Macromolecular adduction by trichloroacetonitrile in the Fischer 344 rat following oral gavage.
Male Fisher 344 rats were administered 1- or 2-[14C]trichloroacetonitrile (TCAN) by oral gavage. DNA was isolated from the liver, kidneys and stomach and several protein fractions (globin, albumin and globulins) were isolated from blood. TCAN binds to both the DNA and the blood proteins in a dose-related manner. More radiolabel was associated with the DNA when the carbon at C2 position was labeled, than at C1 position. However, the position of the radiolabel did not influence the levels of radioactivity associated with the blood proteins. The stomach exhibited the highest level of DNA binding, followed in order by the liver and kidney. TCAN binding level was higher in DNA isolated from rats killed at 24 h than at 4 h after administration. In contrast, the three blood proteins showed similar binding levels, regardless of the exposure time. Radioactivity associated with DNA was not incorporated into the nitrogen bases (i.e. via de novo synthesis) and a covalent binding index (mumol chemical bound/mol nucleotide phosphate per mmol/kg body wt. of chemical administered) of 30-120 was observed for various tissues. Most of the radioactivity (60-80%) associated with globin could be released and separated from the protein by the treatment with concentrated ammonium hydroxide and precipitation of protein by organic solvent. Three peaks were observed in the HPLC elution profiles of the radioactivity released from the globin. Trichloroacetic acid co-eluted with one of these released products (peak II), however, the chemical identity of the material under the major peak (peak III) and peak I are still uncharacterized.
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Environmental Monitoring Systems Laboratory, U.S. Environmental Protection Agency, Cincinnati, OH 45268.
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Daniel
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D000097:Acetonitriles / Q000008:administration & dosage* / Q000737:chemistry; D000284:Administration, Oral; D000477:Alkylating Agents / Q000737:chemistry*; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D005753:Gastric Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009153:Mutagens / Q000737:chemistry; D051381:Rats; D011916:Rats, Inbred F344
D000097:Acetonitriles; D000477:Alkylating Agents; D001798:Blood Proteins; D009153:Mutagens; C029549:trichloroacetonitrile; D004247:DNA