Carcinogenesis Advance Access published online on May 13, 2004
Carcinogenesis, doi:10.1093/carcin/bgh189
© 2004 by Oxford University Press
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1 Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045 Japan
* To whom correspondence should be addressed. E-mail: kwakabay{at}gan2.res.ncc.go.jp.
A novel mutagenic compound, 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH), is shown to be formed by the in vitro enzymatic reaction of 9H-pyrido[3,4-b]indole (norharman) and aniline. APNH generates DNA adducts (dG-C8-APNH), and is potently genotoxic to bacteria and mammalian cells. APNH has also been demonstrated to be formed in vivo from norharman and aniline, and suggested to be a new type of endogenous mutagenic compound. To determine its carcinogenic activity, long term administration of APNH was here investigated in 93 male and 90 female F344 rats. Rats were fed diets containing 0, 20, or 40 ppm from 7 weeks of age. All animals were sacrificed after 85 weeks treatment and necropsy was performed. Hepatocellular carcinomas (HCCs) were induced at incidences of 10 and 79% in male rats fed 20 and 40 ppm APNH, and 34% in female rats fed 40 ppm of APNH, respectively. In addition, colon adenocarcinomas were found at incidences of 3 and 9% in male rats, and 4 and 13% in female rats fed 20 and 40 ppm of APNH, respectively. Other tumors, including thyroid carcinomas, and mononuclear cell leukemia, were also seen in rats fed APNH. PCR-SSCP analysis revealed
Revised May 5, 2004
Accepted May 9, 2004
CARCINOGENESIS
Carcinogenicity of aminophenylnorharman, a possible novel endogenous mutagen, formed from norharman and aniline, in F344 rats
Abstract 
-catenin gene mutations in 24% of HCCs and K-ras, -catenin and Apc gene mutations were found in 22, 44 and 33% of colon cancers induced by APNH, respectively. Most mutations occurred at G:C base pairs. -Catenin protein accumulations in the nucleus and cytoplasm were also revealed in the both liver and colon tumors. Thus, APNH induced liver and colon cancers with K-ras, -catenin and Apc gene mutations in F344 rats.
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