Inhibition of 5,9-dimethyldibenzo[c,g]carbazole-DNA adduct formation in mouse liver by pretreatment with cytochrome P4501A inducers in vivo

Mice of the XVIInc/Z and DBA/2N strains, which are responsive and nonrespon sive, respectively, to the aryl hydrocarbon (Ah) receptor, were treated wit h the hepatocarcinogen 5,9-dimethyldibenzo[c,g]carbazole and their livers w ere examined by nuclease P1-enhanced P-32-postlabeling for the levels of DN A adducts formed. Pretreatment at the doses usually reported in the literat ure with the cytochrome P4501A (CYP1A) inducers 2,3,7,8-tetrochlorodibenzo- p-dioxin (TCDD), beta-naphthoflavone (BNF), and isosafrole modulated DNA ad duction. In XVIInc/Z mice, DNA adduction was totally inhibited by TCDD (a C YP1A1/1A2 inducer), BNF (a CYP1A1/1A2 inducer), and isosafrole (a CYP1A2 in ducer). In DBA/2N mice, in which DNA adduction was also inhibited by TCDD, about 25% of the DNA adduct levels persisted after pretreatment with BNF (n ot a CYP1A1/1A2 inducer in this strain) or isosafrole (a CYP1A2 inducer in this strain). The increase tin all cases less than twofold) in the levels o f the phase-II drug-metabolizing enzymes glutathione S-transferase and urid ine diphospho-glucuronyltransferase after treatment with inducers cannot ex plain the total disappearance of DNA adducts. Assays of 5-bromo-2'-deoxyuri dine incorporation did not show any induction of DNA synthesis which could explain the decrease in adducts. These results suggest that in vivo 1) incr eases in CYP1A enzymes by inducers are not correlated with enhanced levels of certain DNA adducts; and 2) phase-it drug metabolizing enzymes are not t he main cellular protection pathway for detoxification. An additional mecha nism, perhaps also induced by the Ah receptor but highly dependent on the d ose of inducer, could be involved in parallel to multidrug resistance (mdr) ; further experiments are needed to identify this process used by the cell to enhance its protection against toxic or genotoxic effects. Environ. Mol. Mutagen. 32: 314-324, 1998 (C) 1998 Wiley-Liss, Inc.