Mutagenesis, Vol. 16, No. 6, 479-486,
November 2001
© 2001 UK Environmental Mutagen Society/Oxford University Press
N-Benzylimidazole for preparation of S9 fraction with multi-induction of metabolizing enzymes in short-term genotoxicity assays
Laboratory of Radiochemistry, Gifu Pharmaceutical University, 6-1 Mitahora-higashi 5-chome, Gifu 502-8585, Japan
To evaluate the usefulness of N-benzylimidazole (BI) as an inducer with wide spectrum detection of precarcinogens in short-term bioassays, hepatic levels of cytochrome P-450 (CYP) and mutagenic activation of various carcinogens in Wistar and Sprague–Dawley rats orally treated with BI and BI plus ethanol or acetone were compared with those in the same strains of rats treated with 3-methylcholanthrene (MC), phenobarbital (PB) and polychlorobiphenyls (PCB). Immunoblot analyses for microsomal CYP proteins revealed a marked induction by BI in the levels of CYP1A1, CYP2B1 and constitutive CYP1A2 (~11-fold), 2B2 (~21-fold), 2E1 (1.5-fold) and 3A2 (4-fold) in rats of both strains. These levels were comparable with those induced by MC and PB, but were less than the CYP1A1/2 and 2B1 levels induced by PCB, while CYP2B2 was at the same level. In contrast, the level of CYP2E1 was clearly higher in BI-treated rats. The combinations of BI and acetone or ethanol specifically induced CYP2E1 (4-fold) and 2B1 (1.7-fold) levels when compared with BI alone in Wistar rats. The combined treatments also elevated mutagenic activities of eight heterocyclic amines (HCAs), aflatoxin B1 (AFB1), benzo[a]pyrene and 2-aminofluorene in strain TA98 up to 14.3-, 5.1-, 2.8- and 2.1-fold above the untreated group, respectively, and those of five N-nitrosamines in strain TA100 up to 19.1-fold. Induction of specific CYP species responsible for activation of HCAs, AFB1 and N-nitrosamines was confirmed by application of several CYP inhibitors. In addition, BI induced activities of both MC- and PB-inducible UDP-glucuronyltransferases towards 4-nitrophenol and testosterone. These results demonstrate that BI has a bifunctional action, with wide spectrum induction of phase I and II enzymes, and combined treatment with ethanol or acetone would be a pertinent inducer for metabolic enzymes in in vitro bioassays, the potential being comparable with or superior to other typical ones.
1 To whom correspondence should be addressed. Tel: +81 58 237 3931; Fax: +81 58 237 5979; Email: ymori{at}gifu-pu.ac.jp
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