Structures of mutagens produced by the co-mutagen norharman with o- and m-toluidine isomers

Noriyasu Hada, Yukari Totsuka, Takeji Enya, Kumiko Tsurumaki, Mariko Nakazawa, Nobuo Kawahara, Yasuoki Murakami, Yuusaku Yokoyama, Takashi Sugimura, Keiji Wakabayashi

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Norharman, abundantly present in cigarette smoke and cooked foods, is not mutagenic to Salmonella typhimurium strains. However, norharman shows mutagenicity to S. typhimurium TA98 and YG1024 in the presence of S9 mix when coexisting with aromatic amines, including aniline, o- and m-toluidines. We previously reported that the mutagenicity from norharman and aniline in the presence of S9 mix was due to the formation of a mutagenic compound, 9-(4′-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman). In the present study, we analyzed the mutagens produced by norharman with o- or m-toluidine in the presence of S9 mix. When norharman and o-toluidine were reacted at 37°C for 20 min, two mutagenic compounds, which were mutagenic with and without S9 mix, respectively, were produced, and these were isolated by HPLC. The former mutagen was deduced to be 9-(4′-amino-3′-methylphenyl)-9H-pyrido[3,4-b]indole (amino-3′-methylphenylnorharman) on the basis of various spectral data, and this new heterocyclic amine was confirmed by its chemical synthesis. The latter mutagen was identified to be the hydroxyamino derivative. Amino-3′-methylphenylnorharman induced 41,000 revertants of TA98, and 698,000 revertants of YG1024 per μg with S9 mix. Formation of the same DNA adducts was observed in YG1024 when amino-3′-methylphenylnorharman or a mixture of norharman plus o-toluidine was incubated with S9 mix. These observations suggest that norharman reacts with o-toluidine in the presence of S9 mix to produce amino-3′-methylphenylnorharman, and this compound is metabolically activated to yield its hydroxyamino derivative. After activation by O-acetyltransferase, it might bind to DNA and exert mutagenicity in S. typhimurium TA98 and YG1024. When norharman and m-toluidine were reacted in the presence of S9 mix, 9-(4′-amino-2′-methylphenyl)-9H-pyrido[3,4-b]indole (amino-2′-methylphenylnorharman) was identified as a mutagen. Thus, the mutagenicity of norharman with m-toluidine may follow a mechanism similar to that with o-toluidine.

Original languageEnglish
Pages (from-to)115-126
Number of pages12
JournalMutation Research - Genetic Toxicology and Environmental Mutagenesis
Volume493
Issue number1-2
DOIs
Publication statusPublished - 2001 Jun 27
Externally publishedYes

Fingerprint

norharman
2-toluidine
Mutagens
Salmonella typhimurium
Amines
3-toluidine
Carbolines
Acetyltransferases
DNA Adducts

Keywords

  • Amino-2′-methylphenylnorharman
  • Amino-3′-methylphenylnorharman
  • Norharman
  • Toluidine isomers

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Genetics

Cite this

Structures of mutagens produced by the co-mutagen norharman with o- and m-toluidine isomers. / Hada, Noriyasu; Totsuka, Yukari; Enya, Takeji; Tsurumaki, Kumiko; Nakazawa, Mariko; Kawahara, Nobuo; Murakami, Yasuoki; Yokoyama, Yuusaku; Sugimura, Takashi; Wakabayashi, Keiji.

In: Mutation Research - Genetic Toxicology and Environmental Mutagenesis, Vol. 493, No. 1-2, 27.06.2001, p. 115-126.

Research output: Contribution to journalArticle

Hada, N, Totsuka, Y, Enya, T, Tsurumaki, K, Nakazawa, M, Kawahara, N, Murakami, Y, Yokoyama, Y, Sugimura, T & Wakabayashi, K 2001, 'Structures of mutagens produced by the co-mutagen norharman with o- and m-toluidine isomers', Mutation Research - Genetic Toxicology and Environmental Mutagenesis, vol. 493, no. 1-2, pp. 115-126. https://doi.org/10.1016/S1383-5718(01)00168-1
Hada, Noriyasu ; Totsuka, Yukari ; Enya, Takeji ; Tsurumaki, Kumiko ; Nakazawa, Mariko ; Kawahara, Nobuo ; Murakami, Yasuoki ; Yokoyama, Yuusaku ; Sugimura, Takashi ; Wakabayashi, Keiji. / Structures of mutagens produced by the co-mutagen norharman with o- and m-toluidine isomers. In: Mutation Research - Genetic Toxicology and Environmental Mutagenesis. 2001 ; Vol. 493, No. 1-2. pp. 115-126.
@article{9902830e7d324061a177a22dafab5293,
title = "Structures of mutagens produced by the co-mutagen norharman with o- and m-toluidine isomers",
abstract = "Norharman, abundantly present in cigarette smoke and cooked foods, is not mutagenic to Salmonella typhimurium strains. However, norharman shows mutagenicity to S. typhimurium TA98 and YG1024 in the presence of S9 mix when coexisting with aromatic amines, including aniline, o- and m-toluidines. We previously reported that the mutagenicity from norharman and aniline in the presence of S9 mix was due to the formation of a mutagenic compound, 9-(4′-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman). In the present study, we analyzed the mutagens produced by norharman with o- or m-toluidine in the presence of S9 mix. When norharman and o-toluidine were reacted at 37°C for 20 min, two mutagenic compounds, which were mutagenic with and without S9 mix, respectively, were produced, and these were isolated by HPLC. The former mutagen was deduced to be 9-(4′-amino-3′-methylphenyl)-9H-pyrido[3,4-b]indole (amino-3′-methylphenylnorharman) on the basis of various spectral data, and this new heterocyclic amine was confirmed by its chemical synthesis. The latter mutagen was identified to be the hydroxyamino derivative. Amino-3′-methylphenylnorharman induced 41,000 revertants of TA98, and 698,000 revertants of YG1024 per μg with S9 mix. Formation of the same DNA adducts was observed in YG1024 when amino-3′-methylphenylnorharman or a mixture of norharman plus o-toluidine was incubated with S9 mix. These observations suggest that norharman reacts with o-toluidine in the presence of S9 mix to produce amino-3′-methylphenylnorharman, and this compound is metabolically activated to yield its hydroxyamino derivative. After activation by O-acetyltransferase, it might bind to DNA and exert mutagenicity in S. typhimurium TA98 and YG1024. When norharman and m-toluidine were reacted in the presence of S9 mix, 9-(4′-amino-2′-methylphenyl)-9H-pyrido[3,4-b]indole (amino-2′-methylphenylnorharman) was identified as a mutagen. Thus, the mutagenicity of norharman with m-toluidine may follow a mechanism similar to that with o-toluidine.",
keywords = "Amino-2′-methylphenylnorharman, Amino-3′-methylphenylnorharman, Norharman, Toluidine isomers",
author = "Noriyasu Hada and Yukari Totsuka and Takeji Enya and Kumiko Tsurumaki and Mariko Nakazawa and Nobuo Kawahara and Yasuoki Murakami and Yuusaku Yokoyama and Takashi Sugimura and Keiji Wakabayashi",
year = "2001",
month = "6",
day = "27",
doi = "10.1016/S1383-5718(01)00168-1",
language = "English",
volume = "493",
pages = "115--126",
journal = "Mutation Research - Genetic Toxicology and Environmental Mutagenesis",
issn = "1383-5718",
publisher = "Elsevier",
number = "1-2",

}

TY - JOUR

T1 - Structures of mutagens produced by the co-mutagen norharman with o- and m-toluidine isomers

AU - Hada, Noriyasu

AU - Totsuka, Yukari

AU - Enya, Takeji

AU - Tsurumaki, Kumiko

AU - Nakazawa, Mariko

AU - Kawahara, Nobuo

AU - Murakami, Yasuoki

AU - Yokoyama, Yuusaku

AU - Sugimura, Takashi

AU - Wakabayashi, Keiji

PY - 2001/6/27

Y1 - 2001/6/27

N2 - Norharman, abundantly present in cigarette smoke and cooked foods, is not mutagenic to Salmonella typhimurium strains. However, norharman shows mutagenicity to S. typhimurium TA98 and YG1024 in the presence of S9 mix when coexisting with aromatic amines, including aniline, o- and m-toluidines. We previously reported that the mutagenicity from norharman and aniline in the presence of S9 mix was due to the formation of a mutagenic compound, 9-(4′-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman). In the present study, we analyzed the mutagens produced by norharman with o- or m-toluidine in the presence of S9 mix. When norharman and o-toluidine were reacted at 37°C for 20 min, two mutagenic compounds, which were mutagenic with and without S9 mix, respectively, were produced, and these were isolated by HPLC. The former mutagen was deduced to be 9-(4′-amino-3′-methylphenyl)-9H-pyrido[3,4-b]indole (amino-3′-methylphenylnorharman) on the basis of various spectral data, and this new heterocyclic amine was confirmed by its chemical synthesis. The latter mutagen was identified to be the hydroxyamino derivative. Amino-3′-methylphenylnorharman induced 41,000 revertants of TA98, and 698,000 revertants of YG1024 per μg with S9 mix. Formation of the same DNA adducts was observed in YG1024 when amino-3′-methylphenylnorharman or a mixture of norharman plus o-toluidine was incubated with S9 mix. These observations suggest that norharman reacts with o-toluidine in the presence of S9 mix to produce amino-3′-methylphenylnorharman, and this compound is metabolically activated to yield its hydroxyamino derivative. After activation by O-acetyltransferase, it might bind to DNA and exert mutagenicity in S. typhimurium TA98 and YG1024. When norharman and m-toluidine were reacted in the presence of S9 mix, 9-(4′-amino-2′-methylphenyl)-9H-pyrido[3,4-b]indole (amino-2′-methylphenylnorharman) was identified as a mutagen. Thus, the mutagenicity of norharman with m-toluidine may follow a mechanism similar to that with o-toluidine.

AB - Norharman, abundantly present in cigarette smoke and cooked foods, is not mutagenic to Salmonella typhimurium strains. However, norharman shows mutagenicity to S. typhimurium TA98 and YG1024 in the presence of S9 mix when coexisting with aromatic amines, including aniline, o- and m-toluidines. We previously reported that the mutagenicity from norharman and aniline in the presence of S9 mix was due to the formation of a mutagenic compound, 9-(4′-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman). In the present study, we analyzed the mutagens produced by norharman with o- or m-toluidine in the presence of S9 mix. When norharman and o-toluidine were reacted at 37°C for 20 min, two mutagenic compounds, which were mutagenic with and without S9 mix, respectively, were produced, and these were isolated by HPLC. The former mutagen was deduced to be 9-(4′-amino-3′-methylphenyl)-9H-pyrido[3,4-b]indole (amino-3′-methylphenylnorharman) on the basis of various spectral data, and this new heterocyclic amine was confirmed by its chemical synthesis. The latter mutagen was identified to be the hydroxyamino derivative. Amino-3′-methylphenylnorharman induced 41,000 revertants of TA98, and 698,000 revertants of YG1024 per μg with S9 mix. Formation of the same DNA adducts was observed in YG1024 when amino-3′-methylphenylnorharman or a mixture of norharman plus o-toluidine was incubated with S9 mix. These observations suggest that norharman reacts with o-toluidine in the presence of S9 mix to produce amino-3′-methylphenylnorharman, and this compound is metabolically activated to yield its hydroxyamino derivative. After activation by O-acetyltransferase, it might bind to DNA and exert mutagenicity in S. typhimurium TA98 and YG1024. When norharman and m-toluidine were reacted in the presence of S9 mix, 9-(4′-amino-2′-methylphenyl)-9H-pyrido[3,4-b]indole (amino-2′-methylphenylnorharman) was identified as a mutagen. Thus, the mutagenicity of norharman with m-toluidine may follow a mechanism similar to that with o-toluidine.

KW - Amino-2′-methylphenylnorharman

KW - Amino-3′-methylphenylnorharman

KW - Norharman

KW - Toluidine isomers

UR - http://www.scopus.com/inward/record.url?scp=0035958284&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035958284&partnerID=8YFLogxK

U2 - 10.1016/S1383-5718(01)00168-1

DO - 10.1016/S1383-5718(01)00168-1

M3 - Article

VL - 493

SP - 115

EP - 126

JO - Mutation Research - Genetic Toxicology and Environmental Mutagenesis

JF - Mutation Research - Genetic Toxicology and Environmental Mutagenesis

SN - 1383-5718

IS - 1-2

ER -