Carcinogenicity of aminophenylnorharman, a possible novel endogenous mutagen, formed from norharman and aniline, in F344 rats.
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 beta-catenin gene mutations in 24% of HCCs and K-ras, beta-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. beta-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, beta-catenin and Apc gene mutations in F344 rats.
Kawamori
Toshihiko
T
Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
Totsuka
Yukari
Y
Uchiya
Naoaki
N
Kitamura
Tomohiro
T
Shibata
Hideyuki
H
Sugimura
Takashi
T
Wakabayashi
Keiji
K
D000230:Adenocarcinoma / Q000139:chemically induced; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D002243:Carbolines; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced*; D003598:Cytoskeletal Proteins / Q000235:genetics; D005260:Female; D017491:Genes, APC / Q000502:physiology; D011905:Genes, ras / Q000502:physiology; D006247:Harmine / Q000031:analogs & derivatives* / Q000378:metabolism; D007211:Indoles / Q000633:toxicity*; D007938:Leukemia / Q000139:chemically induced; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced*; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011725:Pyridines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013964:Thyroid Neoplasms / Q000139:chemically induced; D015534:Trans-Activators / Q000235:genetics; D051176:beta Catenin
D000814:Aniline Compounds; D002243:Carbolines; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D007211:Indoles; D009153:Mutagens; D011725:Pyridines; D015534:Trans-Activators; D051176:beta Catenin; D006247:Harmine; C010262:norharman; C421010:9-(4'-aminophenyl)-9H-pyrido(3,4-b)indole; C023650:aniline