Pretreatment with mixed‐function oxidase inducers increases the sensitivity of the hepatocyte/DNA repair assay

J. G. Shaddock, R. H. Heflich, D. C. McMillan, J. A. Hinson, D. A. Casciano

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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‐nitropy‐rene, 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 pheno‐barbital‐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.

Original languageEnglish (US)
Pages (from-to)281-288
Number of pages8
JournalEnvironmental and Molecular Mutagenesis
Volume13
Issue number4
DOIs
StatePublished - 1989

Keywords

  • 3,3′,4,4′‐tetrachloroazobenzene
  • Aroclor
  • DNA repair
  • metabolism
  • phenobarbital
  • rat hepatocytes

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

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