Effect of di(2-ethylhexyl) phthalate on DNA repair and lipid peroxidation in rat hepatocytes and on metabolic cooperation in Chinese hamster V-79 cells.
Experiments were conducted to test the hypothesis that the hepatocarcinogenicity of di(2-ethylhexyl) phthalate (DEHP) is due to its ability to produce DNA damage, either directly or as a result of the proliferation of peroxisomes and accompanying increased production of H2O2 and other DNA--damaging oxygen radicals induced by sustained exposure to the plasticizer. DNA repair, as assessed by the autoradiographic measurement of unscheduled DNA synthesis (UDS), was not observed in primary rat hepatocytes exposed in vitro to 10(-5)-10(-2) M DEHP or in vivo by a single gavage dose of 5 g DEHP/kg body weight administered 2, 15, or 24 h prior to the isolation of hepatocytes. Thus, DEHP does not appear to directly produce repairable DNA damage in rat hepatocytes. Sustained feeding of DEHP at a dietary concentration of 2% led to a marked proliferation of peroxisomes in the liver after 4 wk. Additional administration of a single gavage dose of 5 g DEHP/kg body weight to animals fed the 2% diet for 4 or 8 wk, as well as to 4-wk-fed animals that were also pretreated with 3-amino-1,2,4-triazole to inhibit endogenous catalase activity, did not induce any detectable DNA repair in hepatocytes isolated 15 h following the single gavage dose of DEHP. Lipid peroxidation measured in the 9000 X g supernatant of livers from animals treated with a single dose of 5 g DEHP/kg body weight or the 2% DEHP diet for 6 wk plus a single dose of 5 g/kg body weight did not differ from controls. These findings suggest that DEHP does not elicit DNA damage or lipid peroxidation in liver consequent to the proliferation of peroxisomes resulting from prolonged administration. In addition, at noncytotoxic concentrations DEHP failed to produce a positive response in the Chinese hamster V-79 metabolic cooperation assay for tumor promoters.
D015073:2-Acetylaminofluorene / Q000494:pharmacology; D000284:Administration, Oral; D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004260:DNA Repair / Q000187:drug effects*; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D010795:Phthalic Acids / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D008054:Lipid Peroxides; D010795:Phthalic Acids; D015073:2-Acetylaminofluorene; D004051:Diethylhexyl Phthalate; D005978:Glutathione; D000640:Amitrole