Gastric carcinogenesis

2-Chloro-4-methylthiobutanoic acid, a novel mutagen in salted, pickled sanma hiraki fish, or similarly treated methionine

Wei Chen, John H. Weisburger, Emerich S. Fiala, Thomas Spratt, Steven G. Carmella, Di Chen, Stephen S. Hecht

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The customary salting and pickling of fish in high risk gastric cancer regions were modeled to explore the relevant causative chemicals. The fish Sanma hiraki was treated with sodium chloride and sodium nitrite at pH 3. Previously, it had been found that an extract of the treated fish was mutagenic in Salmonella typhimurium TA 1535 without S9 and also that it induced glandular stomach cancer upon garage to rats. We now demonstrate that the mutagenicity was enhanced by preincubation of the raw meat for several days before salt-nitrite treatment. HPLC techniques showed that three mutagens were present in the fish extract. One of the mutagens was found to be stable over the pH range of 1.0-9.0. This mutagen was purified by silica gel solid phase extraction, followed by a series of reverse phase HPLC steps, and was characterized by low and high resolution MS, NMR, and FT-IR. While N- nitroso compounds were generally believed to be associated with gastric carcinogenesis, it was unexpectedly found that the mutagen has the novel structure 2-chloro-4-methylthiobutanoic acid (CMBA). Based on the structure, it seemed likely that methionine might be the precursor, and this was, indeed, proven. Both salt and nitrite are essential factors for forming this mutagen. The yield of CMBA was linear for chloride concentrations from 0 to 800 mM NaCl. Of 20 amino acids reacted with nitrite and chloride at pH 3, only methionine generated a mutagen for S. typhimurium TA 1535. Tryptophan gave a product mutagenic in S. typhimurium TA 100 and TA 98, but not TA 1535, and in the case of tyrosine, the mutagen was active only for TA 100. These results suggest an important role for salt in gastric carcinogenesis and provide new approaches for exploring the formation of mutagens/carcinogens for specific target organs.

Original languageEnglish (US)
Pages (from-to)58-66
Number of pages9
JournalChemical Research in Toxicology
Volume9
Issue number1
DOIs
StatePublished - Jan 1 1996

Fingerprint

Mutagens
Methionine
Fish
Stomach
Carcinogenesis
Fishes
Salmonella typhimurium
Nitrites
Salts
Stomach Neoplasms
Chlorides
High Pressure Liquid Chromatography
Nitroso Compounds
Sodium Nitrite
Pickling
Salmonella
2-chloro-4-methylthiobutanoic acid
Meats
Silica Gel
Solid Phase Extraction

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Chen, Wei ; Weisburger, John H. ; Fiala, Emerich S. ; Spratt, Thomas ; Carmella, Steven G. ; Chen, Di ; Hecht, Stephen S. / Gastric carcinogenesis : 2-Chloro-4-methylthiobutanoic acid, a novel mutagen in salted, pickled sanma hiraki fish, or similarly treated methionine. In: Chemical Research in Toxicology. 1996 ; Vol. 9, No. 1. pp. 58-66.
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abstract = "The customary salting and pickling of fish in high risk gastric cancer regions were modeled to explore the relevant causative chemicals. The fish Sanma hiraki was treated with sodium chloride and sodium nitrite at pH 3. Previously, it had been found that an extract of the treated fish was mutagenic in Salmonella typhimurium TA 1535 without S9 and also that it induced glandular stomach cancer upon garage to rats. We now demonstrate that the mutagenicity was enhanced by preincubation of the raw meat for several days before salt-nitrite treatment. HPLC techniques showed that three mutagens were present in the fish extract. One of the mutagens was found to be stable over the pH range of 1.0-9.0. This mutagen was purified by silica gel solid phase extraction, followed by a series of reverse phase HPLC steps, and was characterized by low and high resolution MS, NMR, and FT-IR. While N- nitroso compounds were generally believed to be associated with gastric carcinogenesis, it was unexpectedly found that the mutagen has the novel structure 2-chloro-4-methylthiobutanoic acid (CMBA). Based on the structure, it seemed likely that methionine might be the precursor, and this was, indeed, proven. Both salt and nitrite are essential factors for forming this mutagen. The yield of CMBA was linear for chloride concentrations from 0 to 800 mM NaCl. Of 20 amino acids reacted with nitrite and chloride at pH 3, only methionine generated a mutagen for S. typhimurium TA 1535. Tryptophan gave a product mutagenic in S. typhimurium TA 100 and TA 98, but not TA 1535, and in the case of tyrosine, the mutagen was active only for TA 100. These results suggest an important role for salt in gastric carcinogenesis and provide new approaches for exploring the formation of mutagens/carcinogens for specific target organs.",
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Gastric carcinogenesis : 2-Chloro-4-methylthiobutanoic acid, a novel mutagen in salted, pickled sanma hiraki fish, or similarly treated methionine. / Chen, Wei; Weisburger, John H.; Fiala, Emerich S.; Spratt, Thomas; Carmella, Steven G.; Chen, Di; Hecht, Stephen S.

In: Chemical Research in Toxicology, Vol. 9, No. 1, 01.01.1996, p. 58-66.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gastric carcinogenesis

T2 - 2-Chloro-4-methylthiobutanoic acid, a novel mutagen in salted, pickled sanma hiraki fish, or similarly treated methionine

AU - Chen, Wei

AU - Weisburger, John H.

AU - Fiala, Emerich S.

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AU - Carmella, Steven G.

AU - Chen, Di

AU - Hecht, Stephen S.

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N2 - The customary salting and pickling of fish in high risk gastric cancer regions were modeled to explore the relevant causative chemicals. The fish Sanma hiraki was treated with sodium chloride and sodium nitrite at pH 3. Previously, it had been found that an extract of the treated fish was mutagenic in Salmonella typhimurium TA 1535 without S9 and also that it induced glandular stomach cancer upon garage to rats. We now demonstrate that the mutagenicity was enhanced by preincubation of the raw meat for several days before salt-nitrite treatment. HPLC techniques showed that three mutagens were present in the fish extract. One of the mutagens was found to be stable over the pH range of 1.0-9.0. This mutagen was purified by silica gel solid phase extraction, followed by a series of reverse phase HPLC steps, and was characterized by low and high resolution MS, NMR, and FT-IR. While N- nitroso compounds were generally believed to be associated with gastric carcinogenesis, it was unexpectedly found that the mutagen has the novel structure 2-chloro-4-methylthiobutanoic acid (CMBA). Based on the structure, it seemed likely that methionine might be the precursor, and this was, indeed, proven. Both salt and nitrite are essential factors for forming this mutagen. The yield of CMBA was linear for chloride concentrations from 0 to 800 mM NaCl. Of 20 amino acids reacted with nitrite and chloride at pH 3, only methionine generated a mutagen for S. typhimurium TA 1535. Tryptophan gave a product mutagenic in S. typhimurium TA 100 and TA 98, but not TA 1535, and in the case of tyrosine, the mutagen was active only for TA 100. These results suggest an important role for salt in gastric carcinogenesis and provide new approaches for exploring the formation of mutagens/carcinogens for specific target organs.

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