Gastric carcinogenesis: 2-chloro-4-methylthiobutanoic acid, a novel mutagen in salted, pickled Sanma hiraki fish, or similarly treated methionine
Gastric carcinogenesis: 2-chloro-4-methylthiobutanoic acid, a novel mutagen in salted, pickled Sanma hiraki fish, or similarly treated methionine
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DOI：
10.1021/tx9500585
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发表时间：
1996-01-01
影响因子：
4.1
通讯作者：
Hecht, SS
中科院分区：
文献类型：
--
作者：
Chen, W;Weisburger, JH;Hecht, SS
以胃癌高发区鱼类腌制方式为例，探讨其相关致病化学物质。用氯化钠和亚硝酸钠在pH 3下处理Sanma Hiraki鱼。此前，已发现经处理鱼的提取物在不含S9的鼠伤寒沙门氏菌TA 1535中具有致突变性，并且在对大鼠灌胃后诱导腺胃癌。我们现在证明，通过在盐-亚硝酸盐处理前将生肉预孵育几天，可增强致突变性。HPLC技术表明，三种诱变剂存在于鱼提取物。发现其中一种诱变剂在pH 1.0-9.0范围内稳定。该诱变剂经硅胶固相萃取、反相高效液相色谱纯化后，用低分辨和高分辨质谱、核磁共振和红外光谱进行了表征。虽然N-亚硝基化合物被普遍认为与胃癌发生有关，但意外地发现该诱变剂具有新的结构2-氯-4-甲硫基丁酸（CMBA）。根据结构，蛋氨酸似乎可能是前体，这一点确实得到了证实。盐和亚硝酸盐是形成这种诱变剂的必要因素。CMBA的产量是线性的氯化物浓度从0到800 mM NaCl。20种氨基酸在pH 3时与亚硝酸盐和氯化物反应，仅蛋氨酸产生S.鼠伤寒TA 1535。色氨酸对S.在酪氨酸的情况下，诱变剂仅对TA 100有活性。这些结果提示盐在胃癌发生中的重要作用，并为探索特定靶器官致突变物/致癌物的形成提供了新的途径。
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 gavage 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.