期刊
TOXICOLOGY
卷 177, 期 1, 页码 11-22出版社
ELSEVIER SCI IRELAND LTD
DOI: 10.1016/S0300-483X(02)00192-0
关键词
dityrosine; neutrophils; oxidized LDL; oxidative stress; atherosclerosis; phenoxyl radical
To kill invading bacteria, viruses, and fungi, phagocytes secrete hydrogen peroxide (H2O2) and the heme enzyme myeloperoxidase. We have explored the possibility that rnyeloperoxidase might use H2O2 to convert L-tyrosine to tyrosyl radical. Activated human neutrophils and monocytes used the system to oxidize free L-tyrosine to o,o'-dityrosine, a stable product of tyrosyl radical. Protein-bound tyrosyl residues exposed to myeloperoxidase, H2O2, and L-tyrosine were also oxidized to o,o'-dityrosine. The cross-linking reaction required free L-tyrosine, suggesting that myeloperoxidase converts the amino acid to a diffusible radical catalyst that promotes protein oxidation. We used electron paramagnetic resonance to provide direct evidence that the oxidizing intermediate is free tyrosyl radical. Myeloperoxidase-gene rated tyrosyl radical also initiates lipid peroxidation, suggesting that activated phagocytes might also be able to oxidize lipids in host tissues. Moreover, myeloperoxidase is present and active in human atherosclerotic tissue, and levels of protein-bound dityrosine are elevated in such lesions. Our recent studies indicate that activated neutrophils use oxidants generated by the phagocyte NADPH oxidase to produce protein-bound dityrosine during acute inflammation. Collectively, these findings suggest that generation of tyrosyl radical by myeloperoxidase allows activated phagocytes to damage both proteins and lipids. Elevated levels of o,o'-dityrosine have been detected in inflammatory lung disease, neurodegenerative disorders, and aging. Thus, oxidation of tyrosine to tyrosyl radical might play a role in the pathogenesis of many diseases. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
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