Coenzyme Q: The Ubiquitous Quinone
Part I
This article first appeared in the
September, 1993
issues of VRP's Newsletter
Coenzyme Q: The Ubiquitous Quinone Part
I
Coenzyme
Q: The Ubiquitous Quinone Part II
Coenzyme
Q: The Ubiquitous Quinone Part III
by A.S. Gissen
Introduction
Coenzyme Q (CoQ), also known as ubiquinone, is a naturally-occurring
substance classified as a fat-soluble quinone with characteristics that are
common to vitamins. Its chemical structure is similar to that of vitamin K,
and it is found naturally in the tissues of animals and plants. Coenzyme Q is
one of the substances in the chain of reactions which produces energy in the
metabolism of food. Because of the necessity of CoQ for energy production,
almost every cell of a living organism contains CoQ. The CoQ content varies
in different organs, being highest in those that produce large amounts of
energy. In humans, CoQ is found in relatively high amounts in the heart,
liver, kidney, and pancreas.(1) CoQ helps drive the mitochondrial energy
production vital to all body functions. The functioning of all organs depends
on each cell having adequate levels of CoQ to provide life-sustaining energy.
Structure and Function
Coenzyme Q was first discovered in 1957 by Dr. Frederick Crane and his
associates at the Enzyme Institute of the University of Wisconsin, when it
was isolated from beef heart and shown to be essential in the process of
bioenergetics.(2) A year later, Dr. Karl Folkers and his coworkers at Merck
& Co., Inc., had succeeded in establishing its structure. The structure
of the Coenzyme Q molecule is that of a quinone with an isoprenoid
side-chain, the number of isoprene units in the side chain varies with each
species of animal or plant. Humans contain Coenzyme Q10, which has 10
isoprene units.
Coenzyme Q is one of a family of brightly colored substances (quinones) that
are widely distributed in nature because they are essential for generating
energy in living things that use oxygen. The name ubiquinone was derived from
the ubiquitous nature of these quinones. Coenzyme Q is a true coenzyme. A
coenzyme is a substance that is necessary for, or enhances, the function of
an enzyme. Bioenergy enzymes are necessary for a cell to generate energy from
its food substances. The cell then uses this energy for its life processes.
Coenzyme Q is an essential coenzyme for several of these bioenergy enzymes.
In cells, the process of generating energy takes place within the
mitochondria, which are the energy-producing structures. In the mitochondria,
molecules of coenzyme Q continually shuttle between bioenergy enzymes,
transporting protons and electrons from one bioenergy enzyme to another.
Cells in the body must continuously generate energy to support their
function, and this process depends on each cell having adequate amounts of
CoQ with which to generate this energy.
With such a fundamental role in energy production, it would be expected that
deficiencies of CoQ would be detrimental to the bodies ability to function
properly. Since CoQ is indispensably involved in the complex mechanism of
respiration, including ATP formation, it is evident that a significant
deficiency of CoQ in cellular respiration may have some detrimental effect
upon the life processes dependent on energy, including mechanical,
electrical, transport work, and biosynthesis. This deficiency could be
reflected by one or more disease states, depending on the location and degree
of the cellular deficiency of CoQ. Therefore, it is not surprising that CoQ
deficiency has been linked to such diverse conditions as heart disease, heart
failure, hypertension, muscular dystrophy, cancer, physical performance and
athletics, diabetes, obesity, periodontal disease, aging, immune function,
cellular antioxidant protection, and brain function.
Occurence and Distribution
CoQ10 in the human body is thought to be provided not only by its
biosynthesis in the body, but also from dietary intake of CoQ from food.(3)
However, it is not clear how much exogenous CoQ contributes to maintain the
body stores of CoQ10. Since CoQ is found in many foods, and is biosynthesized
within the human body, the question of whether a dietary source of CoQ is
essential has been considered. CoQ is found in almost all foodstuffs, albeit
in small quantities. Wheat germ and rice bran are fair sources of CoQ, as is
soy and some other beans. Vegetables are fairly low in CoQ, although spinach
and broccoli are good sources. The major sources of CoQ in the human diet,
however, are meats, fish, and vegetable oils. Soybean, sesame, and rapeseed
oils are high in CoQ10, while corn oil is high in CoQ9. The average person
consumes approximately 5 milligrams a day of CoQ, a level insufficient to
obtain sufficient CoQ for their needs. The remainder of the CoQ10 needed by
the body is synthesized in the cells, especially within the liver.
The production of CoQ10 in the body is a complex process. At least 15
different reactions are necessary (each catalyzed by an enzyme), as well as a
number of cofactor substances including vitamins B3, B5, B6, B12, C, and
folate.(4) In spite of its complex manufacture, most CoQ10 is made within the
body. There is good evidence, however, that dietary CoQ contributes
significantly to the endogenous body-pool of CoQ10. This has been shown in
patients receiving total parenteral nutrition (TPN) that contains no CoQ. In
these patients, who are dependent totally on endogenous CoQ10 synthesis,
CoQ10 levels dropped by almost 50% within 1 week on a diet free of CoQ.(5)
These levels remained depressed for the 12 weeks of the study. This
represents good evidence that dietary sources are indeed a significant
contributor to the body pool of CoQ10.
Bioenergetics and the Heart
The discovery of Coenzyme Q, as well as its function, structure, and ultimate
synthesis, was made in America. The structure was elucidated, and CoQ10 was
synthesized by Dr. Karl Folkers at Merck & Co. However, Merck & Co.
decided not to pursue CoQ10 commercially. This gave the Japanese an
opportunity to produce CoQ10 by synthesis in 1964, and ultimately, by
fermentation in 1977. CoQ10 was clinically developed by the Eisai Co., Ltd.,
to treat congestive heart failure, and it was approved in 1974 by the
Japanese government.
In 1977, a critique of CoQ10 in biochemical and biomedical research, and of
ten years of clinical research with CoQ10 on cardiovascular disease, was
published.(5) This paper was written to make known the clinical results
published in Japan, from ten years of studying the administration of CoQ10 to
cardiac patients. These 24 studies encompassed clinical data from 110 physicians
in 41 medical institutions. The consensus from this decade of clinical
research indicated a therapeutic benefit in about 75% of the patients having
congestive heart failure. In addition, essential hypertension and angina
pectoris appeared to have been improved by treatment with CoQ10. As a result
of these studies, the Japanese government approved CoQ10 to treat congestive
heart failure in 1974. By 1982, it was among the five most widely-used drugs
in Japan. Despite a lack of interest in the US pharmaceutical industry, CoQ
research began in earnest in the late 1970's with the availability of
inexpensive, mass-produced CoQ10 from Japan. The vast majority of this
research was conducted by independent researchers, as no US pharmaceutical
company was interested in developing a non-patentable, natural compound like
CoQ10, regardless of its potential.
In a 1985 review article, a total of 67 clinical studies involving some 1353
patients that had been treated for heart and blood vessel disease were
presented. In these studies, CoQ10 was tested against heart muscle disease,
arrhythmias, damage to the heart from drugs, high blood pressure, and
stroke.(6) In those patients with heart muscle disease, approximately 75%
showed meaningful clinical improvement. In fact, a study published in 1990
showed that CoQ10 significantly improved the survival of cardiomyopathy
patients compared to treatment with traditional drugs.(7) After 3 years, 24%
of the patients on conventional treatment were alive, while 75% of the CoQ10
patients were alive. In addition, most patients with mild cardiomyopathy
became normal on CoQ10 therapy. These studies also indicated that CoQ10 could
successfully treat patients with arrhythmias, angina, ischaemic heart
disease, stroke, and high blood pressure. In an animal model of
cardiomyopathy, CoQ10 was found superior to digoxin, a traditional drug of
choice, in attenuating disease progression.(8) Additionally, a recently
published study showed that heart failure patients who were candidates for a
heart transplant, and were instead treated with CoQ10, improved
significantly.(9) All patients improved, with many requiring no conventional
drugs and having no limitations on life-style.
Although CoQ10
has proven to be an effective treatment for congestive heart failure, two
other nutrients have proven to be synergistic with CoQ10 in the treatment of
congestive heart failure. These nutrients, carnitine and taurine, are similar
to CoQ10 in being consumed in the diet, and produced by the body. Carnitine
has been shown to be synergistic and complementary to CoQ in energetic
metabolism, providing improvements in energy production that CoQ10 or
carnitine alone are incapable of.(10) Taurine, on the other hand, resulted in
improvements in congestive heart failure that were not observed in CoQ10
treated patients, although both groups improved.(11) These results with
taurine are particularly interesting, as it has been known for some time that
taurine deficiency in cats results in dilated cardiomyopathy, and cat food is
now supplemented with taurine to prevent this affliction. There seems little
doubt that in the case of heart failure, the utilization of CoQ10, carnitine,
and taurine would be a useful and effective combination.
Beyond its well researched and approved (in Japan, Italy, Sweden, Denmark,
and Canada) indication for congestive heart failure, CoQ10 is an important
component in other aspects of cardiovascular health. To begin with, CoQ10
treatment reduces blood viscosity in patients with ischaemic heart
disease.(12) This is something that more dangerous blood-thinning drugs are
usually used for. Additionally, dietary supplementation with CoQ10 results in
increased levels of CoQ10 within circulating lipoproteins, and increased
resistance of human low-density lipoprotein (LDL) to the initiation of lipid
peroxidation.(13) This may have far reaching implications for the development
and progression of atherosclerosis, as oxidized LDL has been directly
implicated in the pathogenesis of artery blockage and coronary artery
disease.
The rationale for the use of CoQ10 treatment to provide protection for the
heart in ischaemic cardiovascular syndromes was initially provided by animal
studies which showed that CoQ10 pretreatment provided significant protection
to the ischaemic myocardium (heart muscle).(14) Based on these positive
results in animal studies, human clinical trials were initiated. A number of
clinical trials using CoQ10 in chronic stable angina have been reported. The
results of a double-blind study comparing oral CoQ10 to placebo showed that
exercise time before distress was significantly increased in the CoQ10
treated group.(15) Another study showed that CoQ10 caused a significant
reduction in cumulative exercise-induced electrocardiogram (ECG)
abnormalities when compared to placebo.(16) In this study, CoQ10 also caused
a reduction in exercise-induced systolic blood pressure from placebo values.
It appears that CoQ10 treatment may allow ischaemic tissue to reach higher
levels of energy expenditure before the onset of symptoms or exercise-induced
ECG changes. The conclusion of these studies is that CoQ10 has a favorable
effect on exercise tolerance with minimal adverse reactions.
One of the serious complications of cardiac surgery is the damage caused to
the myocardium. During many cardiac surgical procedures the heart tissue is
rendered ischaemic, due to lack of blood flow during surgery. Subsequently,
the heart is reperfused when blood flow is resumed. It is during this
reperfusion phase that much of the damage to the heart muscle takes place.
The consequence of this damage is usually manifested by post-reperfusion
arrhythmias and low cardiac output. It has been demonstrated that both damage
secondary to reperfusion and post-reperfusion arrhythmias can be inhibited by
pretreatment with CoQ10.(17) Because of its ability to protect myocardial
tissue during ischaemic reperfusion, CoQ10 has been evaluated in patients
undergoing cardiac surgery. CoQ10 pretreatment significantly reduced the
incidence of low cardiac-output postoperatively.(18) CoQ10 has also been
evaluated in patients undergoing coronary-artery bypass surgery. It was found
that the CoQ10 treated group had significantly higher cardiac output, lower
requirements for post-surgical drug support, and significantly lower levels
of creatine phosphokinase-MB (an indicator of heart tissue damage).(19)
Several different classes of pharmaceuticals have side-effects that include
negative impacts on heart function. Some of these drugs, such as doxorubicin
(a powerful anti-cancer drug) have cardiovascular effects so severe that they
are strictly limited in their use by the extent to which the patients
heart-function deteriorates while taking the drug. Others, like some
psychotropics such as phenothiazine neuroleptics and tricyclic
antidepressants, have a less severe effect on heart function; this cardiac
side-effect, however, often makes their continued use dangerous or
impossible. Even drugs such as beta-blockers, which are used to lower blood
pressure and protect the cardiovascular system, have been shown to interfere
with the production and function of CoQ10, and detrimentally effect heart
function. In the case of doxorubicin, it was shown that the negative effects
of this drug on heart function was due to its inhibitory effects on
CoQ10-dependent enzyme systems.(20) Subsequent to this discovery, it was
shown in cancer patients treated with doxorubicin that patients pretreated
with CoQ10 had a reduction in doxorubicin's cardiotoxicity.(21)
Interestingly, the use of CoQ10 with doxorubicin results in a two-fold
increase of anti-tumor activity, in addition to CoQ10's ability to reduce
side-effects.(22) In fact, this combination therapy may allow larger, and
thus more effective, doses of doxorubicin to be administered before
cardiotoxicity becomes a problem.
Undesirable cardiac effects have often been reported from the clinical use of
phenothiazine neuroleptics and tricyclic antidepressants.(23) ECG
abnormalities and arrhythmias appear to be the predominant cardiac
abnormalities caused by these drugs, although heart failure and infarction
are not uncommon. Furthermore, there have been increasing reports of sudden
unexplained death with the administration of psychotropic drugs. CoQ10
reversed most effectively the inhibition of CoQ10-dependent enzymes caused by
phenothiazines and most tricyclic antidepressants, and improved
electrocardiographic changes in patients on psychotropic drugs.(23) One of
the most commonly used classes of drugs in medicine are the beta-blockers.
These drugs, used for the control of high blood pressure, are generally
considered to be safe and effective. These drugs, however, are known to have
antagonistic activities for CoQ10-dependent enzymes.(24) Since CoQ10 also
lowers blood pressure in hypertensive patients, it would seem logical that
the combination of beta-blockers with CoQ10 would be a particularly effective
treatment, both for better control of blood pressure and the prevention of
CoQ10 inhibition by the beta-blocker. In fact, this combined modality has
been extensively reviewed, and found to be successful.(24)
Of all the drugs that have been found to lower the activity of
CoQ10-dependent enzymes, none is more troubling than a class of drugs known
as HMG-CoA reductase inhibitors. In recent years, these drugs have gained
wide clinical acceptance as safe and effective treatments for elevated
cholesterol. One of the more popular drugs in this category is known as lovastatin,
although there are numerous others being developed as pharmaceuticals both in
the US and abroad. These drugs work by inhibiting an enzyme known as HMG-CoA
reductase, and they are very effective in lowering cholesterol levels.
However, this enzyme is responsible not only for the production of
cholesterol, but also for the production of CoQ10. Thus, the cholesterol
lowering effect of these drugs is mirrored by an equivalent lowering of
CoQ10. In patients with existing heart failure, lovastatin causes increased
cardiac disease.(25) This deterioration was life-threatening for some
patients. Interestingly, those patients given oral supplements of CoQ10 along
with lovastatin had an improvement of cardiac function when compared to the
patients given only lovastatin. There is evidence, however, that HMG-CoA
reductase inhibitors cause morphological and physiological changes in cells
that are not prevented by the replacement of CoQ10.(26) Indeed, the long-term
effects of this class of drugs may indeed be very negative, keeping in mind
the detrimental effects of lowering the body's CoQ10 levels. Not
surprisingly, known side effects of these drugs include liver dysfunction and
heart failure. Ironically, supplements of CoQ10 have been shown to lower
cholesterol levels by feedback inhibition of HMG-CoA reductase.(27) Although
the cholesterol lowering effect of CoQ10 awaits definitive proof in
controlled studies, it may someday prove to be an interesting and healthful
alternative to currently available cholesterol-lowering drugs.
References: Part I
1) B.O. Linn, A.C. Page, E.L. Wong, et al, J Am Chem Soc 1959; 81:4007-4010.
2) F.L. Crane, Y. Hatefi, R.L. Lester, et al, Biochim Biophys Acta 1957; 25:
220-221.
3) T. Kishi, T. Okamoto, H. Kishi, et al, In: K. Folkers and Y. Yamamura
(eds.), Biochemical and Clinical Aspects of Coenzyme Q, Vol. 5. Elsevier
Science Publishers, Amsterdam. 1985, p. 119-123.
4) P.M. Kidd, W. Huber, F. Summerfield, et al, Coenzyme Q10: Essential Energy
Carrier and Antioxidant. H.K. Biomedical Consultants, Berkeley. 1988, p.3.
5-a) See reference 3.
5-b) K. Folkers, T. Watanabe, M. Kaji, J Mol Med 1977; 2: 431-460.
6) Y. Yamamura, In: G. Lenaz (ed.), Coenzyme Q, John Wiley & Sons, Ltd.,
1985, p.479.
7) P.H. Langsjoen, P.H. Langsjoen, K. Folkers, In: K. Folkers, G.P. Littarru,
and T. Yamagami (eds.), Biochemical and Clinical Aspects of Coenzyme Q, Vol.
6. Elsevier Science Publichers, Amsterdam. 1991, p. 241-246.
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10) A. Bertelli, G. Ronca, Int J Tissue React 1990; 12: 183-186.
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14) W.G. Nayler, In: Y. Yamamura, K. Folkers and Y. Ito (eds.), Biochemical
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Biomedical Press Amsterdam. 1980, p. 409-425.
15) T. Kamikawa, A. Kobayashi, T. Yamashita, et al, Am J Cardiol 1985;
56:247. 16) F. Shardt, D. Welzel, W. Scheiss, et al, In: K. Folkers and Y.
Yamamura (eds.), Biochemical and Clinical Aspects of Coenzyme Q, Vol. 5.
Elsevier Science Publishers, Amsterdam. 1985, p. 385-394.
17) S. Nagai, Y. Miyazuki, K. Ogawa, et al, J Mol Cell Cardiol 1985; 17:873.
18) J. Tanaka, R. Tominaga, M.D. Yoshitoshi, et al, Ann Thorac Surg 1982; 33:
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19) M. Sunamori, T. Okamura, J. Amano, et al, In: K. Folkers and Y. Yamamura
(eds.), Biochemical and Clinical Aspects of Coenzyme Q, Vol. 4. Elsevier /
North Holland Biomedical Press, Amsterdam. 1984, p. 333-342.
20) Y. Iwamoto, I.L. Hansen, T.H. Porter, et al, Biochem Biophys Res Commun
1974; 58:633.
21) K. Folkers, L. Baker, P.C. Richardson, et al, In: K. Folkers and Y.
Yamamura (eds.), Biochemical and Clinical Aspects of Coenzyme Q, Vol. 3.
Elsevier / North Holland Biomedical Press, Amsterdam. 1981, p. 399-412.
22) N. Yamanaka, T. Kato, K. Nishida, et al, In: Y.Yamamura, K. Folkers, and
Y. Ito (eds.), Biochemical and Clinical Aspects of Coenzyme Q, Vol. 2.
Elsevier/ North Holland Biomedical Press, Amsterdam. 1980, P. 213-224.
23) T. Kishi, K. Makino, T. Okamoto, et al, In: Y. Yamamura, K. Folkers, and
Y. Ito (eds.), Biochemical and Clinical Aspects of Coenzyme Q, Vol. 2.
Elsevier / North Holland Biomedical Press, Amsterdam. 1980, p. 139-157.
24) K. Folkers, In: G. Lenaz (ed.), Coenzyme Q, John Wiley & Sons, Ltd.,
New York. 1985, p. 476.
25) K. Folkers and Per Langsjoen, In: K. Folkers, K. Folkers, G.P. Littarru,
and T. Yamagami (eds.), Biochemical and Clinical Aspects of Coenzyme Q, Vol.
6. Elsevier Science Publishers, Amsterdam. 1991, p. 449-452.
26) M. Bifulco, C. Laezza, S.M. Aloj, et al, J Cell Physiol 1993; 155:
340-348.
27) R.V. Omkumar, A.S. Gaikwad, T. Ramasarma, Biochem Biophys Res Commun
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