N-benzylimidazole for preparation of S9 fraction with multi-induction of metabolizing enzymes in short-term genotoxicity assays

Mutagenesis. 2001 Nov;16(6):479-86. doi: 10.1093/mutage/16.6.479.

Abstract

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 (approximately 11-fold), 2B2 (approximately 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 B(1) (AFB(1)), 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, AFB(1) 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.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Enzyme Induction / drug effects
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology*
  • Isoenzymes / biosynthesis
  • Liver Extracts / chemistry*
  • Liver Extracts / isolation & purification
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Mutagenicity Tests / methods*
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar

Substances

  • Imidazoles
  • Isoenzymes
  • Liver Extracts
  • 1-benzylimidazole
  • Cytochrome P-450 Enzyme System