Carcinogenesis Advance Access published online on September 11, 2003
Carcinogenesis, doi:10.1093/carcin/bgg170
© 2003 by Oxford University Press
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CARCINOGENESIS
1 Division of Genetics and Mutagenesis, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan
* Corresponding author. E-mail: nohmi{at}nihs.go.jp.
Received 10 July 2003
; revised 29 August 2003
; accepted 2 September 2003
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 ppm APNH for 12 weeks. The gpt mutant frequency (MF) in the liver increased 10-fold in 20 ppm APNH-treated mice, which was almost equivalent to the MF observed in the liver of the same transgenic mice treated with 300 ppm MeIQx for 12 weeks. In the colon mucosa, the gpt MF increased about 5-fold in 20 ppm 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 two bps deletions: GCGC to GC and CGCG to CG. The Spi- deletion MF in the liver were 13-fold higher in 20 ppm APNH-treated mice, relative to the control, and were dominated by single bp 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.
Aminophenylnorharman, gpt delta transgenic mouse, mutation frequency, mutation spectrum, heterocyclic amine
Potent genotoxicity of aminophenylnorharman, formed from non-mutagenic norharman and aniline, in the liver of gpt delta transgenic mouse
2 Cancer Prevention Division, National Cancer, Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan
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