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Mutagenic Activation of Environmental Carcinogens by Microsomes of Gastric Mucosa with Intestinal Metaplasia¹

Investigative Treatment Division, National Cancer Center Research Institute East, Kashiwa-shi, Chiba, 277-8577, Japan [M. T., S. N., T. O., H. E.]; Chemical Exposure and Health Effects Research Team, Regional Environmental Research Group, National Institute for Environmental Studies, Tsukuba, 305-0053, Japan [H. S.]; and Internal Medicine, Saiseikai Central Hospital, Tokyo, 108-0073, Japan [M. T., H. N.]

Coexpression of cytochrome P450 monooxygenases (CYPs) and reductase was found in human gastric mucosa with intestinal metaplasia. Immunohistochemistry showed reactivity to P450 reductase in metaplastic epithelial cells and in pyloric gland cells in glands showing intestinal metaplasia. These cells exhibit NADPH-diaphorase activity. Reverse transcription-PCR analysis and Western blotting showed that CYP1A1 and CYP1A2 were expressed in specimens with intestinal metaplasia. Tissue distribution of CYP1A1 coincided with that of P450 reductase. However, immunoreactivity to CYP1A2 protein was localized only in the pyloric gland cells near the intestinal metaplastic gland. Salmonella typhimurium mutagen assay definitively revealed that microsomes prepared from gastric mucosa with intestinal metaplasia, in particular in the pyloric gland, functionally activated benzo(a)pyrene and 2-amino-3-methylimidazo[4,5-f]quinoline. These results indicate that carcinogen activation by CYP enzymes expressed in the gastric mucosa may contribute to carcinogenesis of the stomach.

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