title: Evaluation of the mode of action of mouse lung tumors induced by 4-methylimidazole.
abstract: 4-Methylimidazole (4-MEI) occurs in certain foods and beverages as a product of browning reactions. An increased incidence of lung tumors was reported in mice, but not rats, exposed to levels of 4-MEI in their diet that far exceed human dietary intake. This investigation evaluated the hypothesis that 4-MEI induces mouse lung tumors by the same mode of action (MOA) as styrene: CYP2F2 metabolic activation and increased BrdU labeling. Using styrene (200 mg/kg/day by gavage) as a positive control, histopathology and DNA synthesis (measured by BrdU incorporation) in the bronchiolar region were evaluated in: (1) a 5-day comparative toxicity study in C57BL/6 "wild type" and CYP2F2 "knock out" (KO) mice given 4-MEI at the same dietary concentrations used in the NTP cancer bioassay, and (2) a 13-week comparative toxicity study of C57BL/6 and B6C3F1 mice receiving 0, 1250 or 2500 ppm of 4-MEI in the diet for 6, 15, 34 and 91 days. In contrast to styrene, 4-MEI had no consistent effect on BrdU labeling or histopathology in the lungs of mice in the dose range that had been shown to produce lung tumors in another study. The results of these studies do not support the hypothesis that 4-MEI and styrene induce lung tumors by the same MOA.
authors.affiliation: ToxWorks, 1153 Roadstone Rd., Bridgeton, NJ 08302, USA. Electronic address: toxworks@aol.com.
authors.forename: George
authors.initials: G
authors.lastname: Cruzan
authors.affiliation: Michigan State University, 1129 Farm Ln., Rm. 212, East Lansing, MI 48824, USA. Electronic address: harkemaj@msu.edu.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Harkema
authors.affiliation: WIL Research Laboratories LLC, 1407 George Rd., Ashland, OH 44805, USA. Electronic address: hiromi.hosako@wilresearch.com.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hosako
authors.affiliation: WIL Research Laboratories LLC, 1407 George Rd., Ashland, OH 44805, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Wasil
authors.affiliation: Murray & Associates, 5529 Perugia Cir., San Jose, CA 95138, USA. Electronic address: jmurray2@sbcglobal.net.
authors.forename: F Jay
authors.initials: FJ
authors.lastname: Murray
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000633:toxicity*; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020058:Styrene / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D007093:Imidazoles; D020058:Styrene; C023439:4-methylimidazole
keywords: 4-Methylimidazole; CYP2F2; Lung; Mechanism; Mouse; Styrene; Toxicity