Structural determination of a mutagenic aminophenylnorharman produced by the co-mutagen norharman with aniline

Yukari Totsuka, Noriyasu Hada, Ken Ichiro Matsumoto, Nobuo Kawahara, Yasuoki Murakami, Yuusaku Yokoyama, Takashi Sugimura, Keiji Wakabayashi

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Norharman (9H-pyrido[3,4-b]indole), widely distributed in our environment, including cigarette smoke and cooked foodstuffs, is not mutagenic to Salmonella strains, but becomes mutagenic to S. typhimurium TA98 and YG1024 with S9 mix in the presence of non-mutagenic aromatic amines such as aniline and o-toluidine. To elucidate the mechanisms of co-mutagenicity, we tried to isolate the mutagen(s) produced by a reaction between norharman and aniline with S9 mix. By HPLC purification, two mutagenic compounds (I and II), one (I) showing mutagenicity with and the other (II) without S9 mix, were isolated. The structure of compound I was deduced to be a coupled compound of norharman and aniline, 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman), by a variety of spectrometry techniques and this was confirmed by its chemical synthesis. The mutagenic activity of this novel heterocyclic amine was tested using the pre-incubation method and was found to induce 187,000 revertants in TA98 and 1 783 000 revertants in YG1024 per μg with S9 mix. Compound II was shown to be hydroxyaminophenylnorharman. Formation of the same DNA adducts was observed in YG1024 when aminophenylnorharman or a mixture of norharman plus aniline was incubated, with S9 mix. The hydroxyamino derivative also yielded the same DNA adducts in YG1024. Thus, the appearance of mutagenicity by norharman with aniline in the presence of S9 mix suggests that the coupled mutagenic compound, aminophenylnorharman, is formed from norharman and aniline, then converted to the hydroxyamino derivative and forms DNA adducts to induce mutations in TA98 and YG1024.

Original languageEnglish
Pages (from-to)1995-2000
Number of pages6
JournalCarcinogenesis
Volume19
Issue number11
Publication statusPublished - 1998 Nov

Fingerprint

norharman
Mutagens
DNA Adducts
2-toluidine
Amines
Aniline Compounds
Carbolines
Smoke
Tobacco Products
Salmonella
aniline
9-(4'-aminophenyl)-9H-pyrido(3,4-b)indole
Spectrum Analysis
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Cancer Research

Cite this

Totsuka, Y., Hada, N., Matsumoto, K. I., Kawahara, N., Murakami, Y., Yokoyama, Y., ... Wakabayashi, K. (1998). Structural determination of a mutagenic aminophenylnorharman produced by the co-mutagen norharman with aniline. Carcinogenesis, 19(11), 1995-2000.

Structural determination of a mutagenic aminophenylnorharman produced by the co-mutagen norharman with aniline. / Totsuka, Yukari; Hada, Noriyasu; Matsumoto, Ken Ichiro; Kawahara, Nobuo; Murakami, Yasuoki; Yokoyama, Yuusaku; Sugimura, Takashi; Wakabayashi, Keiji.

In: Carcinogenesis, Vol. 19, No. 11, 11.1998, p. 1995-2000.

Research output: Contribution to journalArticle

Totsuka, Y, Hada, N, Matsumoto, KI, Kawahara, N, Murakami, Y, Yokoyama, Y, Sugimura, T & Wakabayashi, K 1998, 'Structural determination of a mutagenic aminophenylnorharman produced by the co-mutagen norharman with aniline', Carcinogenesis, vol. 19, no. 11, pp. 1995-2000.
Totsuka Y, Hada N, Matsumoto KI, Kawahara N, Murakami Y, Yokoyama Y et al. Structural determination of a mutagenic aminophenylnorharman produced by the co-mutagen norharman with aniline. Carcinogenesis. 1998 Nov;19(11):1995-2000.
Totsuka, Yukari ; Hada, Noriyasu ; Matsumoto, Ken Ichiro ; Kawahara, Nobuo ; Murakami, Yasuoki ; Yokoyama, Yuusaku ; Sugimura, Takashi ; Wakabayashi, Keiji. / Structural determination of a mutagenic aminophenylnorharman produced by the co-mutagen norharman with aniline. In: Carcinogenesis. 1998 ; Vol. 19, No. 11. pp. 1995-2000.
@article{ea68643809c74881aebbde8052a885dd,
title = "Structural determination of a mutagenic aminophenylnorharman produced by the co-mutagen norharman with aniline",
abstract = "Norharman (9H-pyrido[3,4-b]indole), widely distributed in our environment, including cigarette smoke and cooked foodstuffs, is not mutagenic to Salmonella strains, but becomes mutagenic to S. typhimurium TA98 and YG1024 with S9 mix in the presence of non-mutagenic aromatic amines such as aniline and o-toluidine. To elucidate the mechanisms of co-mutagenicity, we tried to isolate the mutagen(s) produced by a reaction between norharman and aniline with S9 mix. By HPLC purification, two mutagenic compounds (I and II), one (I) showing mutagenicity with and the other (II) without S9 mix, were isolated. The structure of compound I was deduced to be a coupled compound of norharman and aniline, 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman), by a variety of spectrometry techniques and this was confirmed by its chemical synthesis. The mutagenic activity of this novel heterocyclic amine was tested using the pre-incubation method and was found to induce 187,000 revertants in TA98 and 1 783 000 revertants in YG1024 per μg with S9 mix. Compound II was shown to be hydroxyaminophenylnorharman. Formation of the same DNA adducts was observed in YG1024 when aminophenylnorharman or a mixture of norharman plus aniline was incubated, with S9 mix. The hydroxyamino derivative also yielded the same DNA adducts in YG1024. Thus, the appearance of mutagenicity by norharman with aniline in the presence of S9 mix suggests that the coupled mutagenic compound, aminophenylnorharman, is formed from norharman and aniline, then converted to the hydroxyamino derivative and forms DNA adducts to induce mutations in TA98 and YG1024.",
author = "Yukari Totsuka and Noriyasu Hada and Matsumoto, {Ken Ichiro} and Nobuo Kawahara and Yasuoki Murakami and Yuusaku Yokoyama and Takashi Sugimura and Keiji Wakabayashi",
year = "1998",
month = "11",
language = "English",
volume = "19",
pages = "1995--2000",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "11",

}

TY - JOUR

T1 - Structural determination of a mutagenic aminophenylnorharman produced by the co-mutagen norharman with aniline

AU - Totsuka, Yukari

AU - Hada, Noriyasu

AU - Matsumoto, Ken Ichiro

AU - Kawahara, Nobuo

AU - Murakami, Yasuoki

AU - Yokoyama, Yuusaku

AU - Sugimura, Takashi

AU - Wakabayashi, Keiji

PY - 1998/11

Y1 - 1998/11

N2 - Norharman (9H-pyrido[3,4-b]indole), widely distributed in our environment, including cigarette smoke and cooked foodstuffs, is not mutagenic to Salmonella strains, but becomes mutagenic to S. typhimurium TA98 and YG1024 with S9 mix in the presence of non-mutagenic aromatic amines such as aniline and o-toluidine. To elucidate the mechanisms of co-mutagenicity, we tried to isolate the mutagen(s) produced by a reaction between norharman and aniline with S9 mix. By HPLC purification, two mutagenic compounds (I and II), one (I) showing mutagenicity with and the other (II) without S9 mix, were isolated. The structure of compound I was deduced to be a coupled compound of norharman and aniline, 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman), by a variety of spectrometry techniques and this was confirmed by its chemical synthesis. The mutagenic activity of this novel heterocyclic amine was tested using the pre-incubation method and was found to induce 187,000 revertants in TA98 and 1 783 000 revertants in YG1024 per μg with S9 mix. Compound II was shown to be hydroxyaminophenylnorharman. Formation of the same DNA adducts was observed in YG1024 when aminophenylnorharman or a mixture of norharman plus aniline was incubated, with S9 mix. The hydroxyamino derivative also yielded the same DNA adducts in YG1024. Thus, the appearance of mutagenicity by norharman with aniline in the presence of S9 mix suggests that the coupled mutagenic compound, aminophenylnorharman, is formed from norharman and aniline, then converted to the hydroxyamino derivative and forms DNA adducts to induce mutations in TA98 and YG1024.

AB - Norharman (9H-pyrido[3,4-b]indole), widely distributed in our environment, including cigarette smoke and cooked foodstuffs, is not mutagenic to Salmonella strains, but becomes mutagenic to S. typhimurium TA98 and YG1024 with S9 mix in the presence of non-mutagenic aromatic amines such as aniline and o-toluidine. To elucidate the mechanisms of co-mutagenicity, we tried to isolate the mutagen(s) produced by a reaction between norharman and aniline with S9 mix. By HPLC purification, two mutagenic compounds (I and II), one (I) showing mutagenicity with and the other (II) without S9 mix, were isolated. The structure of compound I was deduced to be a coupled compound of norharman and aniline, 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman), by a variety of spectrometry techniques and this was confirmed by its chemical synthesis. The mutagenic activity of this novel heterocyclic amine was tested using the pre-incubation method and was found to induce 187,000 revertants in TA98 and 1 783 000 revertants in YG1024 per μg with S9 mix. Compound II was shown to be hydroxyaminophenylnorharman. Formation of the same DNA adducts was observed in YG1024 when aminophenylnorharman or a mixture of norharman plus aniline was incubated, with S9 mix. The hydroxyamino derivative also yielded the same DNA adducts in YG1024. Thus, the appearance of mutagenicity by norharman with aniline in the presence of S9 mix suggests that the coupled mutagenic compound, aminophenylnorharman, is formed from norharman and aniline, then converted to the hydroxyamino derivative and forms DNA adducts to induce mutations in TA98 and YG1024.

UR - http://www.scopus.com/inward/record.url?scp=0031784056&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031784056&partnerID=8YFLogxK

M3 - Article

VL - 19

SP - 1995

EP - 2000

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 11

ER -