• Chlorine Online Home
• All about chlorine
• All about the European chlorine industry
• Euro Chlor Regulatory Affairs
• Energy - Climate NEW
• Euro Chlor Science Programme
  • Science communications
  • Focus on Chlorine Science
  • Key Science Information Sheets
  • Science dossiers
  • RCEI: Reactive Chlorine Emission Inventory
  • Natural chemistry of chlorine in the environment
    • The natural chemistry of inorganic chlorine in the lower atmosphere: A potential source for organochlorine compounds
    • Natural organochlorines in precipitation and surface waters
    • Natural organochlorines in groundwater
    • The occurence and origin of organic chlorine in soil
    • Natural organochlorines in sediments
    • The diversity of natural organochlorines in living organisms
    • The natural production of Volatile organochlorines in the oceans
    • Natural production of organochlorines by terrestrial fungi and plants
    • Fungi as sources of chlorinated aromatics in the terrestrial environment
    • Enzymatic halogenation
    • Bio(de)halogenation
    • Protein chlorination in human atherosclerotic heart disease
    • The natural formation of polychlorinated dioxins and dibenzofurans
    • Glossary
    • Further information
    • Contacts
  • Risk & hazard – How they differ
  • Marine risk assessments
  • High Production Volume chemicals
  • The Biocidal Products Directive
• REACH update - Consortia
• Euro Chlor Technical Corner
• News room
• All about Euro Chlor
• The European Chlorinated Solvent Association (ECSA)
• The Chlorinated Paraffins Sector Group
• Library
• Useful links
• Contact us
• How to find us
• Access keys

Protein chlorination in human atherosclerotic heart disease

08/2008

White blood cells generate hydrogen peroxide (H₂O₂) and secrete the heme protein myeloperoxidase. The major reaction catalyzed by myeloperoxidase is the two-electron oxidation of chloride (Cl-) to hypochlorous acid (HOCl).

Cl- + H₂O₂ + H+ = HOCl + H₂O

HOCl is a potent cytotoxin for bacteria, viruses, and fungi. The generation of HOCl by white blood cells plays a key role in host defenses against invading pathogens. Oxidant production by phagocytic white cells is also potentially deleterious, however, and may represent an important pathway for tissue damage in disorders ranging from arthritis to ischemia reperfusion injury to cancer.

Oxidative tissue injury is thought to be of central importance in promoting atherosclerotic heart disease, the leading cause of death in industrialized societies. One important risk factor in atherosclerosis is an elevated level of low density lipoprotein (LDL), the "bad" form of blood cholesterol. It is thus paradoxical that LDL fails to exert effects that promote heart disease in vitro. Oxidation of LDL, however, renders the lipoprotein atherogenic.

Many lines of evidence indicate that oxidation of LDL is of central importance in the promotion of heart disease. Oxidized LDL has been isolated from atherosclerotic lesions, and antioxidants retard atherosclerosis in animals. Moreover, a high intake of antioxidants is associated with a decreased risk of heart disease in humans. More significantly, dietary supplementation with vitamin E - a lipid soluble antioxidant that is carried predominantly in LDL - prevents heart attacks in patients with atherosclerosis.

Despite the intense interest in LDL oxidation, the pathway to promote LDL oxidation in vivo has not yet been identified. One potential mechanism involves white blood cells, the cellular hallmark of the atherosclerotic lesion. We have shown enzymatically-active myeloperoxidase is present in human atherosclerotic tissue, where it co-localizes with white blood cells. This led us to propose that LDL oxidation might involve oxidants generated by myeloperoxidase.

Myeloperoxidase is the only human enzyme known to generate HOCl at plasma concentrations of halide ion. The detection of chlorinated molecules in atherosclerotic lesions would thus constitute strong evidence that myeloperoxidase was one pathway for oxidative damage in vivo. Most oxidation products generated by HOCl are uninformative. However, recent studies demonstrate that myeloperoxidase converts tyrosine into 3-chlorotyrosine, a stable product that may serve as a molecular fingerprint of the enzyme's action.

LDL exposed to the complete myeloperoxidase-hydrogen peroxide-chloride system undergoes chlorination of its protein tyrosyl residues. Reagent HOCl chlorinates tyrosine similarly, implicating this oxidizing intermediate in the enzymic pathway. 3-Chlorotyrosine is undetectable in LDL oxidised with hydroxyl radical, copper, iron, hemin, glucose, peroxynitrite, horseradish peroxidase, lactoperoxidase, or lipoxygenase, indicating it is a highly specific marker of LDL oxidation by myeloperoxidase.

To investigate the role of myeloperoxidase in promoting LDL oxidation in vivo, we used isotope dilution gas chromatography/mass spectrometry to quantify the level of 3-chlorotyrosine in atherosclerotic lesions. In vascular tissue, the level of 3-chlorotyrosine was increased 6-fold in atherosclerotic lesions compared with normal aortic tissue. Moreover, there was a 30-fold increase in the level of 3-chlorotyrosine of LDL isolated from atherosclerotic lesions compared with circulating LDL.

These results provide strong evidence that halogenation reactions catalyzed by myeloperoxidase constitute one pathway for protein oxidation in vivo. Moreover, they suggest that myeloperoxidase may play a critical role in converting LDL into an atherogenic form. Because activated white blood cells participate in most inflammatory disease, we speculate that oxidation reactions catalyzed by myeloperoxidase may be involved in the genesis of other pathological condition.