Effects of pretreatment with pyrazole and inducers of mixed function oxidases on DNA repair elicited by dimethylnitrosamine in rat hepatocytes in vivo and in vitro.
Experiments were performed to investigate the relationship between the rate of oxidative metabolism of dimethylnitrosamine (DMN) by rat liver microsomes (i.e., DMN demethylase activity, DMNd) and its genotoxicity in liver, as assessed by the in vitro and in vivo/in vitro rat hepatocyte primary culture/DNA repair (HPC/DR) assays. Pretreatment of rats with pyrazole (PYR) resulted in a 4-fold increase in DMNd and a 3-fold greater DNA repair response to in vivo administration of 5 mg DMN/kg body weight. Pretreatment with phenobarbital (PB), dichlorodiphenyltrichloroethane (DDT), 3-methylcholanthrene (3-MC), beta-naphthoflavone (beta-NF) or Aroclor 1254 (ARO) produced a variable degree of inhibition of DMNd and had no significant effects on the response to DMN in the in vivo/in vitro HPC/DR assay. DNA repair elicited by DMN in vitro was decreased in hepatocytes from rats pretreated with 3-MC, while PB, DDT, beta-NF and ARO pretreatments had little effect on the response. In contrast, PYR pretreatment produced a 4.5-6.7-fold increase in the in vitro DNA repair response to DMN, and extended detection of positive responses to lower concentrations. Most of the inducers had no effect on DNA repair elicited by the direct acting alkylator, methyl methanesulfonate (MMS). Thus, the pretreatment-related changes in DMN-induced DNA repair were probably due to alterations in DMNd rather than to effects on the DNA repair capacity of the hepatocytes.
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001571:Benzoflavones / Q000494:pharmacology; D002478:Cells, Cultured; D020111:Chlorodiphenyl (54% Chlorine); D019392:Cytochrome P-450 CYP2E1; D003634:DDT / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects*; D004052:Diethylnitrosamine / Q000494:pharmacology; D004128:Dimethylnitrosamine / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008748:Methylcholanthrene / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D019324:beta-Naphthoflavone
D001140:Aroclors; D001571:Benzoflavones; D011720:Pyrazoles; D020111:Chlorodiphenyl (54% Chlorine); D004052:Diethylnitrosamine; C031280:pyrazole; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone; D008741:Methyl Methanesulfonate; D003634:DDT; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D004128:Dimethylnitrosamine; D010634:Phenobarbital