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The potential of acrylonitrile or its metabolites to induce direct DNA damage as a mechanism for acrylonitrile carcinogenicity has been questioned, and recent studies indicate that the mechanism involves the induction of oxidative stress in rat brain. The present study examined the ability of acrylonitrile to induce DNA damage in the DI TNC1 rat astrocyte cell line using the alkaline Comet assay. Oxidized DNA damage also was evaluated using formamidopyrimidine DNA glycosylase treatment in the modified Comet assay. No increase in direct DNA damage was seen in astrocytes exposed to sublethal concentrations of acrylonitrile (0\u20131.0 mM) for 24 hr. However, acrylonitrile treatment resulted in a concentration\u2010related increase in oxidative DNA damage after 24 hr. Antioxidant supplementation in the culture media (\u03b1\u2010tocopherol, (\u2212)\u2212epigallocathechin\u20103 gallate, or trolox) reduced acrylonitrile\u2010induced oxidative DNA damage. Depletion of glutathione using 0.1 mM <jats:sc>DL<\/jats:sc>\u2010buthionine\u2010[S,R]\u2010sulfoximine increased acrylonitrile\u2010induced oxidative DNA damage (22\u201346%), while cotreatment of acrylonitrile with 2.5 mM <jats:sc>L<\/jats:sc>\u20102\u2010oxothiazolidine\u20104\u2010carboxylic acid, a precursor for glutathione biosynthesis, significantly reduced acrylonitrile\u2010induced oxidative DNA damage (7\u201347%). Cotreatment of acrylonitrile with 0.5 mM 1\u2010aminobenzotriazole, a suicidal inhibitor of cytochrome P450, prevented the oxidative DNA damage produced by acrylonitrile. Cyanide (0.1\u20130.5 mM) increased oxidative DNA damage (44\u2013160%) in astrocytes. These studies demonstrate that while acrylonitrile does not directly damage astrocyte DNA, it does increase oxidative DNA damage. The oxidative DNA damage following acrylonitrile exposure appears to arise mainly through the P450 metabolic pathway; moreover, glutathione depletion may contribute to the induction of oxidative DNA damage by acrylonitrile. Environ. Mol. Mutagen., 2006. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/em.20249","type":"journal-article","created":{"date-parts":[[2006,8,18]],"date-time":"2006-08-18T00:25:41Z","timestamp":1155860741000},"page":"631-638","source":"Crossref","is-referenced-by-count":28,"title":["Acrylonitrile\u2010induced oxidative DNA damage in rat astrocytes"],"prefix":"10.1002","volume":"47","author":[{"given":"Xinzhu","family":"Pu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa M.","family":"Kamendulis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James E.","family":"Klaunig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,8,17]]},"reference":[{"key":"e_1_2_1_2_1","first-page":"376","article-title":"Metabolism of acrylonitrile to cyanide: In vitro 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