental ubiquinol over a 4-week period elicits an increased response rate of between 2 and 4 times than found with ubiquinone (Hosoe K., et al. Regul Toxicol Pharmacol. 2007;47(1):19-28).

Keep in mind that both forms of CoQ10 are useful in heart disease. However, the reduced form seems to be much more beneficial in seriously ill patients because intestinal uptake is poor in these patients and ubiquinone absorbed from the GI tract must be reduced to ubiquinol as it passes through the gut wall. This suggests that under circumstances in which there is intestinal edema or gut inflammation, the reduced  ubiquinol form will likely be the better option.

A Role in Obesity & Diabetes?

Clearly useful in managing heart disease, CoQ10 may also be helpful for people struggling with obesity and diabetes. Although not itself a weight-loss agent, it may be helpful for maintaining health in the overweight and in diabetics. There is some evidence that this quasi-vitamin improves pancreatic beta cell response and glycemic control in pre-diabetic and diabetic people (McCarty MF. Med Hypotheses. 2000;54(5):786-93.)  In patients undergoing biliopancreatic diversion as a treatment of obesity, CoQ10 supplementation becomes important for correcting post-surgical metabolic complications (Mancini A, et al.  Metabolism. 2008 Oct;57(10):1384-9).

In an animal model, supplemental CoQ10 (standard ubiquinone) protected against liver damage associated with obesity. In mice fed a high-fat, high-fructose diet, those also receiving supplemental CoQ10 showed lower hepatic inflammatory and metabolic stress markers compared with controls, even though there was no effect on obesity itself or levels of oxidized fat metabolites in other tissues.

The high-fat, high-fructose diet increases reactive oxygen species and inflammation; the supplemental CoQ10 seems to reduce the gene expression underlying this response.  The researchers concluded that CoQ10 given orally is able to target the liver tissue and lessen inflammatory stress associated with obesity independent of any action on lipid peroxidation (Sohet FM, et al. Biochem Pharmacol. 2009 Dec 1;78(11):1391-400). This new finding clearly beckons for exploration in humans.

CoQ10 Slows Senescence, Neurodegeneration

Animal models of senescence and fatigue have helped to tease out the practical implications of supplementation with ubiquinol versus ubiquinone.  In the senescence-accelerated mouse model, at the transition point between middle age and old age (10 months), ubiquinol-supplemented animals were aging 51% slower than placebo-treated mice and 40% slower than those receiving ubiquinone.  At 12 months, which is old age for mice, ubiquinone-treated animals had regressed towards placebo, whereas ubiquinol-treated animals continued to exhibit a 22% slower rate of decline (Yan J, et al. Exp Gerontol. 2006;41(2):130-40.). 

Many researchers have indicated links between neurodegeneration and the steady, age-associated decline in endogenous CoQ10 levels.  Experimentally, CoQ10 therapy attenuates amyloid beta-peptide toxicity in brain mitochondria isolated from aged diabetic rats (Moreira P, et al. Exp Neurol. 2005;196(1):112-9.)  Oral supplementation appears to delay brain atrophy in aged transgenic mice with mutations in the amyloid precursor protein (Li G, et al. Biofactors. 2008;32(1-4):169-78.)  Similar benefits have been shown in experimental models of Parkinsonism (Cleren C, et al. J Neurochem. 2008;104(6):1613-21). These observations also warrant investigation in humans.

Quelling Tocopherol Troubles

Aside from its roles in the mitochondria and Golgi bodies, CoQ10 is present in cell membranes, where it helps to maintain membrane fluidity. It is here that CoQ10 performs some of its antioxidant functions. Cell membranes are largely constructed of lipids, and membrane lipids are often the targets of free radicals.

The alpha-tocopherol form of vitamin E which many people take as an anti-oxidant, can act as a pro-oxidant when taken in excessive amounts. Oral supplementation with alpha-tocopherol taken alone will not only promote cell membrane damage, it can also render serum LDL more prone to oxidation.

Co-supplementation with CoQ10 prevents this pro-oxidant activity of vitamin E, and also provides the lipoprotein with increased resistance to oxidation (Thomas SR, et al.  Arterioscler Thromb Vasc Biol. 1996;16(5):687-96).  Supplementation with alpha-tocopherol actually reduces blood CoQ10 levels (Kaikkonen J, et al. Free Radic Res. 2000;33(3):329-40.).  In order to realize the antioxidant benefits of vitamin E while avoiding potentially harmful reductions in serum and tissue CoQ10, co-supplementation with CoQ10 may be required.

Q10 & BP Regulation

Hypertension is another condition that often responds to CoQ10 supplementation, and the blood pressure regulating effects of CoQ10 seem to be unrelated to its antioxidant effects (Hodgson JM, et al. Eur J Clin Nutr. 2002 ;56(11):1137-42.)  Aging causes structural and functional changes to the vascular walls, resulting in endothelial dysfunction (Matz RL, Andriantsitohaina R. Drugs Aging 2003;20(7)527-50.).

The potential antihypertensive effect was first reported more than 15 years ago. University of Florence researchers studied 26 hypertensive patients treated with 50 mg CoQ10 twice daily for 10 weeks, and found substantial and highly significant hemodynamic changes. Mean systolic pressure decreased from 164.5 +/- 3.1 mmHg at baseline to 146.7 (+/- 4.1) mmHg after 10 weeks on Q10; mean diastolic pressure decreased from 98.1 (+/- 1.7) to 86.1 (+/- 1.3) mmHg (P < 0.001).
The investigators also observed meaningful and beneficial changes in serum lipids: total cholesterol decreased from a mean of 222.9 (+/- 13) mg/dl to 213.3 (+/- 12) mg/dl (P < 0.005), while HDL rose from 41.1 (+/- 1.5) mg/dl to 43.1 (+/- 1.5 mg/dl) ((Digiesi V, et al.  Mol Aspects Med. 1994;15 Suppl:s257-6.).

CoQ10 also exerts a vasodilatory effect and reduces blood viscosity, as has been demonstrated in several clinical trials involving patients with a range of cardiovascular diseases. Kumar and colleagues have just published an excellent review article on these studies (Kumar A, et al.  Pharmacol Ther. 2009 Jul 25. [Epub ahead of print]).

Clinical research on CoQ10 continues to point toward new uses, while confirming more recognized clinical indications. Just as importantly, the recent development of delivery modality of CoQ10 in its reduced form as ubiquinol has opened the possibility of obtaining better clinical outcomes in conditions such as severe heart failure, in which the oxidized form, ubiquinone, has proven less effective than hoped. Ubiquinol, the “other CoQ10,” offers opportunities for greater benefits in heart failure, diabetes and aging in general.

Dallas Clouatre, Ph.D., earned his A.B. from Stanford and his Ph.D. from the University of California at Berkeley.  A Fellow of the American College of Nutrition, he has been a regular contributor to various health publications. He is the author of numerous books, including FAQ:  All About Grapeseed Extract, SAM-e: The Ultimate Methyl Donor, Anti-Fat Nutrients (4th edition) and two chapters in Tocotrienols:  Vitamin E Beyond Tocopherols (Taylor & Francis 2009).

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