Potent genotoxicity of aminophenylnorharman, formed from non-mutagenic norharman and aniline, in the liver of gpt delta transgenic mouse.
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 approximately 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.
Masumura
Ken-ichi
K
Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga Setagaya-ku, Tokyo 158-8501, Japan. nohmi@nihs.go.jp
Totsuka
Yukari
Y
Wakabayashi
Keiji
K
Nohmi
Takehiko
T
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002243:Carbolines; D002273:Carcinogens; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced; D018899:CpG Islands; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D006247:Harmine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008956:Models, Chemical; D009092:Mucous Membrane / Q000473:pathology; D009153:Mutagens; D009154:Mutation; D011725:Pyridines / Q000494:pharmacology*; D013997:Time Factors
D000814:Aniline Compounds; D002243:Carbolines; D002273:Carcinogens; D007211:Indoles; D009153:Mutagens; D011725:Pyridines; D006247:Harmine; C010262:norharman; C421010:9-(4'-aminophenyl)-9H-pyrido(3,4-b)indole; C023650:aniline