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

Kawamori, Toshihiko; Totsuka, Yukari; Uchiya, Naoaki; Kitamura, Toshiya; Shibata, Hideyuki; Sügimura, Takashi; Wakabayashi, Keiji

doi:10.1093/carcin/bgh189

Cited by 31 publications

(31 citation statements)

References 27 publications

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“…13). However, APNH is a more potent carcinogen than Trp-P-1 and MeIQx (10,28), so that the risk of human cancer might be similar. To understand the role of APNH in human cancer development, studies for APNH levels in human urine samples, which are balanced by age and gender, APNH metabolism, and other factors that affect APNH levels, will be required.…”

Section: Discussionmentioning

confidence: 99%

“…Mutagenic activity of APNH in S. typhimurium strains proved comparable with those of 2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline (MeIQx) and 3-amino-1-methyl-5H-pyrido [4,3-b] indole (Trp-P-2), food-borne carcinogenic heterocyclic amines (5,9). In a long-term carcinogenicity experiment using F344 rats, APNH induced tumors in the liver, colon, thyroid, hematopoietic systems, and clitoral gland (10). To investigate the in vivo formation of APNH from norharman and aniline, we analyzed APNH in urine of rats and detected the compound only in animals fed norharman and aniline and not in the controls or with either norharman or aniline alone (11).…”

Section: Introductionmentioning

confidence: 99%

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Detection of Aminophenylnorharman, a Possible Endogenous Mutagenic and Carcinogenic Compound, in Human Urine Samples

Nishigaki

Totsuka

Kataoka

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Mutagenic/carcinogenic 9-(4 ¶-aminophenyl)-9H-pyrido [3,4-b]indole [aminophenylnorharman (APNH)] is formed from norharman and aniline in the presence of cytochrome P450 3A4/1A2. Because both precursors are widely distributed in the environment, human exposure is unavoidable. To clarify APNH formation in the human body, amounts of the compound in 24-h human urine collected from smokers and nonsmokers, eating a normal diet, were analyzed by liquid chromatography/electrospray ionization tandem mass spectrometry. In addition, norharman and aniline were also analyzed by high-performance liquid chromatography and gas chromatography, respectively. APNH could be detected in all urine samples at levels 49 to 449 pg for smokers and 21 to 594 pg for nonsmokers per 24-h urine, respectively. The amounts of norharman and aniline were 46 to 185 ng and 0.70 to 8.10 Mg for smokers and 52 to 447 ng and 0.49 to 5.72 Mg for nonsmokers, respectively, per 24-h urine (none of the levels differing significantly between smokers and nonsmokers). To exclude exogenous exposure to norharman and aniline, we analyzed the levels of APNH, norharman, and aniline in urine samples collected from inpatients receiving parenteral alimentation. Similar to the healthy volunteers, all urine samples contained 12 to 338 pg of APNH, 6 to 75 ng of norharman, and 0.33 to 1.86 Mg of aniline per 24-h urine. These results suggest that APNH should be considered as a novel endogenous mutagen/ carcinogen; thus, it is very important to determine the biological significance of this carcinogen for human cancer development. (Cancer Epidemiol Biomarkers Prev 2007; 16(1):151 -6)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Detection of Aminophenylnorharman, a Possible Endogenous Mutagenic and Carcinogenic Compound, in Human Urine Samples

Nishigaki

Totsuka

Kataoka

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…APNH formed DNA adducts in the liver and induced HCC in F344 rats. 17 However, the mice received with APNH/DSS had no liver tumors in this study. These differences in the liver carcinogenicity of APNH may be due to the differences in the experimental protocol.…”

Section: Discussionmentioning

confidence: 62%

“…In contrast, the location and mutation pattern were slightly different from a report documenting that the b-catenin gene mutations of rat colon tumors induced by APNH; G:C to A:T transition at codon 34 was predominant. 17 Masumura et al has also reported that PhIP…”

Section: Discussionmentioning

confidence: 97%

“…32,33 When given high doses of PhIP for a long-term period, colonic tumors developed in rats. 34 Although dietary APNH at a dose of 20 or 40 ppm for 85 weeks induced colonic tumors in F344 rats, the incidence of colonic tumors was low, being 3 or 9% in males and 4 or 13% in females, respectively, 17 suggesting a weak tumor-initiating ability of APNH in the rat colon. In the current study, colonic neoplasms developed in the mice given APNH at all doses except for 1 mg/ kg b.w., when followed by DSS.…”

Section: Discussionmentioning

confidence: 99%

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Tumor‐initiating potency of a novel heterocyclic amine, aminophenylnorharman in mouse colonic carcinogenesis model

Kohno

Totsuka²,

Yasui

et al. 2007

Intl Journal of Cancer

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A novel heterocyclic amine, 9-(4 0 -aminophenyl)-9H-pyrido [3,4-b]indole (aminophenylnorharman, APNH), which is formed from nonmutagenic 9H-pyrido [3,4-b]indole (norharman) and aniline, is mutagenic to bacteria and mammalian cells and potently carcinogenic in rats. APNH is detected in human urine samples, suggesting that humans are continuously exposed to APNH. In the present study, 32 P-postlabelin analysis revealed that the levels of APNH-DNA adduct 24 hr after the treatment with APNH (1, 5 and 20 mg/kg body weight) in male ICR mice were increased in a dose-dependent manner in the colon and liver. Based on these findings, we determined the tumor-initiating potency of APNH in an inflammation-related and two-stage mouse colon carcinogenesis model. Male Crj: CD-1 (ICR) mice were given a single intragastric administration (1, 2, 5 or 10 mg/kg body weight) of APNH and subsequent 1-week oral exposure to dextran sodium sulfate (DSS, 2% in drinking water). Treatment with APNH and DSS resulted in numerous colon tumor development: the incidence and multiplicity of the tumors were the highest in the mice received 10 mg/kg body weight of APNH and followed by DSS. Development of colon tumors was dose-dependent of APNH. Seven of 9 (77.8%) colonic adenocarcinomas developed in mice treated with APNH (10 mg/kg body weight) and DSS had b-catenin gene mutations at codons 32 and 37, being predominantly transversion. These findings indicate that APNH has an initiating activity in inflamed mouse colon and the APNH-DNA adduct formation correlates with its tumorigenic potential. ' 2007 Wiley-Liss, Inc.Key words: aminophenylnorharman; adenocarcinoma; b-catenin; colon; dextran sodium sulfate; DNA adduct; heterocyclic amines; initiation; mice The development of most human cancer might be caused by carcinogenic agents in the diet and cigarette smoke.1 Therefore, identification of mutagens and carcinogens in foods and cigarette smoke is very important for understanding the causal agents of human cancer. A series of mutagenic and carcinogenic heterocyclic amines (HCAs) have been identified in cooked foods and heating amino acids and proteins.2 The b-carboline compound norharman (9H-pyrido [3,4-b]indole) is produced in the pyrolysis of tryptophan.3 Norharman is present at much higher levels than 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in human urine samples. 4 Although norharman is not mutagenic to Salmonella strains, it becomes mutagenic to S. typhimurium TA98 in the presence of S9 mix, when incubated with non-mutagenic aromatic amines, such as aniline.5 A novel HCA, 9-(4 0 -aminophenyl)-9H-pyrido [3,4-b]indole (aminophenylnorharman, APNH) can be formed by this reaction, then converted to the N-hydroxyamino derivative which produces DNA adducts after esterification to induce mutations in S. typhimurium TA98 and YG1024. 6-8 APNH is able to induce sister chromatid exchanges and chromosome aberrations. 9 We have recently demonstrated that APNH forms DNA adducts at the C-...

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Heterocyclic Aromatic Amines

Turesky

2008

Process‐Induced Food Toxicants

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

Cited by 31 publications

References 27 publications

Detection of Aminophenylnorharman, a Possible Endogenous Mutagenic and Carcinogenic Compound, in Human Urine Samples

Detection of Aminophenylnorharman, a Possible Endogenous Mutagenic and Carcinogenic Compound, in Human Urine Samples

Tumor‐initiating potency of a novel heterocyclic amine, aminophenylnorharman in mouse colonic carcinogenesis model

Heterocyclic Aromatic Amines

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