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COENZYME Q10



Table of Contents

image Refractory congestive heart failure successfully managed with high dose coenzyme Q10 administration
image Effects of oral supplementation of coenzyme Q10 on 31P-NMR detected skeletal muscle energy metabolism in middle-aged post-polio subjects and normal volunteers
image The effect of coenzyme Q10 on the exercise performance of cross-country skiers
image T-2 toxin-induced DNA damage in mouse livers: The effect of pretreatment with coenzyme Q10 and alpha-tocopherol
image The mechanisms of coenzyme Q10 as therapy for myocardial ischemia reperfusion injury
image Usefulness of coenzyme Q10 in clinical cardiology: a long-term study
image Perspectives on therapy of cardiovascular diseases with coenzyme Q10 (ubiquinone)
image Coenzyme Q10: a new drug for cardiovascular disease
image Treatment of essential hypertension with coenzyme Q10
image Coenzyme Q10 in essential hypertension
image The effect of coenzyme Q10 on infarct size in a rabbit model of ischemia/reperfusion.
image Protection by coenzyme Q10 of tissue reperfusion injury during abdominal aortic cross-clamping.
image Isoprenoid (coQ10) biosynthesis in multiple sclerosis.
image Two successful double-blind trials with coenzyme Q10 (vitamin Q10) on muscular dystrophies and neurogenic atrophies.
image Biochemical rationale and the cardiac response of patients with muscle disease to therapy with coenzyme Q10.
image [Some indices of energy metabolism in the tissues of mice with progressive muscular dystrophy under the action of ubiquinone]
image The activities of coenzyme Q10 and vitamin B6 for immune responses.
image Research on coenzyme Q10 in clinical medicine and in immunomodulation.
image A modified determination of coenzyme Q10 in human blood and CoQ10 blood levels in diverse patients with allergies.
image Biochemical deficiencies of coenzyme Q10 in HIV-infection and exploratory treatment.
image Immunological senescence in mice and its reversal by coenzyme Q10.
image Treatment of essential hypertension with coenzyme Q10
image Coenzyme Q10 in essential hypertension
image Usefulness of coenzyme Q10 in clinical cardiology: a long-term study
image Influence of coenzyme Q-10 on the hypotensive effects of enalapril and nitrendipine in spontaneously hypertensive rats.
image Isolated diastolic dysfunction of the myocardium and its response to CoQ10 treatment.
image Muscle fibre types, ubiquinone content and exercise capacity in hypertension and effort angina.
image Effect of coenzyme Q10 on structural alterations in the renal membrane of stroke-prone spontaneously hypertensive rats
image Co-enzyme Q10: a new drug for cardiovascular disease
image Coenzyme Q10: a new drug for myocardial ischemia?
image Clinical study of cardiac arrhythmias using a 24-hour continuous electrocardiographic recorder (5th report)--antiarrhythmic action of coenzyme Q10 in diabetics.
image Bioenergetics in clinical medicine. XVI. Reduction of hypertension in patients by therapy with coenzyme Q10.
image Prospects for nutritional control of hypertension
image Bioenergetics in clinical medicine XV. Inhibition of coenzyme Q10-enzymes by clinically used adrenergic blockers of beta-receptors.
image Bioenergetics in clinical medicine. VIII. Adminstration of coenzyme Q10 to patients with essential hypertension.
image Bioenergetics in clinical medicine. III. Inhibition of coenzyme Q10-enzymes by clinically used anti-hypertensive drugs
image Bioenergetics in clinical medicine. Studies on coenzyme Q10 and essential hypertension.
image Plasma ubiquinol-10 is decreased in patients with hyperlipidaemia
image Coenzyme Q10 increases T4/T8 ratios of lymphocytes in ordinary subjects and relevance to patients having the AIDS related complex
image The clinical and hemodynamic effects of Coenzyme Q10 in congestive cardiomyopathy
image Fish oil and other nutritional adjuvants for treatment of congestive heart failure
image NADH-coenzyme Q reductase (complex I) deficiency: heterogeneity in phenotype and biochemical findings.
image Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase.
image Effect of protection and repair of injury of mitochondrial membrane-phospholipid on prognosis in patients with dilated cardiomyopathy.
image [Therapeutic effects of coenzyme Q10 on dilated cardiomyopathy: assessment by 123I-BMIPP myocardial single photon emission computed tomography (SPECT): a multicenter trial in Osaka University Medical School Group]
image Italian multicenter study on the safety and efficacy of COENZYME Q10 as adjunctive therapy in heart failure.
image [Coenzyme Q10 (ubiquinone) in the treatment of heart failure. Are any positive effects documented?]
image Italian multicenter study on the safety and efficacy of COENZYME Q10 as adjunctive therapy in heart failure (interim analysis). The CoQ10 Drug Surveillance Investigators.
image Effect of COENZYME Q10 therapy in patients with congestive heart failure: a long-term multicenter randomized study.
image Role of metabolic therapy in cardiovascular disease.
image Cardiac performance and COENZYME Q10 in thyroid disorders
image A clinical study of the effect of COENZYME Q on congestive heart failure.
image Effects of coenzyme Q10 administration on pulmonary function and exercise performance in patients with chronic lung diseases.
image Unrecognized pandemic subclinical diabetes of the affluent nations: Causes, cost and prevention
image [Effect of biological membrane stabilizing drugs (coenzyme Q10, dextran sulfate and reduced glutathione) on adriamycin (doxorubicin)-induced toxicity and microsomal lipid peroxidation in mice]
image Coenzyme Q10, plasma membrane oxidase and growth control.
image Protective effects of various drugs on adriamycin (doxorubicin)-induced toxicity and microsomal lipid peroxidation in mice and rats.
image Tissue concentration of doxorubicin (adriamycin) in mouse pretreated with alpha-tocopherol or coenzyme Q10.
image [Electrocardiogram analysis of adriamycin cardiotoxicity in 160 cases]
image Progress on therapy of breast cancer with vitamin Q10 and the regression of metastases.
image Apparent partial remission of breast cancer in 'high risk' patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10.
image Effects of isoprenoids (coQ10) on growth of normal human mammary epithelial cells and breast cancer cells in vitro.
image Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10.
image An expanded concept of "insurance" supplementation--broad-spectrum protection from cardiovascular disease.
image Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure (interim analysis)
image [Effects of 2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone (CV-2619) on adriamycin-induced ECG abnormalities and myocardial energy metabolism in spontaneously hypertensive rats]
image Effects of short-term supplementation with coenzyme Q10 on myocardial protection during cardiac operations
image Myocardial preservation by therapy with coenzyme Q10 during heart surgery
image Effect of CoQ10 on myocardial ischemia/reperfusion injury in the isolated rat heart
image Measurement of the ratio between the reduced and oxidized forms of coenzyme Q10 in human plasma as a possible marker of oxidative stress.
image The role of free radicals in disease
image Coenzyme Q10 and coronary artery disease
image Isoprenoids (coQ10) in aging and neurodegeneration.
image Muscle biopsy in Alzheimer's disease: Morphological and biochemical findings
image Relevance of the biosynthesis of coenzyme Q10 and of the four bases of DNA as a rationale for the molecular causes of cancer and a therapy
image Natural products and their derivatives as cancer chemopreventive agents
image Thesis of coenzyme Q10 and of the four bases of DNA as a rationale for the molecular causes of cancer and a therapy
image Anti-atherogenic effect of coenzyme Q10 in apolipoprotein E gene knockout mice.
image Coenzyme Q10 enrichment decreases oxidative DNA damage in human lymphocytes.
image A role for reduced coenzyme Q in atherosclerosis?
image Oxidation and antioxidation of human low-density lipoprotein and plasma exposed to 3-morpholinosydnonimine and reagent peroxynitrite.
image Oxidation of high density lipoproteins. I. Formation of methionine sulfoxide in apolipoproteins AI and AII is an early event that accompanies lipid peroxidation and can be enhanced by alpha-tocopherol.
image Oxidation of free fatty acids in low density lipoprotein by 15-lipoxygenase stimulates nonenzymic, alpha-tocopherol-mediated peroxidation of cholesteryl esters.
image Alpha-tocopheryl hydroquinone is an efficient multifunctional inhibitor of radical-initiated oxidation of low density lipoprotein lipids.
image Plasma and LDL levels of major lipophilic antioxidants are similar in patients with advanced atherosclerosis and age-matched controls.
image Inhibition of LDL oxidation by ubiquinol-10. A protective mechanism for coenzyme Q in atherogenesis?
image 3-Hydroxyanthranilic acid is an efficient, cell-derived co-antioxidant for alpha-tocopherol, inhibiting human low density lipoprotein and plasma lipid peroxidation.
image Radical-initiated lipid peroxidation in low density lipoproteins: insights obtained from kinetic modeling.
image Cosupplementation with coenzyme Q prevents the prooxidant effect of alpha-tocopherol and increases the resistance of LDL to transition metal-dependent oxidation initiation.
image Coantioxidants make alpha-tocopherol an efficient antioxidant for low-density lipoprotein.
image Inverse deuterium kinetic isotope effect for peroxidation in human low-density lipoprotein (LDL): a simple test for tocopherol-mediated peroxidation of LDL lipids.
image Prevention of tocopherol-mediated peroxidation in ubiquinol-10-free human low density lipoprotein.
image Radical-mediated oxidation of isolated human very-low-density lipoprotein.
image Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation.
image The oxidation of blood plasma and low density lipoprotein components by chemically generated singlet oxygen.
image Extracellular reduction of ubiquinone-1 and -10 by human Hep G2 and blood cells.
image Circulating lipid hydroperoxide levels in human hyperhomocysteinemia. Relevance to development of arteriosclerosis.
image Comparative antioxidant activity of tocotrienols and other natural lipid-soluble antioxidants in a homogeneous system, and in rat and human lipoproteins.
image Oxidation of low-density lipoprotein with hypochlorite causes transformation of the lipoprotein into a high-uptake form for macrophages.
image Autoxidation of lipids and antioxidation by alpha-tocopherol and ubiquinol in homogeneous solution and in aqueous dispersions of lipids: unrecognized consequences of lipid particle size as exemplified by oxidation of human low density lipoprotein.
image Vitamin E in human low-density lipoprotein. When and how this antioxidant becomes a pro-oxidant.
image High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors.
image The participation of nitric oxide in cell free- and its restriction of macrophage-mediated oxidation of low-density lipoprotein.
image Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation.
image Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol.
image Oxidative stress and abnormal cholesterol metabolism in patients with adult respiratory distress syndrome.


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Anti-atherogenic effect of coenzyme Q10 in apolipoprotein E gene knockout mice.

Witting PK, Pettersson K, Letters J, Stocker R Biochemistry Group, Heart Research Institute, Camperdown, NSW, Australia.

Free Radic Biol Med 2000 Aug;29(3-4):295-305

Oxidation of low-density lipoprotein (LDL) lipid is implicated in atherogenesis and certain antioxidants inhibit atherosclerosis. Ubiquinol-10 (CoQ10H2) inhibits LDL lipid peroxidation in vitro although it is not known whether such activity occurs in vivo, and, if so, whether this is anti-atherogenic. We therefore tested the effect of ubiquinone-10 (CoQ10) supplemented at 1% (w/w) on aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice fed a high-fat diet. Hydroperoxides of cholesteryl esters and triacylglycerols (together referred to as LOOH) and their corresponding alcohols were used as the marker for lipoprotein lipid oxidation. Atherosclerosis was assessed by morphometry at the aortic root, proximal and distal arch, and the descending thoracic and abdominal aorta. Compared to controls, CoQ10-treatment increased plasma coenzyme Q, ascorbate, and the CoQ10H2:CoQ10 + CoQ10H2 ratio, decreased plasma alpha-tocopherol (alpha-TOH), and had no effect on cholesterol and cholesterylester alcohols (CE-OH). Plasma from CoQ10-supplemented mice was more resistant to ex vivo lipid peroxidation. CoQ10 treatment increased aortic coenzyme Q and alpha-TOH and decreased the absolute concentration of LOOH, whereas tissue cholesterol, cholesteryl esters, CE-OH, and LOOH expressed per bisallylic hydrogen-containing lipids were not significantly different. CoQ10-treatment significantly decreased lesion size in the aortic root and the ascending and the descending aorta. Together these data show that CoQ10 decreases the absolute concentration of aortic LOOH and atherosclerosis in apoE-/- mice.

PMID: 11035258

Coenzyme Q10 enrichment decreases oxidative DNA damage in human lymphocytes.

Tomasetti M, Littarru GP, Stocker R, Alleva R Institute of Biochemistry, Faculty of Medicine, University of Ancona, Italy. ralleva@jth.it

Free Radic Biol Med 1999 Nov;27(9-10):1027-32

Ubiquinol-10, the reduced form of coenzyme Q10, is a powerful antioxidant in plasma and lipoproteins. It has been suggested that endogenous ubiquinol-10 also exerts a protective role even towards DNA oxidation mediated by lipid peroxidation. Even though the antioxidant activity of coenzyme Q10 is mainly ascribed to ubiquinol-10, a role for ubiquinone-10 (the oxidized form), has been suggested not only if appropriate reducing systems are present. To investigate whether the concentration of ubiquinol-10 or ubiquinone-10 affects the extent of DNA damage induced by H2O2, we supplemented in vitro human lymphocytes with both forms of coenzyme Q10 and evaluated the DNA strand breaks by Comet assay. The exposure of lymphocytes to 100 microM H2O2 resulted in rapid decrease of cellular ubiquinol-10 content both in ubiquinol-10-enriched and in control cells, whereas alpha-tocopherol and beta-carotene concentration were unchanged. After 30 min from H2O2 exposure, the amount of DNA strand breaks was lower and cells' viability was significantly higher in ubiquinol-10-enriched cells compared with control cells. A similar trend was observed in ubiquinone-10-enriched lymphocytes when compared with control cells. Our experiments suggest that coenzyme Q10 in vitro supplementation enhances DNA resistance towards H2O2-induced oxidation, but it doesn't inhibit directly DNA strand break formation.

PMID: 10569635

A role for reduced coenzyme Q in atherosclerosis?

Thomas SR, Witting PK, Stocker R Biochemistry Group, Heart Research Institute, Camperdown, NSW, Australia.

Biofactors 1999;9(2-4):207-24

Substantial evidence implicates oxidative modification of low density lipoprotein (LDL) as an important event contributing to atherogenesis. As a result, the elucidation of the molecular mechanisms by which LDL is oxidized and how such oxidation is prevented by antioxidants has been a significant research focus. Studies on the antioxidation of LDL lipids have focused primarily on alpha-tocopherol (alpha-TOH), biologically and chemically the most active form of vitamin E and quantitatively the major lipid-soluble antioxidant in extracts prepared from human LDL. In addition to alpha-TOH, plasma LDL also contains low levels of ubiquinol-10 (CoQ10H2; the reduced form of coenzyme Q10). Recent studies have shown that in oxidizing plasma lipoproteins alpha-TOH can exhibit anti- or pro-oxidant activities for the lipoprotein's lipids exposed to a vast array of oxidants. This article reviews the molecular action of alpha-TOH in LDL undergoing "mild" radical-initiated lipid peroxidation, and discusses how small levels of CoQ10H2 can represent an efficient antioxidant defence for lipoprotein lipids. We also comment on the levels alpha-TOH, CoQ10H2 and lipid oxidation products in the intima of patients with coronary artery disease and report on preliminary studies examining the effect of coenzyme Q10 supplementation on atherogenesis in apolipoprotein E knockout mice.

Publication Types: Review Review, academic

PMID: 10416033

Oxidation and antioxidation of human low-density lipoprotein and plasma exposed to 3-morpholinosydnonimine and reagent peroxynitrite.

Thomas SR, Davies MJ, Stocker R The Biochemistry and EPR Groups, The Heart Research Institute, 145 Missenden Road, Camperdown, Sydney, NSW 2050, Australia. biochemistry@hri.edu.au

Chem Res Toxicol 1998 May;11(5):484-94

As peroxynitrite is implicated as an oxidant for low-density lipoprotein (LDL) in atherogenesis, we investigated this process using reagent peroxynitrite (ONOO-) and 3-morpholinosydnonimine (SIN-1, which produces peroxynitrite via generation of NO. and O2.-). LDL oxidation was assessed by the consumption of ubiquinol-10 (CoQ10H2) and alpha-tocopherol (alpha-TOH), the accumulation of cholesteryl ester hydro(pero)xides, the loss of lysine (Lys) and tryptophan (Trp) residues, and the change in relative electrophoretic mobility. Exposure to ONOO- or SIN-1 resulted in rapid (<1 min) and time-dependent oxidation, respectively, of LDL's lipids and protein. Manipulating the alpha-TOH content by in vivo or in vitro means showed that when ONOO- or SIN-1 was used at oxidant-to-LDL ratios of <100:1 the extent of LDL lipid peroxidation increased with increasing initial alpha-TOH content. In contrast, in vivo enrichment with the co-antioxidant CoQ10H2 decreased LDL lipid peroxidation induced by SIN-1. At oxidant-to-LDL ratios of >200:1, alpha-TOH enrichment decreased LDL lipid peroxidation for both SIN-1 and ONOO-. In contrast to lipid peroxidation, altering the alpha-TOH content of LDL did not affect Trp or Lys loss, independent of the amounts of either oxidant added. Aqueous antioxidants inhibited ONOO--induced lipid and protein oxidation with the order of efficacy: 3-hydroxyanthranilate (3-HAA) > urate > ascorbate. With SIN-1, these antioxidants inhibited Trp consumption, while only the co-antioxidants ascorbate and 3-HAA prevented alpha-TOH consumption and lipid peroxidation. Exposure of human plasma to SIN-1 resulted in the loss of ascorbate followed by loss of CoQ10H2 and bilirubin. Lipid peroxidation was inhibited during this period, though proceeded as a radical-chain process after depletion of these antioxidants and in the presence of alpha-TOH and urate. Bicarbonate at physiological concentrations decreased ONOO--induced lipid and protein oxidation, whereas it enhanced SIN-1-induced lipid peroxidation, Trp consumption, and alpha-tocopheroxyl radical formation in LDL. These results indicate an important role for tocopherol-mediated peroxidation and co-antioxidation in peroxynitrite-induced lipoprotein lipid peroxidation, especially when peroxynitrite is formed time-dependently by SIN-1. The studies also highlight differences between ONOO-- and SIN-1-induced LDL oxidation with regards to the effects of bicarbonate, ascorbate, and urate.

Publication Types: Clinical trial

PMID: 9585479

Oxidation of high density lipoproteins. I. Formation of methionine sulfoxide in apolipoproteins AI and AII is an early event that accompanies lipid peroxidation and can be enhanced by alpha-tocopherol.

Garner B, Witting PK, Waldeck AR, Christison JK, Raftery M, Stocker R Biochemistry, The Heart Research Institute, Sydney New South Wales 2050, Australia.

J Biol Chem 1998 Mar 13;273(11):6080-7

The lipids of high density lipoproteins (HDL) are initially oxidized in preference to those in low density lipoprotein when human plasma is exposed to aqueous peroxyl radicals. In this work we report on the relative susceptibility of HDL protein and lipid to oxidation and on the role HDL's alpha-tocopherol (alpha-TOH) plays in modulating protein oxidation. Exposure of isolated HDL to either low fluxes of aqueous peroxyl radicals, Cu2+ ions, or soybean lipoxygenase resulted in the oxidation of apoAI and apoAII during the earliest stages of the reaction, i.e. after consumption of ubiquinol-10 and in the presence of alpha-TOH. Hydro(pero)xides of cholesteryl esters and phospholipids initially accumulated together with specific oxidized forms of apoAI and apoAII, separated by high pressure liquid chromatography. The specific oxidized forms of apoAI were 16 and 32 mass units heavier than those of the native apolipoproteins and contained 1 and 2 methionine sulfoxide residues per protein, respectively. The third methionine residue in apoAI, as well as Trp residues, remained unoxidized during the earliest stages of HDL oxidation examined. Exposure of isolated apoAI to peroxyl radicals, Cu2+, or soybean lipoxygenase resulted in nonspecific (for peroxyl radicals) or no discernible protein oxidation (Cu2+ and soybean lipoxygenase). This indicated that the formation of the specific oxidized forms of apoAI observed with native HDL was not the result of direct reaction of these oxidants with the apolipoprotein. In vitro and in vivo enrichment of HDL with alpha-TOH resulted in a dose-dependent increase in the extent of peroxyl radical-induced formation of HDL cholesteryl ester hydroperoxides (r = 0.96) and cholesteryl ester hydroxides (r = 0. 92), as well as the loss of apoAI (r = 0.96) and apoAII (r = 0.94). alpha-TOH enrichment also enhanced HDL lipid and protein oxidation induced by Cu2+ or soybean lipoxygenase. These results indicate that the earliest stages of HDL oxidation are accompanied by the oxidation of specific methionine residues in apoAI and apoAII and that in the absence of co-antioxidants, alpha-TOH can promote this process.

PMID: 9497325

Oxidation of free fatty acids in low density lipoprotein by 15-lipoxygenase stimulates nonenzymic, alpha-tocopherol-mediated peroxidation of cholesteryl esters.

Upston JM, Neuzil J, Witting PK, Alleva R, Stocker R Biochemistry Unit, The Heart Research Institute, 145 Missenden Road, Camperdown NSW 2050, Australia.

J Biol Chem 1997 Nov 28;272(48):30067-74

15-Lipoxygenase has been implicated in the in vivo oxidation of low density lipoprotein (LDL) a process thought to be important in the origin and/or progression of human atherogenesis. We have suggested previously that oxidation of LDL's cholesteryl esters (CE) and phospholipids by soybean (SLO) or human recombinant 15-lipoxygenase (rhLO) can be ascribed largely to alpha-tocopherol (alpha-TOH)-mediated peroxidation (TMP). In this study we demonstrate that addition to LDL of unesterified linoleate (18:2), other free fatty acid (FFA) substrates, or phospholipase A2 (PLA2) significantly enhanced the accumulation of CE hydro(pero)xides (CE-O(O)H) induced by rhLO, whereas the corresponding CE and nonsubstrate FFA were without effect. The enhanced CE-O(O)H accumulation showed a dependence on the concentration of free 18:2 in LDL. In contrast, addition of 18:2 had little effect on LDL oxidation induced by aqueous peroxyl radicals or Cu2+ ions. Analyses of the regio- and stereoisomers of oxidized 18:2 in SLO-treated native LDL demonstrated that the small amounts of 18:2 associated with the lipoprotein were oxidized enzymically and within minutes, whereas cholesteryl linoleate (Ch18:2) was oxidized nonenzymically and continuously over hours. alpha-Tocopheroxyl radical (alpha-TO.) formed in LDL exposed to SLO was enhanced by addition of 18:2 or PLA2. With rhLO and 18:2-supplemented LDL, oxidation of 18:2 was entirely enzymic, whereas that of Ch18:2 was largely, though not completely, nonenzymic. The small extent of enzymic Ch18:2 oxidation increased with increasing enzyme to LDL ratios. Ascorbate and the reduced form of coenzyme Q, ubiquinol-10, which are both capable of reducing alpha-TO. and thereby preventing TMP, inhibited nonenzymic Ch18:2 oxidation induced by rhLO. Trolox and ascorbyl palmitate, which also inhibit TMP, ameliorated both enzymic and nonenzymic oxidation of LDL's lipids, whereas probucol, a radical scavenger not capable of preventing TMP, was ineffective. These results demonstrate that rhLO-induced oxidation of CE is largely nonenzymic and increases with LDL's content of FFA substrates. We propose that conditions which increase LDL's FFA content, such as the presence of lipases, increase 15-LO-induced LDL lipid peroxidation and that this process requires only an initial, transient enzymic activity.

PMID: 9374483

Alpha-tocopheryl hydroquinone is an efficient multifunctional inhibitor of radical-initiated oxidation of low density lipoprotein lipids.

Neuzil J, Witting PK, Stocker R Biochemistry Unit, The Heart Research Institute, 145 Missenden Road, Camperdown, NSW 2050, Australia.

Proc Natl Acad Sci U S A 1997 Jul 22;94(15):7885-90

As the oxidation of low density lipoprotein (LDL) lipids may be a key event in atherogenesis, there is interest in antioxidants as potential anti-atherogenic compounds. Here we report that alpha-tocopheryl hydroquinone (alpha-TQH2) strongly inhibited or completely prevented the (per)oxidation of ubiquinol-10 (CoQ10H2), alpha-tocopherol (alpha-TOH), and both surface and core lipids in LDL exposed to either aqueous or lipophilic peroxyl radicals, Cu2+, soybean lipoxygenase, or the transition metal-containing Ham's F-10 medium in the absence or presence of human monocyte-derived macrophages. The antioxidant activity of alpha-TQH2 was superior to that of several other lipophilic hydroquinones, including endogenous CoQ10H2, which is regarded as LDL's first line of antioxidant defence. At least three independent activities contributed to the antioxidant action of alpha-TQH2. First, alpha-TQH2 readily associated with LDL and instantaneously reduced the lipoprotein's ubiquinone-10 to CoQ10H2, thereby maintaining this antioxidant in its active form. Second, alpha-TQH2 directly intercepted aqueous peroxyl radicals, as indicated by the increased rate of its consumption with increasing rates of radical production, independent of LDL's content of CoQ10H2 and alpha-TOH. Third, alpha-TQH2 rapidly quenched alpha-tocopheroxyl radical in oxidizing LDL, as demonstrated directly by electron paramagnetic resonance spectroscopy. Similar antioxidant activities were also seen when alpha-TQH2 was added to high-density lipoprotein or the protein-free Intralipid, indicating that the potent antioxidant activity of alpha-TQH2 was neither lipoprotein specific nor dependent on proteins. These results suggest that alpha-TQH2 is a candidate for a therapeutic lipid-soluble antioxidant. As alpha-tocopherylquinone is formed in vivo at sites of oxidative stress, including human atherosclerotic plaque, and biological systems exist that reduce the quinone to the hydroquinone, our results also suggest that alpha-TQH2 could be a previously unrecognized natural antioxidant.

PMID: 9223282

Plasma and LDL levels of major lipophilic antioxidants are similar in patients with advanced atherosclerosis and age-matched controls.

Cleary J, Mohr D, Adams MR, Celermajer DS, Stocker R Biochemistry Unit, Royal Prince Alfred Hospital, Sydney NSW, Australia.

Free Radic Res 1997 Feb;26(2):175-82

Oxidative modification of low-density lipoprotein (LDL), regarded an early event in atherogenesis, is associated with the depletion of the lipoprotein's antioxidants. We tested whether the levels of major lipophilic antioxidants in the blood of patients with advanced atherosclerosis are different to those in age-matched controls. On average, plasma ubiquinol-10, total coenzyme Q and coenzyme Q redox status were slightly lower whereas the levels of alpha-tocopherol were slightly higher in patients (63 +/- 11 years, n = 32) than controls (64 +/- 10 years, n = 24). However, these differences were not statistically significant (p > 0.05). The levels of antioxidants in LDL isolated from a subset of patients (n = 20) and controls (n = 15) were also indifferent, and hydroperoxides of cholesteryl esters were undetectable (detection limit 10 nM) in plasma of patients (n = 11) and controls (n = 10). The data suggests that plasma and LDL levels of lipophilic antioxidants are not depleted in patients suffering from severe atherosclerosis, and that neither parameter serves as a useful diagnostic indicator for this disease.

PMID: 9257129

Inhibition of LDL oxidation by ubiquinol-10. A protective mechanism for coenzyme Q in atherogenesis?

Thomas SR, Neuzil J, Stocker R Biochemistry Unit, Heart Research Institute, Sydney, NSW, Australia.

Mol Aspects Med 1997;18 Suppl:S85-103

The oxidation of low density lipoprotein (LDL) is now commonly regarded as an important early event in atherogenesis. As such there is considerable interest in the ability of antioxidant supplementation to attenuate LDL oxidation and hence atherosclerosis. A majority of studies on LDL antioxidation have focused on alpha-tocopherol (alpha-TOH), biologically and chemically the most active form of vitamin E and quantitatively the major lipid-soluble antioxidant in extracts prepared from human LDL. In addition to alpha-TOH, circulating LDL also contains low levels of ubiquinol-10 (CoQ10H2; the reduced form of coenzyme Q). Recent studies have shown that in intact, isolated LDL, alpha-TOH can act as either an anti- or prooxidant for the lipoprotein's lipids. This article reviews the molecular action of alpha-TOH in LDL undergoing radical-initiated oxidation, and how the presence of CoQ10H2 suppresses the pro-oxidant or complements the antioxidant activity of the vitamin. We also comment on the plasma and intimal levels of alpha-TOH and CoQ10H2 in patients suffering from coronary artery disease and discuss the potential implications of these results for atherogenesis.

Publication Types: Review Review, tutorial

PMID: 9266510

3-Hydroxyanthranilic acid is an efficient, cell-derived co-antioxidant for alpha-tocopherol, inhibiting human low density lipoprotein and plasma lipid peroxidation.

Thomas SR, Witting PK, Stocker R Biochemistry Unit, The Heart Research Institute, 145 Missenden Road, Camperdown, Sydney, New South Wales 2050, Australia. r.stocker@hri.edu.au

J Biol Chem 1996 Dec 20;271(51):32714-21

alpha-Tocopherol (alpha-TOH) can promote lipid peroxidation in human low density lipoprotein (LDL) unless co-antioxidants are present that eliminate the chain-carrying alpha-tocopheroxyl radical (alpha-TO.) (Bowry, V. W., Mohr, D., Cleary, J., and Stocker, R. (1995) J. Biol. Chem. 270, 5756-5763). Interferon-gamma inhibits human monocyte/macrophage-facilitated LDL lipid peroxidation via induction of cellular tryptophan degradation and production and release of 3-hydroxyanthranilic acid (3HAA) (Christen, S., Thomas, S. R., Garner, B., and Stocker, R. (1994) J. Clin. Invest. 93, 2149-2158). We now report on the mechanism of antioxidant action of 3HAA. 3HAA directly reduced alpha-TO. in UV-exposed micellar dispersions of alpha-TOH or in LDL incubated with soybean 15-lipoxygenase (SLO), as assessed by electron paramagnetic resonance spectroscopy. 3HAA did not inhibit SLO enzyme activity. Anthranilic acid, which lacks the phenoxyl group, was incapable of reducing alpha-TO.. 3HAA dose-dependently inhibited the peroxidation of surface phospholipids and core cholesteryl esters in LDL exposed to SLO, peroxyl radicals (ROO.), or Cu2+; oxidants that convert alpha-TOH to alpha-TO.. In all cases, sparing of LDL's alpha-TOH, but not ubiquinol-10 (CoQ10H2), was observed until the majority of 3HAA was consumed. Addition of 3HAA or ascorbate prevented further consumption of alpha-TOH and accumulation of lipid hydroperoxides when added to aqueous or lipophilic ROO.-oxidizing LDL after complete and partial consumption of CoQ10H2 and alpha-TOH, respectively. In contrast, addition of urate, an efficient ROO. scavenger incapable of scavenging alpha-TO., did not efficiently inhibit ongoing lipid peroxidation. Oxidation of 3HAA-supplemented human plasma by aqueous ROO. resulted in the successive consumption of ascorbate, CoQ10H2, 3HAA, bilirubin, alpha-TOH, and urate. Lipid peroxidation was prevented as long as ascorbate, CoQ10H2, and 3HAA were present, but subsequently proceeded as a free-radical chain reaction concomitant with alpha-TOH, bilirubin, and urate consumption. Addition of 3HAA to aqueous ROO.-oxidizing plasma, after complete consumption of ascorbate and CoQ10H2, strongly inhibited ongoing lipid peroxidation and consumption of alpha-TOH, bilirubin, and urate immediately and as efficiently as did ascorbate. These findings demonstrate that 3HAA is a highly efficient co-antioxidant for plasma lipid peroxidation by virtue of its ability to interact with alpha-TO. in lipoproteins. Since interferon-gamma is the principal inducer of tryptophan degradation and release of 3HAA by monocytes/macrophages, this may represent a localized extracellular antioxidant defense against LDL oxidation in inflammation.

PMID: 8955104

Radical-initiated lipid peroxidation in low density lipoproteins: insights obtained from kinetic modeling.

Waldeck AR, Stocker R Biochemistry Unit, Heart Research Institute, Sydney, NSW, Australia.

Chem Res Toxicol 1996 Sep;9(6):954-64

We present kinetic models of various complexity for radical-initiated lipid peroxidation in low density lipoproteins (LDL). The models, comprised of simultaneous differential equations programmed in Mathematica, were used to evaluate the concentration profiles of the reactants of interest. Single-phase reaction schemes describing lipid peroxidation and antioxidation according to the "conventional" and tocopherol-mediated peroxidation (TMP) model were simulated for conditions of low and high radical fluxes produced by thermolabile azo initiators. The results show that the particular dependencies of the rates of lipid peroxidation (Rp) on the rates of initiation (Ri) for the two reaction schemes were accurately predicted by the simulations. Both models qualitatively predicted inhibition of lipid peroxidation in the presence of alpha-tocopherol (alpha-TOH) under high radical flux conditions, suggesting that both can describe inhibited lipid peroxidation in solution under these conditions. TMP, but not the conventional model, could also predict the experimentally observed complex behavior of LDL lipid peroxidation induced with different concentrations of azo initiators. Specifically, TMP faithfully reproduced the observed kinetic chain length of lipid peroxidation of > > 1 at low and < < 1 at high concentration of the initiator (i.e., 0.2 and 10 mM, respectively for LDL at 1 mumol apoB-100/L) during the alpha-TOH-containing period of oxidation. It also demonstrated the experimentally observed nondependence of RpTMP on Ri. Kinetic analysis of radical generation and initiation of lipid peroxidation in an extended, two-compartment model of TMP showed that phase separation of bimolecular reactions in a suspension of LDL particles can lead to a approximately 400-fold increase in the rate of lipid hydroperoxide formation. The experimentally observed co-antioxidant action of water-soluble ascorbate and lipid-soluble ubiquinol-10 were verified using this model. A simple biophysical model constituting the reactions of TMP and incorporating the compartmental nature of an LDL suspension is proposed. Together, the results demonstrate that TMP is the only model that fits the experimental data describing the early stages of LDL lipid peroxidation under various oxidizing conditions. The implications of our findings are discussed in relation to atherogenesis and a recently proposed alternative model of LDL lipid peroxidation (Abuja and Esterbauer (1995) Chem. Res. Toxicol. 8, 753).

PMID: 8870982

Cosupplementation with coenzyme Q prevents the prooxidant effect of alpha-tocopherol and increases the resistance of LDL to transition metal-dependent oxidation initiation.

Thomas SR, Neuzil J, Stocker R Biochemistry Group, Heart Research Institute, Camperdown, Sydney, NSW, Australia.

Arterioscler Thromb Vasc Biol 1996 May;16(5):687-96

There is considerable interest in the ability of antioxidant supplementation, in particular with vitamin E, to attenuate LDL oxidation, a process implicated in atherogenesis. Since vitamin E can also promote LDL lipid peroxidation, we investigated the effects of supplementation with vitamin E alone or in combination with coenzyme Q on the early stages of the oxidation of isolated LDL. Isolated LDL was obtained from healthy subjects before and after in vitro enrichment with vitamin E (D-alpha-tocopherol, alpha-TOH) or dietary supplementation with D-alpha-TOH (1 g/d) and/or coenzyme Q (100 mg/d). LDL oxidation initiation was assessed by measurement of the consumption of alpha-TOH and cholesteryl esters containing polyunsaturated fatty acids and the accumulation of cholesteryl ester hydroperoxides during incubation of LDL in the transition metal-containing Ham's F-10 medium in the absence and presence of human monocyte-derived macrophages (MDMs). Native LDL contained 8.5 +/- 2 molecules of alpha-TOH and 0.5 to 0.8 molecules of ubiquinol-10 (CoQ10H2, the reduced form of coenzyme Q) per lipoprotein particle. Incubation of this LDL in Ham's F-10 medium resulted in a time-dependent loss of alpha-TOH with concomitant stoichiometric conversion of the major cholesteryl esters to their respective hydroperoxides. MDMs enhanced this process. LDL lipid peroxidation occurred via a radical chain reaction in the presence of alpha-TOH, and the rate of this oxidation decreased on alpha-TOH depletion. In vitro enrichment of LDL with alpha-TOH resulted in an LDL particle containing sixfold to sevenfold more alpha-TOH, and such enriched LDL was more readily oxidized in the absence and presence of MDMs compared with native LDL. In vivo alpha-TOH-deficient LDL, isolated from a patient with familial isolated vitamin E deficiency, was highly resistant to Ham's F-10-initiated oxidation, whereas dietary supplementation with vitamin E restored the oxidizability of the patient's LDL. Oral supplementation of healthy individuals for 5 days with either alpha-TOH or coenzyme Q increased the LDL levels of alpha-TOH and CoQ10H2 by two to three or three to four times, respectively. alpha-TOH-supplemented LDL was significantly more prone to oxidation, whereas CoQ10H2-enriched LDL was more resistant to oxidation initiation by Ham's F-10 medium than native LDL. Cosupplementation with both alpha-TOH and coenzyme Q resulted in LDL with increased levels of alpha-TOH and CoQ10H2, and such LDL was markedly more resistant to initiation of oxidation than native or alpha-TOH-enriched LDL. These results demonstrate that oral supplementation with alpha-TOH alone results in LDL that is more prone to oxidation initiation, whereas cosupplementation with coenzyme Q not only prevents this prooxidant activity of vitamin E but also provides the lipoprotein with increased resistance to oxidation.

PMID: 8963727

Coantioxidants make alpha-tocopherol an efficient antioxidant for low-density lipoprotein.

Thomas SR, Neuzil J, Mohr D, Stocker R Biochemistry Group, Heart Research Institute, Camperdown, Sydney, New South Wales, Australia.

Am J Clin Nutr 1995 Dec;62(6 Suppl):1357S-1364S

The oxidation of low-density lipoproteins (LDLs) is now commonly implicated as an important early event in atherogenesis. The resulting interest in LDL antioxidation has focused on alpha-tocopherol, the biologically and chemically most active form of vitamin E and quantitatively the major lipid-soluble antioxidant in extracts prepared from human LDL. We review advances made in our understanding of the molecular action of alpha-tocopherol in radical-mediated oxidation of isolated human LDL and how the vitamin's antioxidant activity is enhanced or even dependent on the presence of suitable reducing species, which are referred to as coantioxidants.

Publication Types: Review Review, tutorial

PMID: 7495231

Inverse deuterium kinetic isotope effect for peroxidation in human low-density lipoprotein (LDL): a simple test for tocopherol-mediated peroxidation of LDL lipids.

Witting PK, Bowry VW, Stocker R Biochemistry Group, Heart Research Institute, Sydney, N.S.W., Australia.

FEBS Lett 1995 Nov 13;375(1-2):45-9

alpha-Tocopherol (alpha-TOH) can act as a pro- or antioxidant for isolated ubiquinol-10-free human low density lipoprotein (LDL). We demonstrate that alpha-TOH is a more potent pro-oxidant than other forms of vitamin E for LDL peroxidation initiated by mild fluxes of aqueous peroxyl radicals and low concentrations of Cu2+. A simple deuterium exchange test shows that alpha-TOH switches from pro- to anti-oxidant at Cu2+:LDL ratios > 2.5. The results suggest that this test may be useful to distinguish 'inhibited' peroxidation of emulsion lipids propagated via the lipid peroxyl radical from that mediated via the antioxidant radical.

PMID: 7498477

Prevention of tocopherol-mediated peroxidation in ubiquinol-10-free human low density lipoprotein.

Bowry VW, Mohr D, Cleary J, Stocker R Biochemistry Group, Heart Research Institute, Sydney, New South Wales, Australia.

J Biol Chem 1995 Mar 17;270(11):5756-63

Oxidation of low density lipoprotein (LDL) may be involved in the development of atherosclerosis. It has recently been shown that alpha-tocopherol (alpha-TOH) can act either as an antioxidant or prooxidant for isolated low density lipoprotein (LDL). In the absence of an effective co-antioxidant, alpha-TOH is a prooxidant and this activity is evidently due to reaction of the alpha-tocopheroxyl radical (alpha-TO.) with the LDL's polyunsaturated lipids (Bowry, V. B., and Stocker, R. (1993) J. Am. Chem. Soc. 115, 6029-6045). Herein we examined the effectiveness of selected natural and synthetic radical scavengers as co-antioxidants for inhibiting peroxyl radical-induced peroxidation in LDL that is devoid of ubiquinol-10 (an effective endogenous co-antioxidant) but still contains most of its natural complement of alpha-TOH. Various quinols, catechols, and aminophenols, as well as ascorbate, 6-palmityl ascorbate, and bilirubin, were very effective co-antioxidants under our test conditions, whereas ordinary phenolic antioxidants, including short-tailed alpha-TOH homologues, were less effective. Reduced glutathione, urate, and Probucol were ineffective. These findings confirm that the prooxidant activity of alpha-TOH in LDL relies heavily on the segregation of water-insoluble radicals (particularly alpha-TO.) into individual LDL particles, since it was those compounds that are expected to either irreversibly reduce alpha-TO. or accelerate the diffusion of radicals between particles which most effectively inhibited the tocopherol-mediated phase of peroxidation. Theoretical and practical implications of these findings are discussed, as is their relevance to the "LDL oxidation" hypothesis of atherogenesis.

PMID: 7890704

Radical-mediated oxidation of isolated human very-low-density lipoprotein.

Mohr D, Stocker R Heart Research Institute, Camperdown, Australia.

Arterioscler Thromb 1994 Jul;14(7):1186-92

Oxidative modification of human low-density lipoprotein (LDL) has received much attention because of its suggested involvement in the early events of atherogenesis. In contrast, little data exist concerning the oxidation of human very-low-density lipoprotein (VLDL), although such modification promotes foam cell formation by these lipoproteins. We therefore investigated the radical-mediated oxidation of VLDL by using controlled oxidizing conditions and sensitive and specific methods to assess lipoprotein lipid oxidation and antioxidation. We observed that the ratio of alpha-tocopherol to coenzyme Q10 in VLDL was close to that of LDL, suggesting that these lipoproteins may transport some coenzyme Q10 to extrahepatic tissues, as they do tocopherol. Most of the coenzyme Q10 associated with VLDL was present in its reduced, antioxidant active form, ubiquinol-10. The small amounts of ubiquinol-10 in VLDL provided the lipoprotein lipids with a highly efficient antioxidant protection. Also, the kinetics of radical-mediated lipid peroxidation in VLDL resembled that in LDL and therefore also probably proceeded via the recently described tocopherol-mediated peroxidation mechanism. Oxidation competition experiments using aqueous radicals and physiological concentrations and molar ratios of LDL and VLDL indicated that in contrast to the situation with high-density lipoproteins, lipid peroxidation was initiated and detected simultaneously in the former two lipoprotein particles. However, once initiated, peroxidation propagated at an approximately twofold higher rate in VLDL than LDL. Our studies suggest that radical-mediated lipid (per)oxidation proceeds via similar mechanisms in isolated LDL and VLDL. We conclude that efficient LDL antioxidants are also likely to be effective protective agents for VLDL.

PMID: 8018676

Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation.

Neuzil J, Stocker R Biochemistry Group, Heart Research Institute, Sydney, New South Wales, Australia.

J Biol Chem 1994 Jun 17;269(24):16712-9

Peroxidation of the lipid moieties of low density lipoproteins (LDL) is regarded as an early event in atherogenesis. Because bilirubin is a physiological reductant with antioxidant activities, we investigated its inhibitory action on the radical-mediated oxidation of LDL and plasma lipids. Exposing fresh human blood plasma to lipophilic peroxyl radicals generated from 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN) resulted in rapid oxidation of ubiquinol-10, followed by that of ascorbate and bilirubin. Plasma lipids were well protected from peroxidation as long as these three antioxidants were present, as assessed by the amounts of cholesterylester hydroperoxides formed during this period. Following consumption of these antioxidants, and in the presence of alpha-tocopherol, the rate of hydroperoxide formation increased sharply with roughly 2 molecules of cholesterylester hydroperoxides being formed for each peroxidation initiating event. Supplementation of AMVN-oxidizing plasma with exogenous bilirubin at the onset of rapid lipid peroxidation, i.e. after depletion of endogenous ubiquinol-10, ascorbate, and bilirubin, led to a halt in both hydroperoxide formation and consumption of alpha-tocopherol. When isolated LDL was incubated with AMVN, approximately 9 molecules of cholesterylester hydroperoxides were formed per peroxidation initiating event and while alpha-tocopherol was consumed. Addition of free or albumin-bound bilirubin to isolated LDL at the onset of oxidation resulted in a strong inhibition of hydroperoxide formation and alpha-tocopherol consumption, the effect being more pronounced with the free pigment. Addition of the corresponding amounts of albumin alone was without effect. In the presence of albumin-bound bilirubin, some 30% of the pigment was initially converted into biliverdin, whereas formation of this oxidation product was not observed with the free pigment. Also, the presence of bilirubin oxidase partially reversed the inhibitory activity of bilirubin on AMVN-induced LDL oxidation in the absence but not presence of albumin. An attenuation of hydroperoxide formation and a temporary increase in LDL's alpha-tocopherol concentration were observed when free- or albumin-bound bilirubin were added to AMVN-oxidizing, alpha-tocopherol-containing LDL. In contrast, hydroperoxide formation was not inhibited significantly when the albumin-bound pigment was added to oxidizing LDL after complete consumption of its alpha-tocopherol. Our results show that bilirubin inhibits oxidation of LDL lipids initiated within the lipoprotein core and indicate that this activity is mediated by interaction of the pigment with LDL's alpha-tocopherol.

PMID: 8206992

The oxidation of blood plasma and low density lipoprotein components by chemically generated singlet oxygen.

Wagner JR, Motchnik PA, Stocker R, Sies H, Ames BN Division of Biochemistry and Molecular Biology, University of California, Berkeley 94720.

J Biol Chem 1993 Sep 5;268(25):18502-6

Human blood plasma and freshly isolated LDL were exposed to singlet oxygen (1O2) by thermal decomposition of synthetic endoperoxides. Exposure of blood plasma to 20 mM water-soluble 1O2 generator resulted in the depletion of ascorbate (100%), urate (75%), ubiquinol-10 (65%), protein thiols (50%), and bilirubin (25%), whereas under these conditions the levels of alpha-tocopherol, beta-carotene, and lycopene remained unchanged. The following rates of depletion were obtained by kinetic analysis (moles depleted per 100 mol of 1O2 consumed): protein thiols (5), urate (5), ascorbate (4), bilirubin (1), and ubiquinol-10 (0.008). In contrast, the rates of depletion using the lipid-soluble 1O2 generator were faster for bilirubin (13-fold), protein thiols (9-fold), ubiquinol-10 (8-fold), and ascorbate (5-fold), and slower for urate (2-fold). The formation of lipid hydroperoxides, including mostly cholesteryl linoleate hydroperoxide, was observed in 1O2-treated plasma (0.007-0.009 mol/100 mol 1O2) and LDL solutions (0.086 mol/100 mol 1O2). Based on competition kinetics, we estimate that 98% of 1O2 generated in the aqueous phase of plasma is quenched by components in this phase, mostly by plasma protein (63%; 6% by protein thiols), urate (9%; 5% by chemical quenching), and bilirubin (5%; 1% by chemical quenching). Ascorbate and ubiquinol-10 do not contribute to 1O2 quenching in plasma, and their oxidation is probably mediated secondary species. The remaining 1O2 generated in plasma (2%) diffuses into lipoprotein leading to the formation of lipid hydroperoxides with an efficiency of about 100-fold greater than that compared to aqueous generated 1O2. The principal 1O2 quenchers in LDL include apoB (42%), lycopene and beta-carotene (40%), and alpha-tocopherol (17%). The importance of carotenoids in the quenching of 1O2 in lipoprotein suggest that the beneficial effects of these compounds in health may in part be due to the elimination of this species in biology and medicine.

PMID: 8360151

Extracellular reduction of ubiquinone-1 and -10 by human Hep G2 and blood cells.

Stocker R, Suarna C Biochemistry Group, Heart Research Institute, Camperdown, NSW, Australia.

Biochim Biophys Acta 1993 Aug 20;1158(1):15-22

Ubiquinol-10 (CoQ10H2) is present in human low density lipoproteins (LDL) where it contributes significantly to the antioxidant defenses against radical-mediated oxidative damage. As CoQ10H2 becomes oxidized to ubiquinone-10 (CoQ10) during the earliest stages of in vitro oxidation of LDL, we investigated a possible cellular recycling of oxidized CoQ10H2, adding CoQ10 or its ambiphilic, short-chain analogue ubiquinone-1 (CoQ1), to cells that are exposed to LDL in vivo. Whole blood, isolated red blood cells and human hepatoma Hep G2 cells (used as a model of hepatocytes) rapidly and efficiently reduced added CoQ1 to ubiquinol-1 (CoQ1H2) detectable outside the cells. In whole blood the same steady-state level of CoQ1H2 was reached whether an equimolar amount of CoQ1 or CoQ1H2 was added. Red cell membranes also showed some reducing activity, whereas CoQ1 added to human blood plasma remained largely in its oxidized form. Cell- and membrane-mediated reduction of CoQ1 was enhanced by NADH, FAD, or human plasma. In comparison to this rapid reduction of extracellular CoQ1, formation of CoQ10H2 from CoQ10 incorporated into human LDL by red blood and Hep G2 cells was slow. Our results show that although human blood cells and Hep G2 cells are endowed with a highly reducing activity for CoQ1, the natural CoQ10 does not appear to represent an efficient substrate for this activity.

PMID: 8394740

Circulating lipid hydroperoxide levels in human hyperhomocysteinemia. Relevance to development of arteriosclerosis.

Dudman NP, Wilcken DE, Stocker R Department of Cardiovascular Medicine, University of New South Wales, Prince Henry Hospital, Little Bay, Australia.

Arterioscler Thromb 1993 Apr;13(4):512-6

Elevated circulating homocyst(e)ine is a risk factor for occlusive vascular disease. We explored whether elevated plasma homocyst(e)ine is associated with increased plasma lipid hydroperoxides that might trigger vascular disease. We obtained plasma containing high levels of homocyst(e)ine from four patients with a homozygous deficiency of cystathionine beta-synthase activity and also from four heterozygotes with a deficiency of this enzyme after an oral methionine load. The mean plasma non-protein-bound homocyst(e)ine level in all subjects was more than 11-fold higher than the mean normal fasting value. Levels of high density lipoprotein (HDL) cholesteryl ester hydroperoxides (CEOOH), normalized against the concentration of free cholesterol in HDL, were not elevated in our subjects (mean +/- SD, 0.0091 +/- 0.0061) compared with values for 14 fasting healthy donors (0.0164 +/- 0.0086). An inverse dependency was observed between plasma total homocyst(e)ine and HDL CEOOH (r = -0.78, p = 0.023). Also, the ubiquinol-10/ubiquinone-10 ratio in HDL, which is expected to fall during oxidative stress, increased with plasma homocyst(e)ine. Since HDL contains the majority of detectable plasma lipid hydroperoxides, of which CEOOHs are the most abundant, our data suggest that an elevated plasma homocyst(e)ine level does not enhance oxidative stress, increase the levels of lipid hydroperoxides in plasma, or generate vascular damage by this mechanism.

PMID: 8466886

Comparative antioxidant activity of tocotrienols and other natural lipid-soluble antioxidants in a homogeneous system, and in rat and human lipoproteins.

Suarna C, Hood RL, Dean RT, Stocker R Biochemistry Group, Heart Research Institute, Camperdown, Australia.

Biochim Biophys Acta 1993 Feb 24;1166(2-3):163-70

The antioxidant activity of tocotrienols toward peroxyl radicals was compared with that of other natural lipid-soluble antioxidants in three different systems by measuring the temporal disappearance of antioxidants and the formation of lipid hydroperoxides. In homogeneous solution, the initial rates of consumption of the various antioxidants, assessed by competition experiments between pairs of antioxidants for radicals, decreased in the order: ubiquinol-10 approximately ubiquinol-9 > alpha-tocopherol approximately alpha-tocotrienol > beta-carotene approximately lycopene > gamma-tocopherol approximately gamma-tocotrienol. Following in vitro incubation of human plasma with alpha-tocotrienol, this form of vitamin E was present in all classes of lipoproteins isolated from the supplemented plasma. Dietary supplementation of rats and humans with a tocotrienol-rich preparation resulted in a dose-dependent appearance of alpha- and gamma-tocotrienols in plasma and all circulating lipoproteins, respectively. Exposure of such enriched rat plasma to aqueous peroxyl radicals resulted in simultaneous consumption of the alpha- and then gamma-isomers of vitamin E. The sequence of radical-induced consumption of antioxidants in freshly isolated, in vitro and in vivo tocotrienol-enriched low density lipoprotein (LDL) was again ubiquinol-10 > alpha-tocotrienol approximately alpha-tocopherol > carotenoids > gamma-tocopherol approximately gamma-tocotrienol. Under conditions where radicals were generated at constant rates, the rate of lipid hydroperoxide formation in LDL was not constant. It proceeded in at least three stages separated by the phase of ubiquinol-10 consumption and, subsequently, that of alpha-tocopherol/alpha-tocotrienol. Our results show that dietary tocotrienols become incorporated into circulating human lipoproteins where they react with peroxyl radicals as efficiently as the corresponding tocopherol isomers.

PMID: 8443232

Oxidation of low-density lipoprotein with hypochlorite causes transformation of the lipoprotein into a high-uptake form for macrophages.

Hazell LJ, Stocker R Heart Research Institute, Biochemistry Group, Camperdown, N.S.W., Australia.

Biochem J 1993 Feb 15;290 ( Pt 1):165-72

Oxidation of low-density lipoprotein (LDL) lipid is thought to represent the initial step in a series of oxidative modification reactions that ultimately transform this lipoprotein into an atherogenic high-uptake form that can cause lipid accumulation in cells. We have studied the effects of hypochlorite, a powerful oxidant released by activated monocytes and neutrophils, on isolated LDL. Exposure of LDL to reagent hypochlorite (NaOCl) at 4 degrees C resulted in immediate and preferential oxidation of amino acid residues of apoprotein B-100, the single protein associated with LDL. Neither lipoprotein lipid nor LDL-associated antioxidants, except ubiquinol-10, represented major targets for this oxidant. Even when high concentrations of NaOCl were used, only low levels of lipid hydroperoxides could be detected with the highly sensitive h.p.l.c. post-column chemiluminescence detection method. Lysine residues of apoprotein B-100 quantitatively represented the major target, scavenging some 68% of the NaOCl added, with tryptophan and cysteine together accounting for an additional 10% of the oxidant. Concomitant with the loss of LDL's amino groups, chloramines were formed and the anionic surface charge of the lipoprotein particle increased, indicated by a 3-4-fold increase in electrophoretic mobility above that of native LDL on agarose gels. While both these changes could be initially reversed by physiological reductants such as ascorbic acid and methionine, incubation of the NaOCl-modified LDL at 37 degrees C resulted in increasing resistance of the modified lysine residues against reductive reversal. Exposure of mouse peritoneal macrophages to NaOCl-oxidized LDL resulted in increased intracellular concentrations of cholesterol and cholesteryl esters. These findings suggest that lipid-soluble antioxidants associated with LDL do not efficiently protect the lipoprotein against oxidative damage mediated by hypochlorite, and that extensive lipid oxidation is not a necessary requirement for oxidative LDL modification that leads to a high-uptake form of the lipoprotein.

PMID: 8439285

Autoxidation of lipids and antioxidation by alpha-tocopherol and ubiquinol in homogeneous solution and in aqueous dispersions of lipids: unrecognized consequences of lipid particle size as exemplified by oxidation of human low density lipoprotein.

Ingold KU, Bowry VW, Stocker R, Walling C Steacie Institute for Molecular Sciences, National Research Council of Canada, Ottawa, ON.

Proc Natl Acad Sci U S A 1993 Jan 1;90(1):45-9

Recent studies on the initial stages in oxidation of low density lipoprotein (LDL) have revealed certain previously unrecognized similarities to emulsion polymerization and some quite unexpected features including the following: (i) ascorbate is an extremely effective antioxidant for LDL containing alpha-tocopherol (alpha-TOH); (ii) in the presence of alpha-TOH and in the absence of both ascorbate and ubiquinol 10 (Q10H2), oxidation of LDL occurs via a free radical chain; (iii) Q10H2 is a much better antioxidant for LDL than alpha-TOH, although the reverse is true in homogeneous systems. We show here that these problems can be solved on the basis of three simple hypothesis, each of which is based on known chemistry: (i) alpha-TOH in LDL can be regenerated from its radical, alpha-TO., by ascorbate; (ii) in the absence of ascorbate and Q10H2, the alpha-TOH in LDL acts as a chain-transfer agent rather than as a radical trap; (iii) Q10H2 is a much more effective chain-breaking antioxidant than alpha-TOH in LDL because the semiquinone radical Q10H. exports its radical character from the LDL into the aqueous phase. Our conclusions imply that the search for better antiatherosclerotic drugs might profitably focus on antioxidants capable of exporting radicals from LDL particles or otherwise increasing the traffic of radicals between particles.

PMID: 8419943

Vitamin E in human low-density lipoprotein. When and how this antioxidant becomes a pro-oxidant.

Bowry VW, Ingold KU, Stocker R Biochemistry Group, Heart Research Institute, Sydney, New South Wales, Australia.

Biochem J 1992 Dec 1;288 ( Pt 2):341-4

Uptake of oxidatively modified low-density lipoprotein (LDL) by cells in the arterial wall is believed to be an important early event in the development of atherosclerosis. Because vitamin E is the major antioxidant present in human lipoproteins, it has received much attention as a suppressor of LDL lipid oxidation and as an epidemiological marker for ischaemic heart disease. However, a careful examination of lipid peroxidation in LDL induced by a steady flux of aqueous peroxyl radicals has demonstrated that, following consumption of endogenous ubiquinol-10, the rate of peroxidation (i) declines as vitamin E is consumed, (ii) is faster in the presence of vitamin E than following its complete consumption, (iii) is substantially accelerated by enrichment of the vitamin in LDL, either in vitro or by diet, and (iv) is virtually independent of the applied radical flux. We propose that perodixation is propagated within lipoprotein particles by reaction of the vitamin E radical (i.e. alpha-tocopheroxyl radical) with polyunsaturated fatty acid moieties in the lipid. This lipid peroxidation mechanism, which can readily be rationalized by the known chemistry of the alpha-tocopheroxyl radical and by the radical-isolating properties of fine emulsions such as LDL, explains how reagents which reduce the alpha-tocopheroxyl radical (i.e. vitamin C and ubiquinol-10) strongly inhibit lipid peroxidation in vitamin E-containing LDL.

PMID: 1463440

High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors.

Bowry VW, Stanley KK, Stocker R Biochemistry Group, Heart Research Institute, Sydney N.S.W., Australia.

Proc Natl Acad Sci U S A 1992 Nov 1;89(21):10316-20

Analysis of untreated fresh blood plasma from healthy, fasting donors revealed that high density lipoprotein (HDL) particles carry most (approximately 85%) of the detectable oxidized core lipoprotein lipids. Low density lipoprotein (LDL) lipids are relatively peroxide-free. In vitro the mild oxidation of gel-filtered plasma from fasting donors with a low, steady flux of aqueous peroxyl radicals initially caused preferential oxidation of HDL rather than LDL lipids until most ubiquinol-10 present in LDL was consumed. Thereafter, LDL core lipids were oxidized more rapidly. Isolated lipoproteins behaved similarly. Preferential accumulation of lipid hydroperoxides in HDL reflects the lack of antioxidants in most HDL particles compared to LDL, which contained 8-12 alpha-tocopherol and 0.5-1.0 ubiquinol-10 molecules per particle. Cholesteryl ester hydroperoxides (CEOOHs) in HDL and LDL were stable when added to fresh plasma at 37 degrees C for up to 20 hr. Transfer of CEOOHs from HDL to LDL was too slow to have influenced the in vitro plasma oxidation data. Incubation of mildly oxidized LDL and HDL with cultured hepatocytes afforded a linear removal of CEOOHs from LDL (40% loss over 1 hr), whereas a fast-then-slow biphasic removal was observed for HDL. Our data show that HDL is the principal vehicle for circulating plasma lipid hydroperoxides and suggest that HDL lipids may be more rapidly oxidized than those in LDL in vivo. The rapid hepatic clearance of CEOOHs in HDL could imply a possible beneficial role of HDL by attenuating the build-up of oxidized lipids in LDL.

PMID: 1332045

The participation of nitric oxide in cell free- and its restriction of macrophage-mediated oxidation of low-density lipoprotein.

Jessup W, Mohr D, Gieseg SP, Dean RT, Stocker R Cell Biology Group, Heart Research Institute, Sydney, Australia.

Biochim Biophys Acta 1992 Oct 13;1180(1):73-82

The potential role of nitric oxide radical (NO .) in macrophage-mediated oxidation and conversion of human low density lipoprotein (LDL) to a high-uptake form was examined by exposing LDL to aerobic solutions of either NO . or 3-morpholino-sydnonimine-hydrochloride (SIN-1, a compound that spontaneously forms NO . and superoxide anion radical) or to mouse peritoneal macrophages in the presence and absence of modulators of cellular NO . synthesis. Incubation with NO . alone caused oxidation of LDL's ubiquinol-10 and accumulation of small amounts of lipid hydroperoxides, but failed to form any high-uptake ligand for endocytosis by macrophages and did not alter the LDL particle charge or the integrity of apoB. Exposure of LDL to SIN-1 resulted in complete consumption of all antioxidants and substantial formation of lipid hydroperoxides, but again had little effect on the lipoprotein particle charge or generation of high-uptake form. Preincubation of macrophages with interferon-gamma increased the cells ability to generate reactive nitrogen metabolites. The extent of cell-mediated oxidation of LDL and the generation of high-uptake LDL was substantial in resident cells in which NO . synthesis was barely detectable, depressed in cells active in NO . synthesis and restored when NO . synthesis was suppressed by the arginine analogue, NMMA. These results suggest that, while together with superoxide anion radical, NO . can oxidize LDL, its synthesis is not required for macrophage-mediated oxidation of LDL in vitro; rather it exerts a protective role in preventing oxidative LDL modification by macrophages.

PMID: 1327163

Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation.

Mohr D, Bowry VW, Stocker R Biochemistry Group, Heart Research Institute, Sydney, Australia.

Biochim Biophys Acta 1992 Jun 26;1126(3):247-54

Ubiquinol-10 (CoQH2, the reduced form of coenzyme Q10) is a potent antioxidant present in human low-density lipoprotein (LDL). Supplementation of humans with ubiquinone-10 (CoQ, the oxidized coenzyme) increased the concentrations of CoQH2 in plasma and in all of its lipoproteins. Intake of a single oral dose of 100 or 200 mg CoQ increased the total plasma coenzyme content by 80 or 150%, respectively, within 6 h. Long-term supplementation (three times 100 mg CoQ/day) resulted in 4-fold enrichment of CoQH2 in plasma and LDL with the latter containing 2.8 CoQH2 molecules per LDL particle (on day 11). Approx. 80% of the coenzyme was present as CoQH2 and the CoQH2/CoQ ratio was unaffected by supplementation, indicating that the redox state of coenzyme Q10 is tightly controlled in the blood. Oxidation of LDL containing various [CoQH2] by a mild, steady flux of aqueous peroxyl radicals resulted immediately in very slow formation of lipid hydroperoxides. However, in each case the rate of lipid oxidation increased markedly with the disappearance of 80-90% CoQH2. Moreover, the cumulative radical dose required to reach this 'break point' in lipid oxidation was proportional to the amount of CoQH2 incorporated in vivo into the LDL. Thus, oral supplementation with CoQ increases CoQH2 in the plasma and all lipoproteins thereby increasing the resistance of LDL to radical oxidation.

PMID: 1637852

Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol.

Stocker R, Bowry VW, Frei B Heart Research Institute, Sydney, New South Wales, Australia.

Proc Natl Acad Sci U S A 1991 Mar 1;88(5):1646-50

The temporal disappearance of natural antioxidants associated with human low density lipoprotein (LDL) in relation to the appearance of various classes of lipid hydroperoxides was investigated under three types of oxidizing conditions. Freshly isolated LDL from plasma of healthy subjects was free of detectable amounts of lipid hydroperoxides as measured by HPLC postcolumn chemiluminescence detection. Exposure of such LDL to a mild, constant flux of aqueous peroxyl radicals led to rapid and complete oxidation of ubiquinol-10, followed by slower partial depletion of lycopene, beta-carotene, and alpha-tocopherol. After an initial lag period of complete inhibition of detectable lipid peroxidation, formation of hydroperoxides of cholesterol esters, triglycerides, and phospholipids was observed. The onset of detectable lipid peroxidation corresponded closely with the completion of ubiquinol-10 consumption. However, small amounts of ascorbate, present as a contaminant in the LDL preparation, rather than ubiquinol-10 itself were responsible for the initial lag period. Thus, complete consumption of ubiquinol-10 was preceded by that of ascorbate, and exposure of ascorbate-free LDL to aqueous peroxyl radicals resulted in immediate formation of detectable amounts of lipid hydroperoxides. The rate of radical-mediated formation of lipid hydroperoxides in ascorbate-free LDL was low as long as ubiquinol-10 was present, but increased rapidly after its consumption, even though more than 80% and 95% of endogenous carotenoids and alpha-tocopherol, respectively, were still present. Qualitatively similar results were obtained when peroxyl radicals were generated within LDL or when the lipoprotein was exposed to oxidants produced by activated human polymorphonuclear leukocytes. LDL oxidation was reduced significantly by supplementing the lipoprotein preparation with physiological amounts of either ascorbate or ubiquinol-10. Our data show that ubiquinol-10 is much more efficient in inhibiting LDL oxidation than either lycopene, beta-carotene, or alpha-tocopherol.

PMID: 2000375

Oxidative stress and abnormal cholesterol metabolism in patients with adult respiratory distress syndrome.

Cross CE, Forte T, Stocker R, Louie S, Yamamoto Y, Ames BN, Frei B Department of Medicine, University of California, Davis.

J Lab Clin Med 1990 Apr;115(4):396-404

Oxidative stress has been implicated in the adult respiratory distress syndrome (ARDS). In this study, we determined the levels of selected antioxidants in the plasma of 25 patients with ongoing ARDS and 16 healthy control subjects. We also examined these plasmas and pulmonary edema fluid of ARDS patients for lipid hydroperoxides. Both ascorbate and ubiquinol-10 concentrations in ARDS plasma were significantly lower than in normal plasma. alpha-Tocopherol concentrations, when standardized to total plasma cholesterol, were not lower in ARDS patients than in normal subjects. A pattern of antioxidant levels virtually identical to that observed in ARDS plasma was obtained after in vitro incubation of healthy plasma with stimulated polymorphonuclear leukocytes: very low ascorbate, decreased ubiquinol-10, and unchanged alpha-tocopherol concentrations. Nanomolar concentrations of lipid hydroperoxides were found in pulmonary edema fluid of ARDS patients, but not in plasma, nor in the plasma of healthy individuals, when a sensitive and selective chemiluminescence assay for hydroperoxides was used. ARDS patients also showed significant decreases in plasma levels of cholesterol esters in conjunction with discoidal high-density lipoprotein profiles, indicating a decrease in lecithin-cholesterol acyltransferase activity. We conclude that ARDS is associated with oxidative stress, possibly exerted by oxidants released from activated phagocytic leukocytes, and major changes in plasma cholesterol metabolism.

PMID: 2324609
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