Carcinogenesis Advance Access originally published online on September 11, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis, Vol. 24, No. 12, 1985-1993,
December 2003
© Oxford University Press; all rights reserved
CARCINOGENESIS |
Potent genotoxicity of aminophenylnorharman, formed from non-mutagenic norharman and aniline, in the liver of gpt delta transgenic mouse
1 Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga Setagaya-ku, Tokyo 158-8501, Japan and 2 Cancer Prevention Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan
Aminophenylnorharman (APNH) is formed from non-mutagenic norharman and aniline, and is mutagenic to Salmonella typhimurium TA98 with S9 mix. Norharman and aniline are present in cigarette smoke and cooked foods and both compounds are detected in human urine samples, suggesting that APNH could be a mutagenic and carcinogenic human risk factor. The purpose of the present study was to determine the in vivo mutagenicity of APNH. Male gpt delta transgenic mice were fed a diet containing 10 or 20 p.p.m. APNH for 12 weeks. The gpt mutant frequency (MF) in the liver increased 10-fold in 20 p.p.m. APNH-treated mice, which was almost equivalent to the MF observed in the liver of the same transgenic mice treated with 300 p.p.m. 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline for 12 weeks. In the colon mucosa, the gpt MF increased 
5-fold in 20 p.p.m. APNH-treated mice. Our results suggest that APNH is a strong hepatic mutagen in mice. The APNH-induced gpt mutations in the liver were dominated by G:C to T:A transversions, followed by G:C to A:T transitions. They also included single G:C deletions in G:C run sequences and 2 bp deletions: GCGC to GC and CGCG to CG. The Spi- deletion MF in the liver was 13-fold higher in 20 p.p.m. APNH-treated mice, relative to the control, and were dominated by single base pair deletions, in particular, in G:C run sequences. Large deletions were rare. The mutational characteristics induced by APNH are compared with those induced by other heterocyclic amines, and the human risk of APNH is discussed.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  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]
|
|
|
|
 |
|
 T. Kawamori, Y. Totsuka, N. Uchiya, T. Kitamura, H. Shibata, T. Sugimura, and K. Wakabayashi Carcinogenicity of aminophenylnorharman, a possible novel endogenous mutagen, formed from norharman and aniline, in F344 rats Carcinogenesis, October 1, 2004; 25(10): 1967 - 1672. [Abstract] [Full Text] [PDF]
|
|