DNA fragmentation, DNA-protein crosslinks, postlabeled nucleotidic modifications, and 8-hydroxy-2'-deoxyguanosine in the lung but not in the liver of rats receiving intratracheal instillations of chromium(VI). Chemoprevention by oral N-acetylcysteine.
An in vivo study was carried out with the objectives of evaluating (a) the localization of DNA lesions resulting from exposure to chromium(VI) by the respiratory route, (b) the molecular nature of DNA alterations, and (c) modulation of DNA damage by a known chemopreventive agent. To this purpose, Sprague-Dawley rats received intratracheal instillations of sodium dichromate (0.25 mg/kg body weight) for three consecutive days, and the day after the last treatment lung and liver were removed for DNA purification. The results showed a selective localization of DNA lesions in the lung but not in the liver, which can be ascribed to toxicokinetics and metabolic characteristics of chromium(VI). DNA alterations included DNA-protein crosslinks, DNA fragmentation, nucleotidic modifications, and 8-hydroxy-2'-deoxyguanosine. The last two endpoints were evaluated, for the first time in chromium toxicology, by means of postlabeling procedures. This methodology was adapted to the detection of the DNA damage produced by those reactive oxygen species which result from the intracellular reduction of chromium(VI). The oral administration of the thiol N-acetylcysteine completely prevented any induction of DNA lesions in lung cells.
Institute of Hygiene and Preventive Medicine, University of Genoa, Via A. Pastore 1, Genoa I-16132, Italy.
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Izzotti
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Bagnasco
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Camoirano
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Orlando
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De Flora
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D016587:Antimutagenic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002840:Chromates / Q000008:administration & dosage / Q000633:toxicity; D002857:Chromium / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D007442:Intubation, Intratracheal; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009711:Nucleotides / Q000378:metabolism; D010761:Phosphorus Radioisotopes; D011506:Proteins / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016587:Antimutagenic Agents; D002840:Chromates; D009711:Nucleotides; D010761:Phosphorus Radioisotopes; D011506:Proteins; D002857:Chromium; C074702:chromium hexavalent ion; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; C016104:sodium bichromate; D003849:Deoxyguanosine; D000111:Acetylcysteine