Review Coenzyme Q10 in Health and Disease

Review

Coenzyme Q10 in health and disease

K Overvad1*, B Diamant1, L Holm1, G Hùlmer1, SA Mortensen1 and S Stender1

1The Danish Nutrition Council, Sùborg, Denmark

The literature concerning the importance of coenzyme Q10 in health and disease has been reviewed. Usual dietary intake together with normal in vivo synthesis seems to ful®l the demands for Q10 in healthy individuals. The importance of Q10 supplementation for general health has not been investigated in controlled experiments. The literature allows no ®rm conclusions about the signi®cance of Q10 in physical activity. In different cardiovascular diseases, including cardiomyopathy, relatively low levels of Q10 in myocardial tissue have been reported. Positive clinical and haemodynamic effects of oral Q10 supplementation have been observed in double- blind trials, especially in chronic heart failure. These effects should be further examined. No important adverse effects have been reported from experiments using daily supplements of up to 200 mg Q10 for 6 ± 12 months and 100 mg daily for up to 6 y. Descriptors: Coenzyme Q10; health; physical activity; cardiovascular diseases; supplementation

Introduction the mevanolate pathway, and ®nally condensation of these structures by means of the enzyme polyprenyl-transferase, In 1955 ± 1957 two scienti®c groups identi®ed a new possibly in the Golgi apparatus. An essential step regulating substance with a role in electron transport in the cells. the synthesis seems to be the hydroxymethylglutaryl Festenstein et al (1955) named the substance ubiquinone, (HMG)-coenzyme A reductase reaction, common with a while Crane et al (1957) chose the name coenzyme Q. step in cholesterol synthesis, but other steps may also be The name ubiquinone means `ubiquitous quinone' and regulated (Figure 2). relates to the presence of the substance in all cells. The As mentioned, Q plays an important role as electron name coenzyme Q refers to the chemical structure and in 10 and proton transporter in the mitochondria. Circumstances coenzyme Q , the human form, the molecule contains one 10 which change the quantity of Q in the inner mitochondrial quinone group and 10 isoprenyl units. Chemically Q is 10 10 membrane correspondingly change the electron transport designated 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzo- rate, thus in¯uencing the ef®cacy of the ATP production. quinone (Figure 1). In this review the abbreviation `Q ' 10 Q exists both in an oxidised and a reduced form, will be used. 10 ubiquinone and ubiquinol, respectively. Therefore Q Q acts as an electron carrier in the mitochondrial 10 10 also has a role as a lipid soluble antioxidant. Several studies electron transport chain. This aspect will not be in focus have described reduced LDL oxidation in vitro and in vivo in the present review, which concentrates on the health after Q supplementation (Alleva et al, 1995; Kaikkonen effects and the safety of Q as a dietary supplement. 10 10 et al, 1997). A sparing effect on vitamin E as well as a It is characteristic that the major part of the results of the direct anti-oxidative effect has been reported (Stocker et al, early studies regarding Q were not published in recog- 10 1996). nised scienti®c journals, but in separate reports mostly from international symposia. Therefore, part of this literature is not registered in the scienti®c reference data systems. Occurrence Several of the studies concerning Q10 in relation to diseases are not well controlled and conclusions have often been Coenzyme Q has been found in both microorganisms and drawn on insuf®cient data. plants, as well as in animals. Q10 is the most prevalent form in humans and most mammals (Ramasarma et al, 1985). However, Q9 is the primary form found in rats and mice. Q Q and Q are found in yeast and bacteria. Biochemistry and physiological effects 6, 7 8 Q10 is present in most tissues, but in varying amounts. The biosynthesis of Q10 involves three major steps (Olson The highest concentrations in human tissues are found in & Rudney, 1983) Ð synthesis of the ring structure from the heart, liver and kidney, approximately 110, 60 and 70 mg=g essential amino acids tyrosine or phenylalanine, formation tissue, respectively, and the lowest concentration, 8 mg=g, of the isoprenoid side chain from acetyl-CoA residues via in lung tissue (Ernster & Forsmark-AndreÂe, 1993). The major part is in the reduced form, except in brain and lung tissue. *Correspondence: K Overvad, MùkhùjgaÊrd, Mùrkhùj Bygade 19, DK- In numerous studies the amount of Q in human plasma 2860 Sùborg, Denmark. 10 Guarantor: K. Overvad, The Danish Nutrition Council has been found to be in the range of 0.75 ± 1.00 mg=ml, of Contributorship: All authors read and discussed the literature and agreed which 75% is in the reduced form (Ernster & Forsmark- on the ®nd AndreeÂ, 1993). Q10 is thought to be primarily bound to Coenzyme Q10 in health and disease K Overvad et al 765

Figure 1 Structure of coenzyme Q (ubiquinone). Q10 contains 10 isoprene units (n 10).

LDL (Bowry et al, 1992). The total content in the body is estimated to 1.0 ± 1.5 g, most of this being found in muscle cells (Karlsson et al, 1993; Gale et al, 1961). It has been reported that the Q10 levels in humans decline with age (Ernster & Forsmark-Andree, 1993). Tissue Q10 originates from endogenous synthesis as well as from food intake and from oral supplements. A survey of the amount of coenzyme Q in selected food items is given Figure 2 Biosynthetic pathways leading to coenzyme Q (ubiquinone) and cholesterol. in Table 1. There are substantial variations in the values, which may be due to differences in analytical methodology and differences in species as well as seasonal variations. Prepared foods were found to have values 15 ± 30% lower yet been reported, thus it can be assumed that a varied diet than similar raw products (Weber et al, 1997). and a normal in vivo synthesis will supply suf®cient Q10 to Based on food frequency studies in 1985 and 1995 by healthy individuals. the National Food Agency of Denmark, the dietary intake of Q was estimated to be 3 ± 5 mg=d in Denmark. The 10 Pharmacology intake of Q9 was around 1 mg=d (Weber et al, 1997). A recommended daily intake has not yet been deter- Studies of Q10's pharmacology have been complicated by mined. The manufacturers of supplements recommend an the fact that Q10 is both synthesised in the body and intake of 10 ± 30 mg=d for healthy individuals. In the obtained from food. Tomono et al (1986) by-passed this general population no proven de®ciency symptoms have dif®culty as they studied the pharmacokinetics using

Table 1 The Q10 and Q9 content in selected food items (Karlsson et al, 1986)

a a Food group Food item n Cooking Q10 (mg=g food) Q9 (mg=g food) Meat and poultry Pork heart 9 Fried 203 (151 ± 282) 3.9 (1.7 ± 6.1) Beef 1 Fried 31 2.6 Chicken 1 Fried 17 0.8 Pork chop 3 Fried 14 (9.0 ± 17.8) 1.0 Ham 3 Boiled 7.7 (5.4 ± 9.4) 0.3 Fish Herring 1 Marinated 27 n.d. Rainbow trout 1 Steamed 11 n.d. Salmon 1 Smoked 4.3 n.d. Cereals Bread (rye) 1 None < 0.2 4.7 Bread (wheat) 1 None < 0.1 1.1 Rice 1 Boiled 0.2 n.d. Vegetables Broccoli 3 Boiled 6.6 (5.9 ± 7.7) 0.6 (0.6 ± 0.7) Cauli¯ower 1 Boiled 4.9 n.d. Potato 1 Boiled 0.5 n.d. Tomato 1 None 0.2 n.d. Carrot 1 None < 0.2 n.d. Carrot 1 Boiled < 0.2 n.d. Cucumber 1 None < 0.1 0.1 Fruit Orange 1 None 2.2 0.4 Apple 1 None 1.1 n.d. Kiwi 1 None 0.5 0.3 Dairy products Yoghurt 1 None 1.2 0.3 Hard cheese 1 None < 0.2 n.d. Cream cheese 1 None < 0.3 n.d. Egg Hen's egg 2 None 1.5 (1.0 ± 2.1) 0.4 (0.3 ± 0.5) Hen's egg 2 Boiled 2.3 (1.7 ± 2.9) 0.3 (0.2 ± 0.4)

aThe values represent means of triplicate measurements. The range of different samples is given in parentheses. The s.d. of the analysis was 6.2% , ranging from 2.3% to 9.3%. When no Q10 peak was seen in the chromatogram the detection limit for the analysis is given. n.d.: below detection limit. Coenzyme Q10 in health and disease K Overvad et al 766 deuterium-labelled Q10 in 16 healthy volunteers. Following Laaksonen et al, 1995; Malm et al, 1997; Weston et al, intake of 100 mg Q10, blood values reached a maximum 1997; Ylikoski et al, 1997). Out of 11 studies, ®ve after approximately 6 h, indicating a relatively slow absorp- indicated a positive effect of Q10 on physical capacity, tion which relates to the high molecular weight and the ®ve indicated no effect and one study a negative effect of lipid solubility of Q10. In most of the subjects a secondary Q10. The differences in the results could not be explained peak was found in the blood 24 h after intake, which is by differences in gender, age nor levels of physical capacity explained by absorption in the liver and subsequent redis- prior to supplementation. The results of the best studies, tribution via VLDL. The plasma half-life was about 33 h. from a methodological point of view, indicated no effect of The administered Q10 dose did not affect the plasma levels Q10. of endogeneous synthesised Q10 for up to 72 h after intake. One of the experimental studies found an increase in The formulation of Q10 was not described. creatine kinase levels in the blood after intake of a Q10 After intakes of 3620 mg Q10 per day for 4 d, in six supplement (Malm et al, 1996). This may be due to different formulations an increase in the plasma level of up increased cell damage. However, these results were not to 2.8 times the baseline level was observed. Q10 dissolved supported by other studies, where the creatine kinase levels in oil and formulated as capsules appears to have the best were unchanged during Q10 supplementation. Other major bioavailability. side effects were not reported from the studies on Q10 and Mohr et al (1992) found increased levels of Q10 in physical capacity. lipoproteins after oral supplementation and also an incresed The experimental studies so far have not clari®ed the resistance of LDL to incipient lipid peroxidation. importance of Q10 in physical capacity. Increased myocardial tissue content of Q10 via exogen- ously administered Q has been shown both in animal 10 Heart failure experiments (Crestanello et al, 1996) and in man (Folkers et al, 1985). After a supplementation period of 5 months At the cellular level, oxidative stress, mitochondrial dys- with Q10 100 mg=d in patients with cardiomyopathy, the function and energy starvation are supposed to play im- percentage increases of Q10 in the myocardium ranged portant pathophysiological roles in heart failure. When from 19 to 86% (endomyocardial biopsies). compared to normal subjects, reduced blood and myocar- Case reports have suggested interaction between Q10 dial tissue content of Q10 has been detected in heart failure and warfarin. In pigs a thrombocyte anti-aggregating effect and in endomyocardial tissue samples from patients with has been found after chronic dosing of 200 ± 400 mg=d. dilated cardiomyopathy (Mortensen, 1989). The level of Some studies suggest relatively low Q10 concentration in blood and myocardial Q10 was negatively associated with the myocardium after administration of anthracyclines, and the severity of symptoms and the degree of left ventricular other studies suggest that Q10 administration may reduce dysfunction. the cardiotoxicity of anthracyclines (Karlsson et al, 1986). The importance of Q10 treatment in heart failure has Most of the widely used HMG-coenzyme A-reductase initially been examined in patients with dilated cardio- inhibitors, which inhibit cholesterol synthesis, result in myopathy. This is a severe disease, mainly affecting reduced synthesis and thereby reduced Q10 levels in men around 40 years of age. The incidence rate is about plasma (Bargossi et al, 1994). This dose-related decrease 30 ± 100 cases per million per year in the Western World. is true for, among others, lovastatin and pravastatin (Mor- The lethality is around 50% at 2 y and a substantial number tensen et al, 1997). The signi®cance of this is not known; may be heart transplant candidates. however, the impaired biosynthesis and consequent Q10 Several open treatment experiments have suggested downregulation deserves further evaluation in long-term positive effects of Q10 supplements in patients with trials considering the oxidative theory for the development severe heart failure (NYHA classes III and IV). Nine of atherosclerosis. relevant randomised double-blind placebo-controlled stu- In placebo-controlled long-term studies no serious or dies concerning treatment of heart failure of various etiol- frequent side effects to intake of doses of 200 mg Q10=d ogies with Q10 were published between 1985 and 1995 for up to 12 months and 100 mg Q10=d for up to 6 y have (Table 2). In eight of these studies signs of improvement in been found. However, none of the controlled studies were clinical parameters, haemodynamic parameters and=or speci®cally designed to examine possible side effects. exercise capacity were registered when conventional treatment was accompanied by Q10 supplementation. The studies primarily included patients with advanced heart Physical capacity failure. Relatively low blood levels of Q10 in individuals at high The existing randomised, controlled studies are not levels of physical activity have been demonstrated (Karls- suf®ciently large to indicate any changes in mortality in son et al, 1993). One study showed a positive association the Q10-treated group and studies with the primary end- between blood levels of Q10 and maximal oxygen uptake point of mortality are required. However, Q10 is devoid of (Battino et al, 1997), and non-randomised experimental signi®cant side-effects and for patients with heart failure an studies have suggested that supplementation with Q10 has a improvement of 1 ± 2 NYHA classes may constitute a positive effect on physical capacity (Vanfraechem et al, signi®cantly improved quality of life. 1986; Yamabe & Fukuzake, 1991). However, several of the experiments did not include a reference group, and placebo Acute myocardial infarction effect, information bias and confounding may have in¯u- enced the results. In a recent randomised experiment supplementation with Several randomised experimental studies on Q10 supple- Q10 reduced development of angina pectoris, arrhythmias mentation and physical capacity have been undertaken and ventricular dysfunction in patients with acute myocar- (Braun et al, 1991; Snider et al, 1992; Porter et al, 1995; dial infarction (Singh et al, 1998). Coenzyme Q10 in health and disease K Overvad et al 767 Table 2 Double-blind, placebo-controlled studies of the effects of Q10 supplement in chronic heart failure

NYHA class Q10 administration Treatment period Reference Diagnosis n Design entering the study (mg=d) (months) Results

Langsjoen et al(1985) DCM 19 Cross-over III ± IV 100 263EF:, improved physical capacity Judy et al (1986) DCM 14 Cross-over IV 100 263EF:,SV:,CO:,EDVI; Permanetter et al (1989) DCM 25 Cross-over I ± III 100 2 64 No effect Rossi et al (1991) IHD 20 Parallel groups Unknown 200 3 Working capacity :, EF and CO resting unaltered, pulse and blood pressure during work unaltered Serra et al (1991) Mixed aetiology 20 Cross-over II ± III 60 2 61SV:,CO:, working capacity: Pogessi et al (1991) Mixed aetiology 20 Cross-over II ± III 100 2 62EF:,FS:, PET=LVET:, pulse and blood pressure unaltered, no change in NYHA class Morisco et al (1993) Mixed aetiology 641 Parallel groups III ± IV 100 12 NYHA class improved, hospitalisation;, left ventricular failure; Morisco et al (1994) Mixed aetiology 6 Cross-over II ± IV 150 2 61 EF during work:, CO during work: Hofman-Bang et al (1995) Mixed aetiology 79 Cross-over II ± IV 100 2 63 Working capacity:,EF unaltered, quality of life:

DCM: dilated cardiomyopathy. IHD: ischaemic heart disease. EF: ejection fraction. SV: stroke volume. CO: cardiac output. EDVI: end diastolic volume index. PEP=LVET: systolic time intervals. FS: fractional shortening.

Angina pectoris delaying the onset of angina pectoris. Several of the studies found that fewer angina pectoris attacks were provoked and In animal models Q prevents the damage that occurs 10 that daily use of nitroglycerine was reduced. However, when the blood supply to the myocardium is reduced for a larger, long-term studies are necessary to con®rm these brief period. This observation is the basis for ®ve rando- observations. mised, double-blind, placebo-controlled experiments exam- ining Q10's effect on angina pectoris in humans (Table 3). The studies differed in study design, Q10 dosage and treatment period. In four of these studies there are problems Hypertension with the randomisation, blinding and evaluation of the results. Generally the studies found that Q10 increased the Several non-controlled experiments concerning th effect of patients' stamina during exercise on a treadmill or an Q10 supplementation on high blood pressure in humans exercise bike, delaying the development ST depression as have been conducted. With one exception all these studies a sign of oxygen de®ciency in the myocardium, and found that Q10 supplementation decreased blood pressure.

Table 3 Double-blind, placebo-controlled experiments concerning effects of Q10 supplement in angina pectoris

Q10 Treatment Reference Diagnosis Characteristics Design administration period Results

Hiasa et al (1984) Stable angina pectoris, 18 patients 13<, Two parallel 1.5 mg=kg=d 7 d Improved work tolerance, NYHA II 5,,58Æ 9y groups intravenous tendency to less ST-depression, pulse and blood pressure unaltered Kamikawa et al (1985) Stable angina pectoris 12 patients 10<, Cross-over 150 mg=d, capsules 4 weeks Improved work tolerance, less 2,,50Æ 6y ST-depression, pulse and blood pressure unaltered, tendency to fewer angina pectoris attacks and decreased nitroglycerin consumption Schardt et al (1986) Stable angina pectoris 15 patients 3<, Cross-over 600 mg=d, capsules 4 d Less ST-depression, reduced 12,, 50 ± 60 y systolic blood pressure, pulse and diastolic blood pressure unaltered Mazzola et al (1991) Stable angina pectoris and 20 patients 11<, Cross-over 60 mg=d, capsules 4 weeks Improved work tolerance, fewer slight to moderate 9,,59Æ 7y angina pectoris attacks, heart failure decreased nitroglycerin consumption, pulse and blood pressure unaltered Wilson et al (1991) Stable angina pectoris 58 patients, mainly Three parallel 30 mg=d, 150 mg=d, 4 weeks Improved work tolerance, no <, average age groups capsules dose response coherence, 60 y unaltered nitroglycerin consumption, unaltered pulse and blood pressure

ST: ST-segment in EKG. Coenzyme Q10 in health and disease K Overvad et al 768 Two minor, randomised, double-blind, placebo-con- unfortunately insuf®ciently described. It is not stated trolled experiments have found a blood pressure lowering whether the experiment was blinded, nor is information effect of Q10 (Yamagami et al, 1986); Digiesi et al, 1990). given on how the Q10 was injected and what dose was Both systolic and diastolic blood pressure were reduced. given. The observed differences in gingival index and Further investigations are clearly necessary before Q10's gingival bleeding were small, but as a pilot study the potential in the treatment of high blood pressure is fully experiment is of interest and the method warrants further explored. investigation.

Cardiac and vascular surgery Diseases in the nervous system

Several experiments have described the effect of Q10 Q10 has been used alone and in combination with other supplement on different clinical, haemodynamical and agents in the treatment of patients with muscular dystrophy. biochemical parameters in connection with cardiac surgery Relevant statistical analysis revealed no effect of the Q10 for ischemic heart disease or valvular heart disease (Chello treatment (Folkers & Simonsen, 1995). et al, 1994; Judy et al, 1993). In one controlled double- blind study of patients with peripheral vascular disease, Chello et al found less enzyme leakage (creatinekinase and Q10 and male fertility lactatedehydrogenase) and lower levels of split products of Q10 is important in energy production and in prevention of the oxidative burst in the Q10 pre-treated patients (Chello et al, 1996). Separately the experiments support the notion oxidative damage. Energy production and low levels of oxidation are important in sperm motility and function. A that pre-treatment of the patients with Q10 for at least one week may have favourable effects. Long-term survival recent study demonstrated a positive correlation between studies with larger patient groups are relevant. Q10 levels and sperm counts in seminal plasma and negative correlations with hydroperoxide levels (Lewin & Laron, 1997). Further, Q10 seems to increase sperm motility Cancer diseases in sperm samples initially demonstrating low motility (Alleva et al, 1997). Animal experiments have suggested that Q10 plays a role in the blood cell formation and in the function of the immune system. This has been the rationale for studies on Q and 10 Use of Q supplements in Denmark cancer. 10 Folkers et al compared the Q10 content in blood from In connection with this review the Danish Nutrition Coun- patients with various cancerous diseases to blood levels in cil commissioned a telephone interview survey of the an unspeci®ed reference group (Folkers et al, 1991). The consumption of Q10 in the Danish population. Q10 content was lower in blood from the cancer patients Data were collected by telephone interviews during than in the reference subjects. It is not possible to determine February 1996. A random sample of 1,800 individuals of whether this is causal or a consequence of the disease. more than 15 years of age was drawn from the CPR In one open treatment experiment, 32 patients with register. Non-respondents comprised 143 who did not breast cancer received, concomitant with their conventional have a telephone, 326 who did not wish to take part and treatment, a supplement consisting of Q10 , other antiox- 304 who did not answer the telephone. In all, 1,027 idants and essential fatty acids (Lockwood et al, 1994). individuals (62%) were interviewed. Based on national life expectancy data for breast cancer Seventy percent of the interviewees stated that they had patients, four deaths were predicted in the treated group. heard of Q10. Approximately 6% (95% con®dence limits All the subjects survived an 18-month follow-up period. A 4 ± 7%) of the interviewees were currently taking a Q10 speci®c effect of Q10 cannot be determined from this study supplement. A larger proportion of the interviewees, 17% because several different treatments are administered at the had previously taken Q10. Tendencies in gender and age same time. It is further unlikely that the subjects entering distribution were similar to those regarding current use of the experiment are a random sample of patients with breast Q10 supplements. Reasons given for taking a Q10 supple- cancer and confounding is therefore probable. ment were: 43% hoped for better well-being, 34% hoped to There is little scienti®c evidence to support the hypoth- feel more energetic and 23% hoped to affect a speci®c esis that Q10 should play a preventive role in the aetiology disease. Almost all the disorders discussed in this review of cancer. Both the case-referent experiment and the treat- were found in this last group. The most frequent disorder ment experiment discussed are inconclusive. reported was parodontal disease (14 individuals).

Parodontal disease References It is known that the level of Q10 in the gingiva declines with age, and that the frequency of parodontal disease increases. Alleva R, Tomasetti M, Battino M, Curatola G, Littarru GP & Folkers K Seven studies have described the effect of Q on paro- (1995): The roles of coenzyme Q10 and vitamin E on the peroxidation 10 of human low density lipoprotein subfractions. PNAS 92, dontal disease. The studies differed in the choice of patient 9388 ± 9391. populations, Q10 administration and aims. None of the three Alleva R, Scararmucci A, Mantero F, Bompadre S, Leoni L & Littarru GP randomised, placebo controlled, double-blind experiments (1997): The protective role of ubiquinol Ð 10 against formation of lipid hydroperoxides in human seminal ¯uids. Molec. Asp. Med. 18, 221 ± 228. demonstrated positive effects of Q10 (Wilkinson et al, 1976); Iwamoto et al, 1981; Glavind et al, 1994). Bargossi AM, Battino M, Gaddi A, Fiorella PL, Grossi G, Barozzi G et al (1994): Exogenous coenzyme Q10 preserves plasma ubiquinone levels Hanioka et al administered Q10 locally in each gingiva in patients with 3-hydroxy-3-methylglutaryl coenzyme A reductase pocket (Hanka et al, 1994). The experimental method is inhibitors. Int. J. Clin. Lab. Res. 24, 171 ± 176. Coenzyme Q10 in health and disease K Overvad et al 769 Battino M, Amadio E, Oradel A & Littarru GP (1997): Metabolic and Karlsson J, Folkers K, AstroÈm H, Jansson E, Pernow B & Holmgren A antioxidant markers in the plasma of sportsmen from a Mediterranean (1986): Effect of adriamycin on heart and skeletal muscle coenzyme Q town performing non-agonistic activity. Molec. Asp. Med. 18, 241 ± (CoQ10) in man. In: K Folkers & Y Yamamura, (eds). Biomedical and 245. Clinical Aspects of Coenzyme Q. 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