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S S Hecht

Publications and source records attributed to S S Hecht.

368 records · Page 21Linked to original sources
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Gastric carcinogenesis: 2-chloro-4-methylthiobutanoic acid, a novel mutagen in salted, pickled Sanma hiraki fish, or similarly treated methionine.

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.

Amino Acids↗
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Inhibition of carcinogenesis by isothiocyanates.

Isothiocyanates occur as conjugates in a wide variety of cruciferous vegetables. Consumption of normal amounts of these vegetables results in the uptake of substantial quantities of isothiocyanates. These naturally occurring isothiocyanates as well as many synthetic analogs can be powerful inhibitors of carcinogenesis in laboratory animals. Particularly impressive results have been obtained in animal models of lung and esophageal cancer. This review summarizes available data on inhibition of carcinogenesis by isothiocyanates. The major mechanism of inhibition appears to be selective inhibition of cytochrome P450 enzymes involved in carcinogen metabolic activation. Evidence for this is reviewed. Isothiocyanates also induce Phase II enzymes and enhance apoptosis. These properties may also be involved in their chemopreventive activity. Phenethyl isothiocyanate is a particularly effective inhibitor of lung tumor induction by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and, therefore, is currently being developed as a chemopreventive agent against lung cancer.

Brassicaceae↗
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A/J mouse lung tumorigenesis by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and its inhibition by arylalkyl isothiocyanates.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is an important carcinogen found in tobacco and tobacco smoke. It is a potent lung tumorigen in rodents and appears to be involved in human cancer induced by tobacco products. NNK induces lung tumors in A/J mice after a single dose; tumor multiplicity is higher when the mice are maintained on an AIN-76A diet than when they are maintained on NIH-07 diet. This paper reviews our recent research using this single-dose model. Bioassays of deuterium substituted analogues of NNK have demonstrated that methylation of DNA by NNK is an important step in lung tumor induction. Arylalkyl isothiocyanates inhibit the metabolic activation of NNK and consequently inhibit its DNA binding and tumorigenesis. Structure activity studies have demonstrated that increasing alkyl chain length leads to increasing efficacy in prevention of NNK tumorigenesis. Thus, 3-phenylpropyl isothiocyanate and 4-phenylbutyl isothiocyanate blocked NNK induced lung tumor formation in A/J mice. Lower doses of longer chain arylalkyl isothiocyanates were even more effective as chemopreventive agents.

Animals↗
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Liver tumorigenesis by Helicobacter hepaticus: considerations of mechanism.

A new animal model for the causation of liver tumors via a bacterial infection presented itself fortuitously in the form of a new species, Helicobacter hepaticus. This species of Helicobacter colonizes the hepatic bile canaliculi in susceptible strains of mice, resulting in hepatitis and hepatocellular and hepatocholangiolar adenomas and carcinomas. The mechanism by which this infection leads to cancer is unknown. Tests with Helicobacter hepaticus have revealed thus far that the bacteria do not secrete a mutagen which is capable of detection by the Ames Assay. Measurement of oxidatively damaged bases in the liver DNA of hepaticus infected mice have shown accumulation of 8-oxodeoxyguanosine with disease progression. Other promutagenic DNA lesions, 7-methylguanine and O6-methylguanine, indicative of nitrosation of endogenous amines by nitric oxide, were not detected. Analysis of carcinomas and adenomas taken from H. hepaticus infected A/JCr mice revealed no mutations in ras oncogenes or in exons 5-8 of the p53 gene. These preliminary results indicate that a non-genotoxic tumor promotion mechanism, possibly implemented by reactive oxygen species from the immune response, is more likely than a genotoxic mechanism.

Alkylation↗