vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ16.190vavilov-819Research ArticleФизиологическая генетика и генотоксикологияPhysiological genetics and genotoxicologyИнгибирование мутагенной активации орто-aминоазотолуола повышает его канцерогенность для печени мышейInhibition of mutagenic activation of orthoaminoazotoluene increases its carcinogenicity for mouse liverКалединВ. И.KaledinV. I.

Новосибирск, Россия

Novosibirsk, Russia

kaledin@bionet.nsc.ruОвчинниковаЛ. П.OvchinnikovaL. P.

Новосибирск, Россия

Novosibirsk, Russia

ИльницкаяС. И.IlnitskayaS. I.

Новосибирск, Россия

Novosibirsk, Russia

МорозковаТ. С.MorozkovaT. S.

Новосибирск, Россия

Novosibirsk, Russia

ПоповаН. А.PopovaN. A.

Новосибирск, Россия

Novosibirsk, Russia

Федеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук»РоссияInstitute of Cytology and Genetics SB RASRussian FederationФедеральное государственное бюджетное научное учреждение «Институт молекулярной патологии и патоморфологии»РоссияInstitute of Molecular Pathology and Pathomorphology SB RASRussian FederationФедеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук» Федеральное государственное автономное образовательное учреждение высшего образования «Новосибирский национальный исследовательский государственный университет»РоссияInstitute of Cytology and Genetics SB RAS Novosibirsk State UniversityRussian Federation201631122016205708715Copyright © Каледин В.И., Овчинникова Л.П., Ильницкая С.И., Морозкова Т.С., Попова Н.А., 20162016Каледин В.И., Овчинникова Л.П., Ильницкая С.И., Морозкова Т.С., Попова Н.А.Kaledin V.I., Ovchinnikova L.P., Ilnitskaya S.I., Morozkova T.S., Popova N.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/819

В злокачественных опухолях человека и животных часто обнаруживаются мутантные варианты генов, контролирующих размножение и рост клеток. В то же время многие канцерогены про-являют положительную активность в различных тестах на мутагенность. Это свидетельствует в пользу представлений о генотоксическом механизме канцерогенеза. Считается, что если химически активные канцерогены вызывают мутации при непосредственном взаимодействии с ДНК, то химически неактивные активируются до мутагенных продуктов в процессе метаболических превращений в организме. Было установлено, что аминоазокрасители активируются путем N-гидроксилирования и последующей конъюгации с остатком серной кислоты, катализируемой печеночной сульфотрансферазой, ферментом второй фазы мета-болизма ксенобиотиков. Ранее мы показали, что именно активированные метаболиты орто-аминоазотолуола ответственны за ингибирование глюкокортикоидной индукции тирозинаминотрансферазы у чувствительных к его гепатоканцерогенному действию мышей. Подавление с помощью ингибитора сульфотрансферазы пентахлорфенола сульфатирования 4-аминоазобензола, другого канцерогенного для мышей азокрасителя, приводило, по литературным данным, к снижению его как мутагенной, так и канцерогенной активности. Мы подтвердили это наблюдение. Однако при использовании с орто-аминоазотолуолом пентахлорфенол так же, как в случае с 4-аминоазобензолом, подавлял его мутагенное действие, но значительно усиливал канцерогенное. Следовательно, канцерогенное действие на печень оказывает неме-таболизированный орто-аминоазотолуол или его несульфатированные немутагенные метаболиты. О негенотоксическом механизме действия канцерогенов говорят и наши результаты параллельных опытов с орто-аминоазотолуолом и 3,4-бензпиреном, которые, одинаково активируясь ферментами печени мышей в мутагенном отношении, вызывают опухоли в разных тканях: первый – гепатоцеллюлярные в печени, а второй – лимфоидные в селезенке. Таким образом, принятые представления о генотоксическом механизме действия канцерогенов требуют пересмотра.

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.

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The authors declare that there are no conflicts of interest present.