Dichloroacetate- and trichloroacetate-induced oxidative stress in the hepatic tissues of mice after long-term exposure.
Dichoroacetate (DCA) and trichloroacetate (TCA) were found to be hepatotoxic and hepatocarcinogenic in rodents. To investigate the role of oxidative stress in the long-term hepatotoxicity of the compounds, groups of mice were administered 7.7, 77, 154 and 410 mg kg(-1) per day, of either DCA or TCA, by gavage, for 4 weeks (4-W) and 13 weeks (13-W), and superoxide anion (SA), lipid peroxidation (LP) and DNA-single strand breaks (SSBs) were determined in the hepatic tissues. Significant increases in all of the biomarkers were observed in response to the tested doses of both compounds in the two test periods, with significantly greater increases observed in the 13-W, as compared with the 4-W, period. Hepatomegaly was only observed with a DCA dose of 410 mg kg(-1) per day in the 13-W treatment period, and that was associated with significant declines in the biomarkers, when compared with the immediately lower dose. With the exception of LP production in the 13-W treatment period that was similarly induced by the two compounds, the DCA-induced increases in all of the biomarkers were significantly greater than those of TCA. Since those biomarkers were significantly induced by the compounds' doses that were shown to be carcinogenic but at earlier periods than those demonstrating hepatotoxicity/haptocarcinogencity, they can be considered as initial events that may lead to later production of those long-term effects. The results also suggest LP to be a more significant contributing mechanism than SA and DNA damage to the long-term hepatotoxicity of TCA.
Hassoun
Ezdihar A
EA
College of Pharmacy, University of Toledo, Toledo, OH 43606, USA. ezdihar.hassoun@utoledo.edu
Cearfoss
Jacquelyn
J
Spildener
Jessica
J
D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000187:drug effects; D053904:DNA Breaks, Single-Stranded; D003999:Dichloroacetic Acid / Q000633:toxicity*; D006529:Hepatomegaly / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D014238:Trichloroacetic Acid / Q000633:toxicity*
D002273:Carcinogens; D013481:Superoxides; D014238:Trichloroacetic Acid; D004247:DNA; D003999:Dichloroacetic Acid