Mechanistic studies on chloral toxicity: relationship to trichloroethylene carcinogenesis.
Chloral (trichloroacetaldehyde), the major metabolite of trichloroethylene (TCE), was investigated for its potential to form DNA-protein cross-links (DPX), a lesion produced by other aldehydes. Chloral did not form DPX in rat liver nuclei at concentrations up to 250 mM for 30 min at 37 degrees C, while chloroacetaldehyde (47 mM) and acetaldehyde (200 mM) did form cross-links. Experiments with the aldehyde-trapping reagents thiosemicarbazide and semicarbazide showed that chloral did not react, in contrast with aldehydes that form DPX. This indicates a very strong hydration of chloral. Mice given 800 mg/kg [14C]chloral after pretreatment with 1500 mg/kg TCE for 10 days had no detectable covalent binding of 14C to DNA in the liver. These results do not support a genotoxic theory of carcinogenesis for TCE mediated through chloral.
Keller
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Department of Biochemical Toxicology and Pathobiology, Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Heck
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D000079:Acetaldehyde / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002697:Chloral Hydrate / Q000031:analogs & derivatives* / Q000633:toxicity; D003432:Cross-Linking Reagents / Q000633:toxicity; D004247:DNA; D004249:DNA Damage; D004277:DNA, Single-Stranded; D004357:Drug Synergism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344; D014241:Trichloroethylene / Q000633:toxicity*
D003432:Cross-Linking Reagents; D004277:DNA, Single-Stranded; D014241:Trichloroethylene; D002697:Chloral Hydrate; D004247:DNA; C021100:trichloroacetaldehyde; D000079:Acetaldehyde