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Detection of Aminophenylnorharman, a Possible Endogenous Mutagenic and Carcinogenic Compound, in Human Urine Samples

¹ Cancer Prevention Basic Research Project, National Cancer Center Research Institute; ² Division of Colorectal Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan; ³ Laboratory of Applied Analytical Chemistry, Department of Biological Pharmacy, School of Pharmacy, Shujitsu University, Nishigawara, Okayama, Japan; ⁴ Department of Food Safety, Tokyo Metropolitan Institute of Public Health, Shinjuku-ku, Tokyo, Japan; ⁵ Research Center for Material Cycles and Waste Management, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan; and ⁶ Department of Public Health, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan

Requests for reprints: Keiji Wakabayashi, Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81-3-3547-5271; Fax: 81-3-3543-9305. E-mail: kwakabay{at}gan2.res.ncc.go.jp

Mutagenic/carcinogenic 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole [aminophenylnorharman (APNH)] is formed from norharman and aniline in the presence of cytochrome P450 3A4/1A2. Because both precursors are widely distributed in the environment, human exposure is unavoidable. To clarify APNH formation in the human body, amounts of the compound in 24-h human urine collected from smokers and nonsmokers, eating a normal diet, were analyzed by liquid chromatography/electrospray ionization tandem mass spectrometry. In addition, norharman and aniline were also analyzed by high-performance liquid chromatography and gas chromatography, respectively. APNH could be detected in all urine samples at levels 49 to 449 pg for smokers and 21 to 594 pg for nonsmokers per 24-h urine, respectively. The amounts of norharman and aniline were 46 to 185 ng and 0.70 to 8.10 µg for smokers and 52 to 447 ng and 0.49 to 5.72 µg for nonsmokers, respectively, per 24-h urine (none of the levels differing significantly between smokers and nonsmokers). To exclude exogenous exposure to norharman and aniline, we analyzed the levels of APNH, norharman, and aniline in urine samples collected from inpatients receiving parenteral alimentation. Similar to the healthy volunteers, all urine samples contained 12 to 338 pg of APNH, 6 to 75 ng of norharman, and 0.33 to 1.86 µg of aniline per 24-h urine. These results suggest that APNH should be considered as a novel endogenous mutagen/carcinogen; thus, it is very important to determine the biological significance of this carcinogen for human cancer development. (Cancer Epidemiol Biomarkers Prev 2007;16(1):151–6)