Inhibition of mutagenic activation of orthoaminoazotoluene increases its carcinogenicity for mouse liver
Various mutationally impaired genes are often found in malignant tumors of animals and humans. At the same time, a large number of carcinogens demonstrate positive activity in different in vitro tests for mutagenicity. These findings are indicative of a geno- toxic mechanism of carcinogen action. It...
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Siberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and Breeders
2016-12-01
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| Series: | Вавиловский журнал генетики и селекции |
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| Online Access: | https://vavilov.elpub.ru/jour/article/view/819 |
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| author | V. I. Kaledin L. P. Ovchinnikova S. I. Ilnitskaya T. S. Morozkova N. A. Popova |
| author_facet | V. I. Kaledin L. P. Ovchinnikova S. I. Ilnitskaya T. S. Morozkova N. A. Popova |
| author_sort | V. I. Kaledin |
| collection | DOAJ |
| description | Various mutationally impaired genes are often found in malignant tumors of animals and humans. At the same time, a large number of carcinogens demonstrate positive activity in different in vitro tests for mutagenicity. These findings are indicative of a geno- toxic mechanism of carcinogen action. It is considered that chemically active carcinogens induce mutations (and tumors) directly interacting with DNA, while inactive substances are mutagenically activated in the processes of cellular metabolism in target tissues. The aminoazo dyes was found to be activated by N-hydroxilation and subsequent conjugation with sulfuric acid catalyzed by the enzyme sulfotransferase. Previously we found that it is activated metabolites of ortho-aminoazotoluene that are responsible for its inhibitory effect on hormonal induction of tyrosinaminotransferase activity in the liver of sensitive mice. Inhibition of sulfoconjugation of 4-aminoazobenzene, another hepatocarcinogen for mice, by pentaclorophenol was reported to reduce its both mutagenic and carcinogenic activity. In this paper, we confirmed this observation. But we found that, when used ortho-aminoazotoluene, pentaclorophenol inhibited its mutagenic activity, but significantly stimulated the hepatocarcinogenic potency. It seems that carcinogenic action is provoked by unmetabolysed ortho-aminoazotoluene per se or some of its nonsulfated derivatives. The results of our comparative study with ortho-aminoazotoluene and 3.4-benzopyrene are in contradiction with the genotoxic theory of carcinogenesis: both are similarly activated by mouse liver enzymes, but induce tumors in different tissues: the former, hepatocellular carcinomas and the latter, splenic lymphoma. The conclusion was made that the accepted notion about the mechanism of carcinogenesis has to be revised. |
| format | Article |
| id | doaj-art-19661c9b9bef4ba4abff900206215487 |
| institution | Kabale University |
| issn | 2500-3259 |
| language | English |
| publishDate | 2016-12-01 |
| publisher | Siberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and Breeders |
| record_format | Article |
| series | Вавиловский журнал генетики и селекции |
| spelling | doaj-art-19661c9b9bef4ba4abff9002062154872025-02-01T09:58:03ZengSiberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and BreedersВавиловский журнал генетики и селекции2500-32592016-12-0120570871510.18699/VJ16.190534Inhibition of mutagenic activation of orthoaminoazotoluene increases its carcinogenicity for mouse liverV. I. Kaledin0L. P. Ovchinnikova1S. I. Ilnitskaya2T. S. Morozkova3N. A. Popova4Institute of Cytology and Genetics SB RASInstitute of Cytology and Genetics SB RASInstitute of Cytology and Genetics SB RASInstitute of Molecular Pathology and Pathomorphology SB RASInstitute of Cytology and Genetics SB RAS Novosibirsk State UniversityVarious mutationally impaired genes are often found in malignant tumors of animals and humans. At the same time, a large number of carcinogens demonstrate positive activity in different in vitro tests for mutagenicity. These findings are indicative of a geno- toxic mechanism of carcinogen action. It is considered that chemically active carcinogens induce mutations (and tumors) directly interacting with DNA, while inactive substances are mutagenically activated in the processes of cellular metabolism in target tissues. The aminoazo dyes was found to be activated by N-hydroxilation and subsequent conjugation with sulfuric acid catalyzed by the enzyme sulfotransferase. Previously we found that it is activated metabolites of ortho-aminoazotoluene that are responsible for its inhibitory effect on hormonal induction of tyrosinaminotransferase activity in the liver of sensitive mice. Inhibition of sulfoconjugation of 4-aminoazobenzene, another hepatocarcinogen for mice, by pentaclorophenol was reported to reduce its both mutagenic and carcinogenic activity. In this paper, we confirmed this observation. But we found that, when used ortho-aminoazotoluene, pentaclorophenol inhibited its mutagenic activity, but significantly stimulated the hepatocarcinogenic potency. It seems that carcinogenic action is provoked by unmetabolysed ortho-aminoazotoluene per se or some of its nonsulfated derivatives. The results of our comparative study with ortho-aminoazotoluene and 3.4-benzopyrene are in contradiction with the genotoxic theory of carcinogenesis: both are similarly activated by mouse liver enzymes, but induce tumors in different tissues: the former, hepatocellular carcinomas and the latter, splenic lymphoma. The conclusion was made that the accepted notion about the mechanism of carcinogenesis has to be revised.https://vavilov.elpub.ru/jour/article/view/819ortho-aminoazotoluenesulfoconjugationmutagenic activationcarcinogenicity |
| spellingShingle | V. I. Kaledin L. P. Ovchinnikova S. I. Ilnitskaya T. S. Morozkova N. A. Popova Inhibition of mutagenic activation of orthoaminoazotoluene increases its carcinogenicity for mouse liver Вавиловский журнал генетики и селекции ortho-aminoazotoluene sulfoconjugation mutagenic activation carcinogenicity |
| title | Inhibition of mutagenic activation of orthoaminoazotoluene increases its carcinogenicity for mouse liver |
| title_full | Inhibition of mutagenic activation of orthoaminoazotoluene increases its carcinogenicity for mouse liver |
| title_fullStr | Inhibition of mutagenic activation of orthoaminoazotoluene increases its carcinogenicity for mouse liver |
| title_full_unstemmed | Inhibition of mutagenic activation of orthoaminoazotoluene increases its carcinogenicity for mouse liver |
| title_short | Inhibition of mutagenic activation of orthoaminoazotoluene increases its carcinogenicity for mouse liver |
| title_sort | inhibition of mutagenic activation of orthoaminoazotoluene increases its carcinogenicity for mouse liver |
| topic | ortho-aminoazotoluene sulfoconjugation mutagenic activation carcinogenicity |
| url | https://vavilov.elpub.ru/jour/article/view/819 |
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