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Coenzyme Q10 (Ubiquinone) : Implications
in Clinical Practice
Deepak Langade*, Pratibha Tarapure#, Abhay Jagtap**,
Preeti Arora***, Sanjeev Anand*** |
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INTRODUCTION |
Coenzyme Q10 (CoQ10) is a lipophilic compound naturally
found throughout the body. It is an endogenously synthesized
provitamin that serves as a lipid soluble electron carrier
in the mitochondrial electron transport.1 The alternative
names ubidecarenone and ubiquinone, meaning ubiquitous
quinone, allude to the presence of CoQ10 in all cells.2
The cellular effects of CoQ10 may be important in patients
with cardiac diseases especially coronary artery disease
and congestive cardiac failure. It has been used as an
adjunctive therapy for various cardiovascular conditions
and in some countries it is available as over-the-counter
nutritional supplement.
Coenzyme-Q exists in several forms and can be found in
microorganisms, plants and mammals including humans. Co-enzymes
q6, q7, q8 are found in yeast and bacteria whereas co
enzyme q9 is found in rats and mice. CoQ10 is prevalent
in humans, with high endogenous concentration found in
the heart, liver, kidney and pancreas. Current CoQ10 supplements
are manufactured by the fermentation of beets and sugarcane.
It can be synthesized in the body therefore CoQ10 is
not considered to be an essential nutrient. It is present
in foods such as beef, poultry and broccoli.3 Other sources
of CoQ10 are soy oil, fish oils, peanuts, sardines and
mackerel. Dietary intake of CoQ10 is 2-5 mg per day, which
is always inadequate to provide levels in the body required
to be beneficial in pathological states. The total body
content of CoQ10 is 0.4 to 1.5 gm..
Chemistry
Chemically CoQ10 is 2, 3 dimethoxy - 5 methyl
- 6 decaprenyl benzoquinones. It is a naturally occurring
fat-soluble quinone ubiquitous in eukaryotic cells. (Fig.
1).
Synthesis
CoQ10 is synthesized in almost all tissues in
the body from the amino acid “Tyrosine”. The
biosynthesis of the compound is multifold, with the isoprenyl
side chain deriving from mevolonate, the benzoquinone
ring structure from tyrosine, and condensation of these
structures through polyprenyl transferase enzyme activity.4
The primary regulation of CoQ10 biosynthesis is the 3
hydroxy-methyl glutaryl coenzyme a, (HMG-COA) reductase
reaction that is similar in cholesterol synthesis. (Fig.
2).
History
CoQ10 was first isolated from beef heart mitochondria by Dr. Frederick Crane of University of Wisconsin, USA in 1957, Professor Morton introduced the name ubiquinone, meaning the ubiquitous quinone.1 In 1958, professor Karl Folkers and coworkers determined the precise chemical tructure of CoQ10 as 2, 3, dimethoxy-5 methyl-6 decaprenyl benzoquinones synthesized and were the first to produce it by fermentation.
In 1960, professor Yamamura of Japan became the first in the world to use coenzyme q7 a related Compound in the treatment of human diseases viz. congestive heart failure.
In 1978, Peter Mitchell received the Noble prize for his contribution to the understanding of biological energy transfer through the formulation of the chemiosmotic theory, which includes the vital proton motive role of CoQ10 in energy transfer systems. |
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Mechanism of Action
CoQ10 is a lipid soluble benzoquinone with a 10-isoprenyl
unit side chain, is structurally similar to vitamin-K5.
It is an essential component in the synthesis of ATP and
exhibits both anti-oxidants and membrane stabilizing property.
CoQ10 acts as a redox link between flavoproteins and cytochromes
that are needed for oxidative phosphorylation and synthesis
of ATP. It serves as an electron transport carrier during
the processes of respiration and oxidative phosphorylation.
Thus, it is involved in the manufacture of ATP. CoQ10
directly regulates NADH and succinate dehyrogenase, enabling
reversible reactions between these enzymes in the mitochondrial
electron transport chain. CoQ10 must be reduced to ubiquinol
to wield its anti-oxidative function, and supplementation
with CoQ10 may inhibit lipid oxidizability.
Coenzyme-Q participates in the electron transport inside
the mitochondria of the cell, thus either hydrogen ions
or electrons are gained or lost by CoQ10. It serves as
an electron acceptor for one group of enzymes and as an
electron donor to the next group of enzymes in the electron
transport chain. It helps transport electron from complex-i
to complex-ii and from complex-ii to complex-iii. The
[H]+ accumulated in the intermembrane space of mitochondria
is driven back into the mitochondria matrix via ATP syntheses
(complex-v) with formation of ATP.
Other mechanisms of action may include stabilization
of calcium dependent slow channels, inhibition of intracellular
phospholipases, and alteration of prostaglandin metabolism.5
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Physiological role of CoQ10 |
I. CoQ10 as Energizer
CoQ10 participates in the electron transport inside the
mitochondria of the cell, thus either H+ or e- are gained
or lost by CoQ10. It serves as an electron acceptor for
one group of enzymes and as an electron donor to the next
group of enzymes in the electron transport chain.
ATP synthase is like a turbine where higher concentrations
of H+ leads to more energy trapping and ATP formation
and vice-versa. CoQ10 is the important coenzyme responsible
for taking up electrons and pushing H+ into the intermembrane
space.
Thus, CoQ10 is an essential component in the ATP synthesis
in the mitochondria and high concentrations of CoQ10 can
increase the total utilization of energy released by the
metabolic processes in the body; whereas deficiency of
which may lead to loss of energy generated during the
metabolic processes in the form of heat.
It is a central rate-limiting constituent of the mitochondrial
respiratory chain, which generates most of the ATP within
the cell. Thus CoQ10 acts as an energizer where it improves
the efficiency of the cells to utilize all available energy
from its sources. |
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II. Antioxidant effects of CoQ10 |
It is well known that free radicals cause oxidative
damage in various chronic disease states like atherosclerotic
heart disease, hypertension, congestive heart failure,
diabetes mellitus, ischaemia reperfusion injury, dyslipidaemia
and many other conditions.
Free radicals are the substances, which have one or more
unpaired electrons. These unpaired electrons can easily
react with cell components to cause free radicals injury
or oxidative damage. The unutilized oxygen in the body
can lead to the formation of free oxygen radicals viz.
Suproxide anion (O2-), Hydroxyl radicals (OH-).
Various drugs, chemicals, pesticides, industrial pollutants,
tobacco smoke, sunlight and ionizing radiation can generate
free radicals; whereas in the body they are being constantly
formed in the lysosomes, peroxisomes, endoplasmic reticulum,
plasma membrane and the cytoplasm. Free radicals bring
about modulation of inflammatory process by regulating
prostaglandin synthesis.
Free radicals have high propensity to damage cellular
DNA leading to activation of carcinogenesis. They also
lead to fatty acid peroxidation and damage to the cell
architecture and function. They also damage the various
cellular metabolic processes and interfere with ion channels
located on the cells.
CoQ10 acts as an antioxidant by decreasing formation
of free radicals. It improves the transport of electrons
(e-) and protons (H+) and thus prevents the formation
of superoxide radicals that would otherwise form from
the released O2. It itself is a strong directly acting
endogenous antioxidant. It acts as a substrate for free
radicals and accepts the free electrons from free radicals;
gets converted to reduced CoQ (Ubiquinol), thus rendering
free radicals into harmless compounds. Reduced CoQ10 then
gives up electrons and gets reactivated again for further
activity. CoQ10 is found to regenerate the oxidized Vitamin-E
thus converting it into a strong antioxidant. |
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III. Other possible roles of CoQ |
It may be involved in maintenance of cell membrane
integrity of RBCs and maintains optimum blood viscosity.
It stabilizes the calcium channels and may promote apoptosis
in malignant cells and may improve the immune status of
patients.
Pharmacokinetics
Absorption
In animal studies CoQ10 has an oral bioavailability
of 2-3%. With high doses of dietary CoQ10, the blood concentration
in both rats and humans can be increased about 2 to 4-fold.
Following ingestion of 100 mg of CoQ10,peak plasma levels
occur between 5 and 10 hours. Tmax is approximately 6.5
hours, which indicates slow absorpiton from the GI tract
possibly due to the high molecular weight and low water
solubility of CoQ10.2 Uptake of dietary CoQ10 in the liver
does not affect the synthesis of endogenous CoQ10.
Distribution
The mean plasma levels after a single 100 mg
oral dose of CoQ10 in human subjects is 1.004 ±
0.37 mg/ml. In humans, CoQ10 is found in relatively high
concentrations in the heart, liver, kidney, and pancreas.6
The plasma half-life of CoQ10 in different tissues varies
between 49-125 hours.7 Following absorption from the GI
tract, CoQ10 is taken up by chylomicrons. The major portion
of an exogenous dose of CoQ10 is deposited in the liver
and packaged into VLDL lipoprotein.
Metabolism and Excretion
It is assumed that metabolism and excretion of exogenous
CoQ10 is analogous to endogenously produced CoQ10. The
excretion of CoQ10 predominantly occurs via the biliary
tract. |
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Role in pathological conditions |
Role in CHF
Coenzyme Q10 supplementation as an adjunct to CHF standard
therapy is reported to have positive outcomes, especially
in patients with deficient levels of the provitamin. Heart
failure often is characterized by an energy depletion
status that has been associated with low endogenous CoQ10
levels. The possible usefulness of the CoQ10 in the treatment
of CHF may be related to its ability to increase ATP synthesis
and enhancement of myocardial contractility.5
As with other muscle types, cardiac muscle fibres require
calcium for contraction and relaxation, and more energy
is required for relaxation. These cells rely heavily on
fat sources of energy and hence contain more mitochondria.
Since energy synthesis (ATP Synthesis) from fats requires
a higher oxygen concentration, mitochondria function in
the cardiac myocytes can be significantly impaired in
deficiency of CoQ10. Therefore, administration of CoQ10
increases the energy synthesis in the mitochondria and
significantly improves the cardiac function (contraction
and relaxation), decreases end diastolic ventricular pressure
and improves the ejection fraction in CHF.
Thus, therapy with CoQ10 may be considered to be an efficacious
aid in the traditional treatment of chronic congestive
heart failure along with other agents used in CHF. CoQ10
administration has shown to reduce the signs and symptoms
of CHF like oedema, pulmonary rales, cyanosis, hepatomegaly
and breathlessness on exertion.
CoQ10 is also useful in patients with hypertension, cardiac
transplantation, cardiac bypass surgery, cardiomyopathies
and ischaemic heart disease. In patients of dyslipidaemia
who are on statins, which decrease cholesterol synthesis
by HMG-CoA reductase inhibition, there is an apparent
deficiency of CoQ10 and concurrent CoQ10 administration
in such patients significantly improves the cellular function
and reduces the complications of dyslipidaemia. CoQ10
also reduces the ischaemia-reperfusion injury seen in
patients recovering from myocardial ischaemia. Its antioxidant
properties contribute to prevention of lipid peroxidation,
which alleviates the oxidative stress inherent in CHF.
Patients with severe CHF, i.e. NYHA class III and IV tend
to have lower levels of endogenous CoQ10 than that of
patients with NYHA class-I CHF or healthy subjects.5 Thus,
patients with severe diseases may be more likely to attain
a favourable clinical response to CoQ10 supplementation.
Studies reported clinical benefits from short-term (1-4
wks) and long-term (3 months - 6 yrs) therapy with oral
CoQ10 supplements, 50-100 mg/day, added to conventional
therapy in patients with severe CHF (NYHA class III and
IV).4,5,8-11 Two large multicenter, open-label studies
evaluated the efficacy and safety of CoQ10 as adjuvant
therapy in CHF. The two studies examined a total of more
than 4000 patients with varying severity of CHF (i.e.
patients with NYHA class II and III and class III and
IV CHF) who experienced clinical improvement in signs
and symptoms such as cyanosis, oedema, pulmonary rales,
dyspnoea, and palpitations.12,13
Role in angina
The mechanism for improved exercise tolerance in patients
with stable angina may be due to ischaemic myocardial
protection by CoQ10, allowing tissue to reach higher levels
of energy expenditure.5 Possible activities of the coenzyme
in the maintenance of oxidative phosphorylation, enhancement
of ATP synthesis, or reduction of free radicals formation
create distinctions between the anti-anginal effects of
CoQ10 and the effects of other agents such as nitrates,
calcium channel blockers, or b-adrenergic blockers. The
ability of exogenous CoQ10 to protect the ischaemic myocardium
and reduce or delay signs and symptoms of angina is suggested
by six small randomized, double-blind, placebo-controlled
studies involving patients with stable angina pectoris.14,15-19
All of these studies determined that CoQ10 dosages of
60-600 mg/day significantly prolonged exercise duration,
reduced exercise-induced ischaemic ST-segment depression,
and delayed the onset of stable angina pectoris when compared
with placebo.
Role in hypertension
These effect of CoQ10 to decrease blood pressure is attributed
to the correction of endogenous pro-vitamin deficiency.20,21
In a study of hypertensive rats, a deficiency in the activity
of succinate de-hydrogenase CoQ10 reductase in leucocytes
was found. Deficient activity of this enzyme can result
in decreased levels of CoQ10.22 Having identified same
deficiency in human subject with chronic hypertension,
investigators conducted a pilot study in which they concluded
that increased succinate dehydrogenase CoQ10 reductase
activity and subsequent increased CoQ10 level lead to
decreases in systolic and diastolic blood pressures.20,23
Statistically significant decreases in systolic and diastolic
blood pressure were observed with CoQ10 dosages ranging
from 30-360 mg/day in patients with hypertension but these
results are not consistent among the trials.20,21,24-29
Male infertility
Three important parameters in infertility are count, morphology
and motility of sperm cells. The sperm count and morphology
may be adversely affected due to damage by free radicals.
The reduced sperm motility is the consequence of decrease
in energy production ATP. CoQ10 has been found to be useful
in idiopathic asthenozoospermia, which is loss or decrease
of sperm motility in semen. In Jan 2004 a study was conducted
to evaluate role of CoQ10 in male infertility. In this
study subjects with history of primary infertility received
200 mg twice daily of CoQ10 for 6 months. At the end of
study period CoQ10 levels in seminal plasma and phosphatidylcholine
increased significantly. Motility of sperm cells also
increased from 9.13% to 16.34%.
Testicular tissue and sperm viability are particularly
vulnerable to peroxidation injury produced by free radicals
and reactive oxygen species. Increased lipid peroxidation
of sperm leads to its damage and thereby causing infertility.
The reasons why sperms are vulnerable to damaging effects
of these are: wide surface of the sperm membranes, poor
cytoplasmic defense mechanisms, lack of protection in
the female genital tract once the sperms are ejaculated.
Whenever there is oligoasthenozoospermia, the available
sperm also have a high chance of being damaged by free
radicals.
Asthenospermia and ATP
The main concentration of mitochondria in the sperm is
in its midpiece. The sperm motility is directly dictated
by its ability to generate ATP, which in turn is dependent
on CoQ10 production. The motility of sperm requires a
high-energy expenditure, and hence optimal mitochondrial
ATP generation plays an important role in sperm motility.30
Just before ovulation, the quantity of water and mucus
increases in the living cells of the cervix in female.
The water and salt interact with the glycoproteins present
in mucus to form crystal. This is called ferning and,
as a result of the latter channels is formed in mucus,
which only allows sperms, which are normal, and possess
adequate motility, to navigate successfully so as to reach
the ovum for fertilization in the optimal 69 minutes of
time. CoQ10 encourages better sperm viability due to proving
protection against the damaging effects of reactive oxygen
species, and also by enhancing sperm motility. The CoQ10
concentration in serum is usually 0.081-1.066 mmol, and
good correlation has been demonstrated between these levels
and sperm motility/count.31 Due to its lipophillic nature.
CoQ10 increases the membrane integrity of sperm and increases
defense mechanism of the sperm. Because of its antioxidant
and free radical scavenging activity, CoQ10 prevents the
sperm from free radical induced damage.
After administration, CoQ10 gets incorporated in the
sperm mitochondria during the process of spermatogenesis.
Since the complete process of spermatogenesis requires
a long time CoQ10 should be administered at least for
a period of 10 to 12 weeks
Side-effects
In therapeutic dosages, CoQ10 has proved to be relatively
devoid of major side effects. The most common adverse
effects are nausea, epigastric pain, diarrhoea, heartburn,
and appetite-suppression. However, the prevalence of these
adverse effects was less than 1% in reported studies.3,5
Gastrointestinal effects of CoQ10 may be lessened with
a dosage reduction or may subside with continued therapy.
Asymptomatic elevations in serum lactate dehydrogenase
and hepatic enzymes were observed and may occur with oral
dosages of CoQ10 in excess of 300 mg/day; however, cases
of serious hepatotoxicity have not been reported.6,35
Clinical relapse was noted on withdrawal of CoQ10, whereas
reinstatement of therapy resulted in improvement.36-37
In one withdrawal study, subsequent onset of fatigue and
dyspnoea indicating clinical relapse occurred in 88% of
16 patients, yet 75% improved and regained their clinical
status with resumption of CoQ10.36
Drug interactions
A drug interaction may occur between HMG-CoA
reductase inhibitors and CoQ10 because the coenzyme is
a byproduct of the cholesterol biosynthetic pathway. Use
of HMG-CoA reductase inhibitors (statins i.e. simvastatin,
pravastatin, lovastatin) may result in the diminution
of CoQ10 blood levels due to interruption of synthesis.38-41
Other antilipidaemic agents such as cholestyramine of
fibrate derivatives do not appear to affect CoQ10 concentrations.40
The oral antidiabetic agents (i.e., acetohexamide, glyburide,
phenformin, and tolazamide) may inhibit enzymes (e.g.,
NADH and succinate dehydrogenase) resulting in reductions
in serum CoQ10 levels.42
CoQ10 is structurally related to vitamin-K and subsequently
possesses procoagulant effects. The potentially critical
interaction can result as a diminished response to warfarin
therapy. Several reports describe decreases in international
normalized ratio (INR) after the addition of CoQ10 in
patients previously stabilized with warfarin therapy.43
The concomitant use of warfarin and CoQ10 should be avoided
due to the risk of thrombotic complications.
Also, reduced insulin requirements were observed in patients
with diabetes who were taking CoQ10 because it exerts
favourable effects on ATP, which in turn acts as a chemical
energy carrier in the biosynthesis of insulin.42
CoQ10 supplementation in patients with hepatic insufficiency
or biliary obstruction may increase serum CoQ10 levels
because this molecule is metabolized in liver and excreted
primarily through the biliary tract.35
Safety profile of CoQ10 during pregnancy and lactation
has not been established, and interactions between CoQ10
and food, herbs, or other dietary supplements are not
known.
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Conclusions |
CoQ10 administered orally has favourable actions in various
cardiovascular conditions and appears to be safe and well
tolerated in the adult population. A conservative approach
to CoQ10 therapy is to support its use as adjuvant treatment
for CHF, angina or hypertension. Its favourable effects
on ejection fraction, exercise tolerance, cardiac output,
and stroke volume were demonstrated in CHF. These clinically
significant effects may benefit patients with NYHA class
II, III and IV CHF who are using CoQ10 as an adjuvant to
traditional heart failure therapy. Patients with angina
may see prolonged exercise duration and reduced exercise-induced
ST-segment depression with CoQ10. CoQ10 may possibly find
a place in the therapy of parkinsonism, dyslipidaemia, migraine,
male infertility, and atherosclerosis in near future. |
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Acknowledgement |
The authors wish to thank the Dean, Dr. ME Yeolekar, for
granting us permission to publish this report. |
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MICROSCOPIC COLITIS : ONE TO LOOK FOR
In a Swedish population with non-bloody diarrhoea,
nearly 10% had microscopic colitis found on colonoscopy,
a diagnosis missed in the first histological examination.
The incidence of micro-scopic colitis almost matched
that of Crohn’s disease. The cause of microscopic
colitis is unknown. Budesonide and bismuth subsalicylate
may work as initial therapy.
BMJ, 2004; 2055.
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*Lecturer in Pharmacology, **Lucturer in Biochemistry,
***Trainee Intern, Grant Medical College and Sir JJ Group of Hospitals, Mumbai;
#Lecturer in Pharmacology, TN Medical College and BLY Nair Hospital, Mumbai.
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