harmine and Colonic-Neoplasms

Topics: Animals; Breast Neoplasms; Carbolines; Carcinogens, Environmental; Cattle; Colonic Neoplasms; Cooking; Food; Harmine; Head and Neck Neoplasms; Humans; Imidazoles; Male; Meat; Mutagens; Neoplasms; Nitrates; Nitrites; Nitrosamines; Prostatic Neoplasms

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.

Topics: Adenocarcinoma; Aniline Compounds; Animals; beta Catenin; Carbolines; Carcinoma, Hepatocellular; Colon; Colonic Neoplasms; Cytoskeletal Proteins; Female; Genes, APC; Genes, ras; Harmine; Indoles; Leukemia; Liver; Liver Neoplasms; Male; Mutagens; Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Pyridines; Rats; Rats, Inbred F344; Thyroid Neoplasms; Trans-Activators

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.

Topics: Aniline Compounds; Animals; Carbolines; Carcinogens; Colon; Colonic Neoplasms; CpG Islands; DNA Mutational Analysis; Dose-Response Relationship, Drug; Gene Deletion; Harmine; Humans; Indoles; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Chemical; Mucous Membrane; Mutagens; Mutation; Pyridines; Time Factors