The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 11 No.
6 • October 2008
Myeloperoxidase (MPO), a Risk Factor in Atherogenesis;
Protective Dietary Substances
Myeloperoxidase (MPO) is an important enzyme in immune activity, such as its function as the major component of neutrophil azurophilic granules (release of which is part of the inflammatory process induced by neutrophils) and its presence in monocytes (but not macrophages). MPO uses hydrogen peroxide and chloride anions to produce hypochlorous acid, an important microbial killer.
MPO in Neurodegeneration
Microglia, which are immune cells resident in the brain, also generate MPO, which is associated with the chronic inflammation of neurodegeneration in the brain. It was also reported that MPO is released by microglia during phagocytosis (of, for example, bacteria, fungi, and viruses) but that, since microglia are not very effective phagocytes for beta-amyloid, “frustrated phagocytosis” could lead to copious quantities of MPO in the extracellular milieu because the phagolysosome (where the phagocytosis of beta-amyloid is being “attempted”) does not close.
MPO and Protein Modification
Myeloperoxidase is also involved in protein modifications by a process called carbamylation (in which urea-generated cyanate modifies lysine residues in protein molecules), which can lead to protein dysfunctions, as occur in several diseases.
MPO Damage to HDL and apoA1 Increases Risk of Cardiovascular Disease
It has recently been reported in a number of papers that MPO is an important source of nitrating oxidants that damage the atheroprotective properties of HDL and apoA1. “. . . both in vitro and in vivo studies demonstrate accompanying functional impairment in ABCA1-dependent cholesterol efflux from cholesterol-laden macrophages with increasing levels of oxidation of apoA-1, suggesting that oxidative processes catalyzed by MPO may participate in the development of ‘dysfunctional’ or ‘proinflammatory’ forms of HDL.” “High concentrations of enzymatically active myeloperoxidase have been found in human vascular lesions, and characteristic protein and lipid oxidation products of the enzyme have been detected in LDL isolated from atherosclerotic tissue.”
MPO and Lung Inflammation
Alveolar macrophages (polymorphonuclear leukocyte neutrophils) have also been reported to be activated by myeloperoxidase released in models of lung inflammation, as occurs in (for example) asthma and pneumonia.
MPO and Lipid Peroxidation at Sites of Inflammation
Another paper reports that MPO functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. As the authors of the paper note, “Initiation of lipid peroxidation and the formation of bioactive eicosanoids are pivotal processes in inflammation and atherosclerosis.” The authors suggest that there is a “need for development of inhibitors for MPO as a novel anti-inflammatory therapeutic.”
Natural Products that Inhibit or Reduce MPO Activity
The flavonoid quercetin is a potent inhibitor of human MPO in a system using stimulated human neutrophils. We include 130 mg of quercetin in the recommended 12 capsules per day of our Personal Radical Shield™.
Resveratrol has been reported to inhibit the activity of equine neutrophil MPO by a direct interaction with MPO, inhibiting the chlorination, oxidation, and nitration activities of MPO in a dose-dependent manner. MPO release has been associated with various inflammatory disorders of horses, including laminitis, recurrent airway obstructions, and intestinal strangulation pathologies. In the equine neutrophil system reported in Reference 8, 10 μM resveratrol inhibited 90% of the MPO nitration and chlorination reactions and 80% of the MPO oxidation reactions. Our Durk Pearson & Sandy Shaw’s MealMate™ contains 20 mg of resveratrol per capsule (suggested daily dose 3–8 capsules).
Cocoa flavanols have also been reported to inhibit MPO-induced lipid peroxidation of LDL in the presence of nitrite. The paper reports that “Dietary flavonoids including (-)-epicatechin, a major flavan-3-ol in cocoa products, grapes, and wine, are substrates of MPO as well as potent inhibitors of LPO [lipid peroxidation] in LDL at micromolar concentrations.” As the authors also note, “More recently, it has been reported that MPO modifies not only LDL but also HDL, thereby abolishing the antiatherosclerotic actions of HDL, thus extending our picture on the role of MPO in plasma lipoprotein metabolism.” Our Durk Pearson & Sandy Shaw’s Glycemic Control LifeByChocolate™ high-fiber/high-protein/low-digestible-carbohydrates chocolate pudding mix contains lots of cocoa. A delicious new variation for our chocolate pudding mix is to sprinkle Chinese 5 spice (a fragrant combination of star anise, pepper, fennel, cloves, and cinnamon) on top. We use it generously for a really great flavor burst.
In another paper, which examined the effect of several flavonoids on MPO activity in a chemical assay, it was found that quercetin was the strongest inhibitor of MPO-catalyzed dityrosine formation, followed (in descending order of potency) by: kaempferol > fisetin > luteolin > taxifolin. A major metabolite of quercetin, quercetin-3-β-D-glucuronide, was also a potent inhibitor. They reported that quercetin was also the strongest radical scavenger, followed by luteolin > fisetin > taxifolin > kaempferol.
- Rader & Ischiropoulos. ‘Multipurpose oxidase’ in atherogenesis. Nature Med 13(10):1146-7 (2007).
- Lefkowitz & Lefkowitz. Microglia and myeloperoxidase: a deadly partnership in neurodegenerative disease. Free Rad Biol Med 45:726-31 (2008).
- Zheng et al. Apolipoprotein A-1 is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J Clin Invest 114(4):529-41 (2004).
- Pennathur et al. Human atherosclerotic intima and blood of patients with established coronary artery disease contain high density lipoprotein damaged by reactive nitrogen species. J Biol Chem 279(41):42977-83 (2004).
- Grattendick et al. Alveolar macrophage activation by myeloperoxidase. Am J Respir Cell Mol Biol 26:716-22 (2002).
- Zhang et al. Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. J Biol Chem 277(48):46116-22 (2002).
- Pincemail et al. Human myeloperoxidase activity is inhibited in vitro by quercetin. Comparison with three related compounds. Experientia 44:450-3 (1988).
- Kohnen et al. Resveratrol inhibits the activity of equine neutrophil myeloperoxidase by a direct interaction with the enzyme. J Agric Food Chem 55:8080-7 (2007).
- Schewe & Sies. Myeloperoxidase-induced lipid peroxidation of LDL in the presence of nitrite. Protection by cocoa flavanols. BioFactors 24:49-58 (2005).
- Shiba et al. Flavonoids as substrates and inhibitors of myeloperoxidase: molecular actions of aglycone and metabolites. Chem Res Toxicol 21:1600-9 (2008).