Carcinogenesis Advance Access originally published online on May 13, 2004
Carcinogenesis 2004 25(10):1967-1672; doi:10.1093/carcin/bgh189
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis vol.25 no.10 © Oxford University Press 2004; all rights reserved.
ARTICLE |
Carcinogenicity of aminophenylnorharman, a possible novel endogenous mutagen, formed from norharman and aniline, in F344 rats
Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
2 To whom correspondence should be addressed Email: 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 investigated in 93 male and 90 female F344 rats. Rats were fed diets containing 0, 20 or 40 p.p.m. from 7 weeks of age. All animals were killed 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 p.p.m. APNH, and 34% in female rats fed 40 p.p.m. 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 p.p.m. of APNH, respectively. Other tumors, including thyroid carcinomas and mononuclear cell leukemia, were also seen in rats fed APNH. Polymerase chain reaction–single strand conformation polymorphism analysis revealed ß-catenin gene mutations in 24% of HCCs and K-ras, ß-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. ß-Catenin protein accumulations in the nucleus and cytoplasm were also revealed in both liver and colon tumors. Thus, APNH induced liver and colon cancers with K-ras, ß-catenin and Apc gene mutations in F344 rats.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. Nishigaki, Y. Totsuka, H. Kataoka, H. Ushiyama, S. Goto, T. Akasu, T. Watanabe, T. Sugimura, and K. Wakabayashi Detection of Aminophenylnorharman, a Possible Endogenous Mutagenic and Carcinogenic Compound, in Human Urine Samples Cancer Epidemiol. Biomarkers Prev., January 1, 2007; 16(1): 151 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. B.McKinzie, R. R.Delongchamp, T. Chen, and B. L.Parsons ACB-PCR measurement of K-ras codon 12 mutant fractions in livers of Big Blue(R) rats treated with N-hydroxy-2-acetylaminofluorene Mutagenesis, November 1, 2006; 21(6): 391 - 397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Oda, Y. Totsuka, K. Wakabayashi, F.P. Guengerich, and T. Shimada Activation of aminophenylnorharman, aminomethylphenylnorharman and aminophenylharman to genotoxic metabolites by human N-acetyltransferases and cytochrome P450 enzymes expressed in Salmonella typhimurium umu tester strains Mutagenesis, November 1, 2006; 21(6): 411 - 416. [Abstract] [Full Text] [PDF]
|
|