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Effects of pretreatment with inducers of hepatic mixed function oxidases on DNA repair elicited by various compounds in hepatocytes from adult and neonatal rats

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Studies were conducted to assess the effects of inducers of hepatic mixed function oxidases on DNA repair responses to 13 different genotoxic agents in hepatocytes from adult male mice. Phenobarbital pretreatment increased DNA repair elicited by diethylnitrosamine but had no effect on responses to the other compounds. Pretreatment with p,p′-dichlorodiphenyltrichloroethane, 3-methylcholanthrene or β-naphthoflavone induced the DNA repair responses to a variety of activation-dependent carcinogens. DNA repair responses to the direct-acting alkylating agents methyl methanesulfonate and N-methyl-N′-nitro-N-nitrosoguanidine were not increased by any of the pretreatments, which indicated that the pretreatment-related enhancement of responses to the other compounds was due to induction of their metabolic activation. Taken together, the findings suggest that Aroclor, or other pretreatments, may increase the sensitivity of the hepatocyte DNA repair assay for detecting the genotoxicity of certain compounds; however, the potential benefit may be limited due to specific features of the assay. In contrast, Aroclor pretreatment did not produce any enhancement of in vivo DNA repair elicited by dimethylnitrosamine, diethylnitrosamine, o-aminoazotoluene, 2-acetylaminofluorene, 3-methylcholanthrene or aflatoxin B1, and thus does not appear to be useful for improving the sensitivity of the in vivo/in vitro assay.

Whereas the amount of DNA repair produced by dimethylnitrosamine was not increased by classical inducers of liver microsomal enzymes, pretreatment with pyrazole greatly augmented in vitro and in vivo DNA repair responses to dimethylnitrosamine; responses to diethylnitrosamine were increased to a lesser degree by pyrazole pretreatment. The effects of lactational exposure to enzyme inducing agents on DNA repair in neonatal hepatocytes was also investigated.

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Abbreviations

2-AAF:

2-acetylaminofluorene

4-AB:

4-aminobiphenyl

6-AC:

6-aminochrysene

AFB:

aflatoxin B1

ARO:

Aroclor 1254

o-AT:

o-aminoazotoluene

B(a)P:

benzo[a]pyrene

B-NF:

beta-naphthoflavone

BZ:

benzidine

DDT:

p,p′-dichlorodiphenyltrichloroethane

DDE:

p,p′-dichlorodiphenyldichloroethylene

DEN:

diethylnitrosamine

DMBA:

7,12-dimethylbenzanthracene

DMN:

dimethylnitrosamine

3-MC:

3-methylcholanthrene

MMS:

methyl methanesulfonate

MNNG:

N-methyl-N′-nitro-N-nitrosoguanidine

2-NA:

2-naphthylamine

NNG:

net nuclear grains

PB:

phenobarbital

PYR:

pyrazole

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  1. National Institute of Environmental Health Sciences Research Triangle Park, North Carolina

    Douglas Kornbrust

  2. Research Triangle Institute Research Triangle Park, North Carolina

    Dennis Dietz

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Kornbrust, D., Dietz, D. Effects of pretreatment with inducers of hepatic mixed function oxidases on DNA repair elicited by various compounds in hepatocytes from adult and neonatal rats. Cell Biol Toxicol 3, 143–164 (1987). https://doi.org/10.1007/BF00058453

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