Journal Article

Carcinogenicity of aminophenylnorharman, a possible novel endogenous mutagen, formed from norharman and aniline, in F344 rats

Toshihiko Kawamori, Yukari Totsuka, Naoaki Uchiya, Tomohiro Kitamura, Hideyuki Shibata, Takashi Sugimura and Keiji Wakabayashi

in Carcinogenesis

Volume 25, issue 10, pages 1967-1672
Published in print October 2004 | ISSN: 0143-3334
Published online October 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh189
Carcinogenicity of aminophenylnorharman, a possible novel endogenous mutagen, formed from norharman and aniline, in F344 rats

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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 β-catenin gene mutations in 24% of HCCs and K-ras, β-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. β-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, β-catenin and Apc gene mutations in F344 rats.

Keywords: APNH, aminophenylnorharman, 9-(4′-aminophenyl)-9H-pyrido[3,4-b]indole; norharman, 9H-pyrido[3,4-b]indole; HCCs, hepatocellular carcinomas; IQ, 2-amino-3-methylimidazo[4,5-f]quinoline; PCR–SSCP, polymerase chain reaction–single strand conformation polymorphism

Journal Article.  4827 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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