Lack of chloroform-induced DNA repair in vitro and in vivo in hepatocytes of female B6C3F1 mice.
Chloroform has been shown to induce hepatocellular carcinomas in female B6C3F1 mice when administered by gavage, but not when given in drinking water. When administered in corn oil at the carcinogenic doses of 238 and 477 mg/kg, chloroform induced necrosis and sustained regenerative cell proliferation in the liver. To investigate the mode of action of tumor induction in the target cells, the ability of chloroform to induce unscheduled DNA synthesis (UDS) was examined in the in vitro and in vivo hepatocyte DNA repair assays. In the in vitro assay, primary hepatocyte cultures from female B6C3F1 mice were incubated with concentrations from 0.01 to 10 mM chloroform in the presence of 3H-thymidine. UDS was assessed by quantitative autoradiography. No induction of DNA repair was observed at any concentration. In the in vivo assay, animals were treated by gavage with 238 and 477 mg/kg chloroform in corn oil. Primary hepatocyte cultures were prepared 2 and 12 hr later, incubated with 3H-thymidine, and assessed for induction of UDS as above. No DNA repair activity was seen at either dose or at either timepoint. These negative results in the target organ are consistent with the concept that neither chloroform nor its metabolites are directly DNA reactive and that the carcinogenicity of chloroform is secondary to induced cytolethality and regenerative cell proliferation.
Larson
J L
JL
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Sprankle
C S
CS
Butterworth
B E
BE
D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D002725:Chloroform / Q000008:administration & dosage / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects*; D004260:DNA Repair; D005260:Female; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009153:Mutagens / Q000633:toxicity*
D009153:Mutagens; D002725:Chloroform; D004247:DNA