Hypochlorous acid-induced DNA base modification: potentiation by nitrite: biomarkers of DNA damage by reactive oxygen species.
Chronic inflammation results in increased nitric oxide formation and nitrite (NO-2) accumulation. Activated phagocytes release myeloperoxidase generating the cytotoxic agent hypochlorous acid (HOCl). Reaction of HOCl with NO-2 results in the formation of nitryl chloride (NO2Cl), a potent oxidising, nitrating and chlorinating species. Exposure of DNA to NO-2 alone (up to 250 microM) at pH 7.4 did not induce oxidative DNA base damage. However, incubation of DNA with NO-2 in the presence of HOCl led to increases in thymine glycol, 5-hydroxyhydantoin, 8-hydroxyadenine and 5-chlorouracil to levels higher than those achieved by HOCl alone. No significant increases in 8-hydroxyguanine, xanthine, hypoxanthine, 2-hydroxyadenine, FAPy guanine, FAPy adenine and 8-chloroadenine were observed. HOCl-induced depletion of FAPy guanine and 8-hydroxyguanine was reduced in the presence of NO-2. Modification of DNA by HOCl/NO-2 (presumably generating NO2Cl) produces a pattern of DNA base damage products in isolated DNA that is similar to the pattern produced by HOCl but not other reactive species.
Whiteman
M
M
International Antioxidant Research Centre, Pharmacology Group, University of London, Kings College, Manresa Road, London, SW3 6LX, England. Matt.Whiteman@kcl.ac.uk
Spencer
J P
JP
Jenner
A
A
Halliwell
B
B
D000818:Animals; D002417:Cattle; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D004357:Drug Synergism; D005819:Genetic Markers / Q000187:drug effects; D006827:Hydantoins / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
D005819:Genetic Markers; D006827:Hydantoins; D009573:Nitrites; D016877:Oxidants; D011687:Purines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D006997:Hypochlorous Acid; D004247:DNA