Regulation of acetylation systems in carcinogenesis processes: from phenotype to epigenetics

The study examined the role of acetylation in phenotypic and epigenetic mechanisms of gene expression that do not affect the original sequence by the action of procancerogenic and antineoplastic drugs. Based on the data obtained in vitro experiment on enzymatic activity, gene expression and epigenetic NAT2hom factor of action with an effective inhibitory effect bisphenol substances (nitrosobenzene and diacetoxybiphenyl) and cisplatin for the enzyme N-acetyltransferase NAT2 human. For selected inhibitors studied concentration dependence of the enzymatic activity and determined the concentration value premaxillae inhibition IC₅₀. Create a new model of in vitro evaluation acetylation ability as well as determination of the kinetic parameters of the acetylation of substrates, activators and inhibitors, NAT. The model proposed for the screening of substances that affect the process of acetylation. With its help, as well as on models of transgenic mice carrying the NAT2 gene of the person and the axolotl the nature of the interaction in the "inhibitor - enzyme activity", "inhibitor of expression of a gene" and the predicted level of toxic effects of NAT inhibitors on enzymatic, genetic and epigenetic levels. Experimentally on the example of the impact of the molecules of the toxicants presents a model study of epigenetic factors derived bisphenol and cisplatin in the regulation of epigenetic programs violations regeneration remote extremities of the axolotl, which is expressed in slower growth and changes in the formation of the fingers. There was deceleration of erythropoiesis and increased blood. Cisplatin and derivatives bisphenol cause an increase in the proportion of eosinophils and content of lysosomal cationic protein in neutrophils and a significant increase in the percentage of monocytes, which as a whole confirms the development of oncological processes of any localization.

N-ацетилтрансфераза (NAT), N-acetyltransferase (NAT), transgenic humanized mice by human gene NAT2 and NAT1, NAT2 gene expression, epigenetics, acetylation, carcinogenesis, inhibitors of NAT, axolotl, regeneration, erythropoiesis, leukocyte formula

1. Белицкий Г.А. Прогноз канцерогенности фармакологических средств и вспомогательных веществ в краткосрочных тестах // Ведомости фармкомитета. 1999. № 1. С. 18-31.

2. Каркищенко В.Н., Мартынов В.В. Фармакология, генополиморфизм и клонирование генов NAT у человека и животных-моделей // Биомедицина. 2006. № 4. С. 85-87.

3. Каркищенко В.Н., Рябых В.П., Каркищенко Н.Н., Дуля М.С., Езерский В.А., Колоскова Е.М., Лазарев В.Н., Максименко С.В., Петрова Н.В., Столярова В.Н., Трубицина Т.П. Молекулярно-генетические аспекты технологии получения трансгенных мышей с интегрированными генами N-ацетилтрансферазы (NAT1 и NAT2) человека // Биомедицина. 2016. № 1. С. 4-16.

4. Карлсон Б.М. Регенерация. - М.: Наука. 1986. 191 с.

5. Короткова Г.П. Регенерация животных. - СПб.: Изд-во С.-Петербургского университета. 1997. 480 с.

6. Кэрри Н. Эпигенетика: как современная биология переписывает наши представления о генетике, заболеваниях и наследственности. - Р-н-Д. 2012. 349 с.

7. Пронина Г.И. Использование цитохимических методов для определения фагоцитарной активности клеток крови или гемолимфы разных видов гидробионтов для оценки состояния их здоровья // Известия ОГАУ. 2008. №4(20). С. 160-163.

8. Пронина Г.И., Ревякин А.О., Корягина Н.Ю., Капанадзе Г.Д., Степанова О.И., Курищенко Ж.О. Регенерация патологически измененной печени карпа после межвидовой трансплантации стволовых клеток // Биомедицина. 2015. № 1. С. 85-89.

9. Шехтер А.Б., Серов В.В. Воспаление, адаптивная регенерация и дисрегенерация (анализ межклеточных взаимодействий) // Архив патологии. 1991. Т. 53. № 7. С. 7-15.

10. Шубич М.Г. Выявление катионного белка в цитоплазме лейкоцитов с помощью бромфенолового синего // Цитология. 1974. № 10. С. 1321-1322.

11. Bischoff M., Schnabel R. A posterior centre establishes and maintains polarity of the Caenorhabditis elegans embryo by a Wnt-dependent relay mechanism // PLOS Biology. 2006. No. 4(12). P. 396.

12. Curti A., Fogli M., Ratta M., Biasco G., Tura S., Lemoli R.M. Dendritic cell differentiation from hematopoietic CD34+ progenitor cells // J. Biol. regul. homeost. agents. 2001. Vol. 15. No. 7. P. 49-52.

13. Gardiner D.M., Blumberg B., Komine Y., Bryant S.V. Regulation of HoxA expression in developing and regenerating axolotl limbs // Development. 1995. No. 121(6). P. 1731-41.

14. Hanna P.E. N-acetyltransferases, O-acetyltransferases, and N,O-acetyltransferases: enzymology and bioactivation // Adv. Pharmacol. 1994. No. 27. Р. 401-430.

15. Hein D.W. Acetylator genotype and arylamine-induced carcinogenesis // Biochim. Biophys. Ada. 1998. No. 948. P. 37-66.

16. Hein D.W. Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis // Mutation Research. 2002. No. 506-507. P. 65-77.

17. Kaplow L.S. A histochemical procedure for localizing and evaluating leukocyte alkaline phosphatase activity in smears of blood and marrow // Blood. 1955. Vol. 10. P. 1023-1029.

18. Kawakami Y., Esteban C.R., Matsui T., Rodríguez-León J., Kato S., Izpisúa Belmonte J.C. Wnt/β-catenin signaling regulates vertebrate limb regeneration // Genes&Development. 2006. Vol. 20. P. 3232-3237.

19. Li Z. (J.), Gwinn M. Toxicological review of biphenyl. In: Support of summary information on the Integrated Risk Information System (IRIS). - 2011.

20. Nye H.L., Cameron J.A., Chernoff E.A., Stocum D.L. Regeneration of the urodele limb: a review // Dev. Dyn. 2003. No. 226(2). P. 280-94.

21. Pronina G.I., Revyakin A.O. Changes of the morphophysiological parameters of carp Cyprinus carpio at food limitation in aquaculture conditions // J. of Ichthyology. 2015. Vol. 55. No.

22. P. 297-301. Ragunathan N., Dairou J., Pluvinage B., Martins M., Petit E., Janel N., Dupret J.M., Rodrigues-Lima F. Identification of the xenobiotic-metabolizing enzyme arylamine N-acetiltransferase I as a new target of cisplatin in breast cancer cells: molecular and cellular mechanisms of inhibition // Mol. Pharmacol. 2008. No. 73. P. 1761-1768. Reedijk J., Teuben J.M. In cisplatin: chemistry and biochemistry of a leading anticancer drug / Lippert B., ed. Wiley V.C.H. - Weinheim. Germany. 1999. P. 339-362. Sutherland J., Denyer M., Britland S. Motogenic substrata and chemokinetic growth factors for human skin cells // J. Anat. 2005. Vol. 207. No. 1. P. 67-78. Tanaka E.M. Cell differentiation and cell fate during urodele tail and limb regeneration // Curr. Opin. Genet. Dev. 2003. No. 13(5). P. 497-501. Tank P.W., Carlson B.M., Connelly T.G. A staging system for forelimb regeneration in the axolotl, Ambistoma mexicanum // II J. Morph. 1976. Vol. 150. P. 117-128.