Pretreatment with mixed-function oxidase inducers increases the sensitivity of the hepatocyte/DNA repair assay.
A recent National Toxicology Program evaluation indicates that the rat hepatocyte/DNA repair assay has a high false-negative rate and that it is insensitive to some genotoxic hepatocarcinogens as well as other species and organ-specific carcinogens. In this study, we examined whether the sensitivity of the hepatocyte/DNA repair assay might be increased through animal pretreatment with various hepatic mixed-function oxidase inducers, i.e., Aroclor 1254, phenobarbital, and 3,3',4,4'-tetrachloroazobenzene (TCAB). The effects on unscheduled DNA synthesis (UDS), a measure of DNA damage and repair, were studied in cultures exposed to known and/or potential carcinogens that had been evaluated as negative or questionable or that produced conflicting results with hepatocytes isolated from uninduced animals. 4,4'-Oxydianiline, 1-nitropyrene, and TCAB produced concentration-dependent increases in UDS in hepatocytes from rats pretreated with Aroclor 1254. 4,4'-Oxydianiline and TCAB also induced a dose-dependent increase in DNA repair in hepatocytes from rats pretreated with phenobarbital, whereas 1-nitropyrene was negative. 4,4'-Methylenedianiline produced a marginal response, and 3,3',4,4'-tetrachloroazoxybenzene (TCAOB) was negative in Aroclor- and phenobarbital-induced hepatocytes; however, TCAOB, as well as TCAB, produced concentration-dependent increases in UDS in TCAB-induced hepatocytes. These data indicate that the limited sensitivity to chemical carcinogens displayed by the hepatocyte/DNA repair assay may be increased by using hepatocytes isolated from animals exposed to hepatic mixed-function oxidase inducers.
Shaddock
J G
JG
Department of Health and Human Services, National Center for Toxicological Research, Jefferson, Arkansas 72079.
Heflich
R H
RH
McMillan
D C
DC
Hinson
J A
JA
Casciano
D A
DA
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001345:Autoradiography; D001391:Azo Compounds / Q000494:pharmacology; D002273:Carcinogens; D002478:Cells, Cultured; D002722:Chlorobenzenes / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects*; D004790:Enzyme Induction; D008099:Liver / Q000166:cytology / Q000201:enzymology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D001140:Aroclors; D001391:Azo Compounds; D002273:Carcinogens; D002722:Chlorobenzenes; D009153:Mutagens; C013279:3,4,3',4'-tetrachloroazobenzene; D006899:Mixed Function Oxygenases; D010634:Phenobarbital