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Metabolism of 4-methylimidazole in Fischer 344 rats and B6C3F1 mice

Author:
Fennell, Timothy R., Watson, Scott L., Dhungana, Suraj, Snyder, Rodney W.
Source:
Food and chemical toxicology 2019 v.123 pp. 181-194
ISSN:
0278-6915
Subject:
aerobiosis, bioassays, byproducts, carbon, carbon dioxide, carcinogenicity, females, foods, liquid chromatography, liver, liver microsomes, lung neoplasms, lungs, males, metabolites, mice, oxidation, radioactivity, radionuclides, rats, tandem mass spectrometry, urine
Abstract:
4-Methylimidazole (4-MeI) is a widely used chemical, also identified as a by-product of heating foods. In cancer bioassays, 4-MeI induced lung tumors in mice, but not in rats. To establish if metabolic differences could explain species difference in carcinogenicity, this study investigated metabolism of 4-MeI in rat and mouse lung and liver microsomes and S-9 fractions, and in vivo in rats and mice. No metabolites were detected in rat or mouse lung and liver microsomes, or lung S-9 fractions. Male and female F-344 rats and B6C3F1 mice were administered 50 and 150 mg/kg [14C] 4-MeI by gavage. Excreta, exhaled CO2 and volatiles were collected for 48 h. Elimination was mainly via urine, with 79–89% of the radioactivity in urine in rats and 41–70% in mice. Most of the radioactivity (71–88%) in urine was unchanged 4-MeI. Additional radioactive peaks (the largest metabolite was 8–18%) were characterized by LC-MS/MS as 4-hydroxymethylimidazole, its glucuronide, and other oxidized products, including methylhydantoin. 4-MeI was largely excreted unchanged in rats and mice with limited oxidative metabolism and conjugation. 4-MeI was not oxidized in subcellular fractions from rat and mouse lung and liver. Overall, the metabolism of 4-MeI appeared similar between rats and mice.
Agid:
6179367