vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2022-12-1-90-109vedomostiregmed-407Research ArticleДОКЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯPRECLINICAL STUDIESАктуальные аспекты генетической токсикологии лекарственных средствRelevant Aspects of Drug Genetic Toxicologyhttps://orcid.org/0000-0003-0218-8580ДурневА. Д.DurnevA. D.

Дурнев Андрей Дмитриевич, член-корреспондент Российской академии наук, доктор медицинских наук, профессор

Балтийская ул., д. 8, Москва, 125315

Andrey D. Durnev, Corresponding Member of RAS, Dr. Sci. (Med.), Professor

8 Baltiyskaya St., Moscow 125315

addurnev@mail.ruhttps://orcid.org/0000-0002-7673-8672ЖанатаевА. К.ZhanataevA. K.

Жанатаев Алий Курманович, кандидат биологических наук

Балтийская ул., д. 8, Москва, 125315

Aliy K. Zhanataev, Cand. Sci. (Biol.)

8 Baltiyskaya St., Moscow 125315

azhanataev@yandex.ruФедеральное государственное бюджетное научное учреждение «Научно-исследовательский институт фармакологии имени В. В. Закусова»РоссияZakusov Institute оf PharmacologyRussian Federation20223101202212190109Copyright © Дурнев А.Д., Жанатаев А.К., 20222022Дурнев А.Д., Жанатаев А.К.Durnev A.D., Zhanataev A.K.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.vedomostincesmp.ru/jour/article/view/407

Генотоксические поражения рассматриваются не только как причина наследственной и онкологической патологий, но и как наиболее общий фактор, играющий существенную роль в этиопатологии сердечно-сосудистых, нейродегенеративных заболеваний, репродуктивных потерь, бесплодия и старения. Это определяет необходимость тщательного контроля за распространением потенциальных генотоксикантов, в том числе среди лекарственных средств (ЛС), как группы соединений, направленно и регулярно используемых человеком. Оценка генотоксичности является неотъемлемым элементом в системе доклинических исследований безопасности ЛС. Цель работы — анализ современного состояния и возможных путей решения методологических и регуляторных проблем в области генотоксикологии для надлежащего проведения доклинических исследований безопасности лекарственных средств. В работе обобщены сведения о фундаментальных представлениях, составивших базу для развития современной генетической токсикологии, рассмотрена история развития исследований, направленных на выявление мутагенных, кластогенных и анеугенных эффектов. Проанализированы регуляторные аспекты генотоксикологических исследований ЛС, рассмотрены вопросы совершенствования стратегии проведения тестирования на генотоксичность. Представлены сведения о тестах на генотоксичность, регламентированных для ЛС, рекомендации по выбору взаимозаменяемых тестов в зависимости от особенностей конкретного исследования. Проведен сравнительный анализ преимуществ и недостатков тестов. Подчеркнуто, что исследование каждого ЛС является самостоятельной научной задачей. Обсуждены вопросы интерпретации и трактовки результатов, предиктивность генотоксикологических исследований для прогноза потенциальной канцерогенности. Даны предложения по совершенствованию стратегии оценки генотоксичности ЛС, в частности рассмотрены возможности ее частичного совмещения с исследованиями по общей токсичности. Подчеркнута необходимость разработки методов регистрации генотоксических событий в генеративных клетках, оценены перспективы внедрения новых тестов, рассмотрены направления фундаментальных и поисковых исследований в области лекарственной генотоксикологии.

Genotoxic lesions are not only a cause of genetic pathologies and cancer, but also the most common and significant factor of the etiopathology of cardiovascular and neurodegenerative disorders, reproductive losses, infertility, and aging. This requires careful monitoring of the use of potential genotoxicants including medicinal products (MPs), which are a group of compounds intentionally and routinely used by humans. Genotoxicity assesment is highly essential in preclinical drug safety studies. The aim of the study was to analyse the current situation and reveal possible ways of addressing methodological and regulatory issues in genotoxicology to enable proper conduction of drug safety preclinical studies. The article summarises basic concepts of the modern genetic toxicology development and highlights the history of research aimed at identifying mutagenic, clastogenic, and aneugenic effects. The authors analyse regulatory aspects of genotoxicological studies of MPs and consider issues of improving the strategy for genotoxicity testing. The paper gives information about the genotoxicity tests approved for MPs, recommendations for interchangeability of tests in relation to particular study characteristics. The authors carried out a comparative analysis of the tests’ pros and cons with an emphasis that the study of each MP is a separate scientific task. They discuss interpretation of results and prediction of MP carcinogenic potential in genotoxicological studies. Recommendations are given for the optimisation of the MP genotoxicity assessment strategy, considering its partial integration into general toxicity studies. The article stresses the urgent need to develop registration methods for genotoxic events in germ cells, assesses the prospects of new tests, and reviews new trends in drug genotoxicology fundamental research.

лекарственные средствагенотоксичностьканцерогенностьмутагенностьдоклинические исследованияmedicinal productsgenotoxicitycarcinogenicitymutagenicitypreclinical studiesReferencesДурнев АД, Жанатаев АК, Шредер ОВ, Середенина ВС. Генотоксические поражения и болезни. Молекулярная медицина. 2013;(3):3–19.Durnev AD, Zhanataev AK, Shreder OV, Seredenina VS. Genotoxic events and diseases sicheskie. Molekulyarnaya meditsina = Molecular Medicine. 2013;(3):3–19 (In Russ.)Choudhuri S, Kaur T, Jain S, Sharma C, Asthana S. A review on genotoxicity in connection to infertility and cancer. Chem Biol Interact. 2021;345:109531. https://doi.org/10.1016/j.cbi.2021.109531Choudhuri S, Kaur T, Jain S, Sharma C, Asthana S. A review on genotoxicity in connection to infertility and cancer. Chem Biol Interact. 2021;345:109531. https://doi.org/10.1016/j.cbi.2021.109531Dearfield KL, Cimino MC, McCarroll NE, Mauer I, Valcovic LR. Genotoxicity risk assessment: a proposed classification strategy. Mutat Res. 2002;521(1–2):121– 35. https://doi.org/10.1016/s1383-5718(02)00236-xDearfield KL, Cimino MC, McCarroll NE, Mauer I, Valcovic LR. Genotoxicity risk assessment: a proposed classification strategy. Mutat Res. 2002;521(1–2):121– 35. https://doi.org/10.1016/s1383-5718(02)00236-xДурнев АД. Генетическая токсикология. Вестник РАМН. 2011;(9):35–44.Durnev AD. Genetic toxicology. Vestnik RAMN = Annals of the Russian Academy of Medical Sciences. 2011;(9):35–44 (In Russ.)Ames BN, Gold LS. Endogenous mutagens and the causes of aging and cancer. Mutat Res. 1991;250(1– 2):3–16. https://doi.org/10.1016/0027-5107(91)90157-jAmes BN, Gold LS. Endogenous mutagens and the causes of aging and cancer. Mutat Res. 1991;250(1– 2):3–16. https://doi.org/10.1016/0027-5107(91)90157-jБочков НП, Шрам РИ, Кулешов НП, Журков ВС. Система оценки химических веществ для человека: общие принципы, практические рекомендации и дальнейшие разработки. Генетика. 1975;11(10):156–69.Bochkov NP, Shram RI, Kuleshov NP, Zhurkov VS. Human chemical assessment system: general principles, practical recommendations and further developments. Genetika = Genetics. 1975;11(10):156–69 (In Russ.)Bridges BA. Some general principles of mutagenicity screening and possible framework for testing procedure. Environ Health Perspect. 1973;6:221–7. https://doi.org/10.1289/ehp.7306221Bridges BA. Some general principles of mutagenicity screening and possible framework for testing procedure. Environ Health Perspect. 1973;6:221–7. https://doi.org/10.1289/ehp.7306221Steiblen G, Benthem JV, Johnson G. Strategies in genotoxicology: acceptance of innovative scientific methods in a regulatory context and from an industrial perspective. Mutat Res Genet Toxicol Environ Mutagen. 2020;853:503171. https://doi.org/10.1016/j.mrgentox.2020.503171Steiblen G, Benthem JV, Johnson G. Strategies in genotoxicology: acceptance of innovative scientific methods in a regulatory context and from an industrial perspective. Mutat Res Genet Toxicol Environ Mutagen. 2020;853:503171. https://doi.org/10.1016/j.mrgentox.2020.503171Müller L, Tweats D, Galloway S, Hayashi M. The evolution, scientific reasoning and use of ICH S2 guidelines for genotoxicity testing of pharmaceuticals. In: van der Laan JW, DeGeorge JJ, eds. Global Approach in Safety Testing: ICH Guidelines Explained. Springer; 2013.Müller L, Tweats D, Galloway S, Hayashi M. The evolution, scientific reasoning and use of ICH S2 guidelines for genotoxicity testing of pharmaceuticals. In: van der Laan JW, DeGeorge JJ, eds. Global Approach in Safety Testing: ICH Guidelines Explained. Springer; 2013.Baldrick P. Genotoxicity test battery — an assessment of its utility in early drug development. Mutat Res Genet Toxicol Environ Mutagen. 2021;868–869:503388. https://doi.org/10.1016/j.mrgentox.2021.503388Baldrick P. Genotoxicity test battery — an assessment of its utility in early drug development. Mutat Res Genet Toxicol Environ Mutagen. 2021;868–869:503388. https://doi.org/10.1016/j.mrgentox.2021.503388Richmond J. Refinement, reduction, and replacement of animal use for regulatory testing: future improvements and implementation within the regulatory framework. ILAR J. 2002;43 Suppl:S63–8. https://doi.org/10.1093/ilar.43.suppl_1.s63Richmond J. Refinement, reduction, and replacement of animal use for regulatory testing: future improvements and implementation within the regulatory framework. ILAR J. 2002;43 Suppl:S63–8. https://doi.org/10.1093/ilar.43.suppl_1.s63McCann J, Ames BN. Detection of carcinogens as mutagens in the Salmonella microsome test: assay of 300 chemicals: discussion. Proc Nat Acad Sci USA. 1976;73(3):950–4. https://doi.org/10.1073/pnas.73.3.950McCann J, Ames BN. Detection of carcinogens as mutagens in the Salmonella microsome test: assay of 300 chemicals: discussion. Proc Nat Acad Sci USA. 1976;73(3):950–4. https://doi.org/10.1073/pnas.73.3.950McCann J, Choi E, Yamasaki E, Ames BN. Detection of carcinogens as mutagens in the Salmonella/ microsome test: assay of 300 chemicals: discussion. Proc Nat Acad Sci USA. 1975;72(12):5135–9. https://doi.org/10.1073/pnas.72.12.5135McCann J, Choi E, Yamasaki E, Ames BN. Detection of carcinogens as mutagens in the Salmonella/ microsome test: assay of 300 chemicals: discussion. Proc Nat Acad Sci USA. 1975;72(12):5135–9. https://doi.org/10.1073/pnas.72.12.5135Kirkland D, Aardema M, Henderson L, Muller L. Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens I. Sensitivity, specificity and relative predictivity. Mutat Res. 2005;584(1–2):1–256. https://doi.org/10.1016/j.mrgentox.2005.02.004Kirkland D, Aardema M, Henderson L, Muller L. Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens I. Sensitivity, specificity and relative predictivity. Mutat Res. 2005;584(1–2):1–256. https://doi.org/10.1016/j.mrgentox.2005.02.004Kirkland D, Pfuhler S, Tweats D, Aardema M, Corvi R, Darroudi F, et al. How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: report of an ECVAM workshop. Mutat Res. 2007;628(1):31–55. https://doi.org/10.1016/j.mrgentox.2006.11.008Kirkland D, Pfuhler S, Tweats D, Aardema M, Corvi R, Darroudi F, et al. How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: report of an ECVAM workshop. Mutat Res. 2007;628(1):31–55. https://doi.org/10.1016/j.mrgentox.2006.11.008Fischer I, Milton C, Wallace H. Toxicity testing is evolving! Toxicol Res (Camb). 2020;9(2):67–80. https://doi.org/10.1093/toxres/tfaa011Fischer I, Milton C, Wallace H. Toxicity testing is evolving! Toxicol Res (Camb). 2020;9(2):67–80. https://doi.org/10.1093/toxres/tfaa011Dertinger SD, Bhalli JA, Roberts DJ, Stankowski LF, Gollapudi BB, Lovell DP, et al. Recommendations for conducting the rodent erythrocyte Pig–a assay: a report from the HESI GTTC Pig–a Workgroup. Environ Mol Mutagen. 2021;62(3):227–37. https://doi.org/10.1002/em.22427Dertinger SD, Bhalli JA, Roberts DJ, Stankowski LF, Gollapudi BB, Lovell DP, et al. Recommendations for conducting the rodent erythrocyte Pig–a assay: a report from the HESI GTTC Pig–a Workgroup. Environ Mol Mutagen. 2021;62(3):227–37. https://doi.org/10.1002/em.22427Salk JJ, Kennedy SR. Next-generation genotoxicology: using modern sequencing technologies to assess somatic mutagenesis and cancer risk. Environ Mol Mutagen. 2020;61(1):135–51. https://doi.org/10.1002/em.22342Salk JJ, Kennedy SR. Next-generation genotoxicology: using modern sequencing technologies to assess somatic mutagenesis and cancer risk. Environ Mol Mutagen. 2020;61(1):135–51. https://doi.org/10.1002/em.22342Heflich RH, Johnson GE, Zeller A, Marchetti F, Douglas GR, Witt KL, et al. Mutation as a toxicological endpoint for regulatory decision-making. Environ Mol Mutagen. 2020;61(1):34–41. https://doi.org/10.1002/em.22338Heflich RH, Johnson GE, Zeller A, Marchetti F, Douglas GR, Witt KL, et al. Mutation as a toxicological endpoint for regulatory decision-making. Environ Mol Mutagen. 2020;61(1):34–41. https://doi.org/10.1002/em.22338Morita T, Hamada S, Masumura K. Evaluation of the sensitivity and specificity of in vivo erythrocyte micronucleus and transgenic rodent gene mutation tests to detect rodent carcinogens. Mutat Res Genet Toxicol Environ Mutagen. 2016;802:1–29. https://doi.org/10.1016/j.mrgentox.2016.03.008Morita T, Hamada S, Masumura K. Evaluation of the sensitivity and specificity of in vivo erythrocyte micronucleus and transgenic rodent gene mutation tests to detect rodent carcinogens. Mutat Res Genet Toxicol Environ Mutagen. 2016;802:1–29. https://doi.org/10.1016/j.mrgentox.2016.03.008Kirkland D, Zeiger E, Madia F, Corvi R. Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? II. Construction and analysis of a consolidated database. Mutat Res Genet Toxicol Environ Mutagen. 2014;775–776:69–80. https://doi.org/10.1016/j.mrgentox.2014.10.006Kirkland D, Zeiger E, Madia F, Corvi R. Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? II. Construction and analysis of a consolidated database. Mutat Res Genet Toxicol Environ Mutagen. 2014;775–776:69–80. https://doi.org/10.1016/j.mrgentox.2014.10.006Kirkland D, Uno Y, Luijten M, Beevers C, van Benthem J, Burlinson B, et al. In vivo genotoxicity testing strategies: Report from the 7th International workshop on genotoxicity testing (IWGT). Mutat Res Genet Toxicol Environ Mutagen. 2019;847:403035. https://doi.org/10.1016/j.mrgentox.2019.03.008Kirkland D, Uno Y, Luijten M, Beevers C, van Benthem J, Burlinson B, et al. In vivo genotoxicity testing strategies: Report from the 7th International workshop on genotoxicity testing (IWGT). Mutat Res Genet Toxicol Environ Mutagen. 2019;847:403035. https://doi.org/10.1016/j.mrgentox.2019.03.008Elespuru R, Pfuhler S, Aardema MJ, Chen T, Doak SH, Doherty A, et al. Genotoxicity assessment of nanomaterials: recommendations on best practices, assays, and methods. Toxicol Sci. 2018;164(2):391–416. https://doi.org/10.1093/toxsci/kfy100Elespuru R, Pfuhler S, Aardema MJ, Chen T, Doak SH, Doherty A, et al. Genotoxicity assessment of nanomaterials: recommendations on best practices, assays, and methods. Toxicol Sci. 2018;164(2):391–416. https://doi.org/10.1093/toxsci/kfy100Goodman JI. Goodbye to the bioassay. Toxicol Res (Camb). 2018;7(4):558–64. Erratum in: Toxicol Res (Camb). 2018;7(5):994. https://doi.org/10.1039/c8tx00004bGoodman JI. Goodbye to the bioassay. Toxicol Res (Camb). 2018;7(4):558–64. Erratum in: Toxicol Res (Camb). 2018;7(5):994. https://doi.org/10.1039/c8tx00004bMacGregor JT, Frötschl R, White PA, Crump KS, Eastmond DA, Fukushima S, et al. IWGT report on quantitative approaches to genotoxicity risk assessment I. Methods and metrics for defining exposure-response relationships and points of departure (PoDs). Mutat Res Genet Toxicol Environ Mutagen. 2015;783:55–65. https://doi.org/10.1016/j.mrgentox.2014.09.011MacGregor JT, Frötschl R, White PA, Crump KS, Eastmond DA, Fukushima S, et al. IWGT report on quantitative approaches to genotoxicity risk assessment I. Methods and metrics for defining exposure-response relationships and points of departure (PoDs). Mutat Res Genet Toxicol Environ Mutagen. 2015;783:55–65. https://doi.org/10.1016/j.mrgentox.2014.09.011Adler ID, Ashby J. The present lack of evidence for unique rodent germ-cell mutagens, Mutat. Res. 1989;212(1):55– 66. https://doi.org/10.1016/0027-5107(89)90022-5Adler ID, Ashby J. The present lack of evidence for unique rodent germ-cell mutagens, Mutat. Res. 1989;212(1):55– 66. https://doi.org/10.1016/0027-5107(89)90022-5Yauk CL, Aardema MJ, Benthem J, Bishop JB, Dearfield KL, DeMarini DM, et al. Approaches for identifying germ cell mutagens: report of the 2013 IWGT workshop on germ cell assays. Mutat Res Genet Toxicol Environ Mutagen. 2015;783:36–54. https://doi.org/10.1016/j.mrgentox.2015.01.008Yauk CL, Aardema MJ, Benthem J, Bishop JB, Dearfield KL, DeMarini DM, et al. Approaches for identifying germ cell mutagens: report of the 2013 IWGT workshop on germ cell assays. Mutat Res Genet Toxicol Environ Mutagen. 2015;783:36–54. https://doi.org/10.1016/j.mrgentox.2015.01.008Дурнев АД. Анализ и значение мутаций в зародышевых клетках. Медицинская генетика. 2011;(2):3– 11.Durnev AD. Analysis and importance of germ cells mutations. Meditsinskaya genetika = Medical Genetics. 2011;(2):3–11 (In Russ.)Adler ID, Carere A, Eichenlaub-Ritter U, Pacchierotti F. Gender differences in the induction of chromosomal aberrations and gene mutations in rodent germ cells. Environ Res. 2007;104(1):37–45. https://doi.org/10.1016/j.envres.2006.08.010Adler ID, Carere A, Eichenlaub-Ritter U, Pacchierotti F. Gender differences in the induction of chromosomal aberrations and gene mutations in rodent germ cells. Environ Res. 2007;104(1):37–45. https://doi.org/10.1016/j.envres.2006.08.010Sudman PD, Generoso WM. Female-specific chemical mutagens. Environ Mol Mutagen. 1990;15 Suppl 17:58.Sudman PD, Generoso WM. Female-specific chemical mutagens. Environ Mol Mutagen. 1990;15 Suppl 17:58.Плигина КЛ, Жанатаев АК, Чайка ЗВ, Дурнев АД. Методика цитогенетического анализа ооцитов мышей. Бюллетень экспериментальной биологии и медицины. 2013;156(7):128–32.Pligina KL, Zhanataev AK, Chaika ZV, Durnev AD. Method of cytogenic assay of mouse oocytes. Bulleten eksperimentalnoy biologii i meditsiny = Bulletin of Experimental Biology and Medicine. 2013;156(7):128–32 (In Russ.)Турпаев КТ. Сигнальная система Keap1-Nrf2. Механизмы регуляции и значение для защиты клеток от токсического действия ксенобиотиков и электрофильных соединений. Биохимия. 2013;78(2):147–66.Turpaev KT. Keap1-Nrf2 signaling pathway: mechanisms of regulation and role in protection of cells against toxicity caused by xenobiotics and electrophiles. Biokhimiya = Biochemistry. 2013;78(2):147–66 (In Russ.)Shaw P, Chattopadhyay A. Nrf2-ARE signaling in cellular protection: Mechanism of action and the regulatory mechanisms. J Cell Physiol. 2020;235(4):3119– 30. https://doi.org/10.1002/jcp.29219Shaw P, Chattopadhyay A. Nrf2-ARE signaling in cellular protection: Mechanism of action and the regulatory mechanisms. J Cell Physiol. 2020;235(4):3119– 30. https://doi.org/10.1002/jcp.29219Дурнев АД. Антимутагенез и антимутагены. Физиология человека. 2018;44(3):116–37. https://doi.org/10.7868/S013116461803013XDurnev AD. Antimutagenesis and antimutagens. Fiziologiya cheloveka = Human Physiology. 2018;44(3):116–37 (In Russ.) https://doi.org/10.7868/S013116461803013XДурнев АД. Фармакология мутагенеза. Экспериментальная и клиническая фармакология. 2021;84(2):8–14. https://doi.org/10.30906/0869-2092-2021-84-2-8-14Durnev AD. Pharmacology of mutagenesis. Eksperimental’naya i klinicheskaya farmakologiya = Experimental and Clinical Pharmacology. 2021;84(2):8–14 (In Russ.) https://doi.org/10.30906/0869-2092-2021-84-2-8-14Дурнев АД, Середенин СБ. Мутагены: скрининг и фармакологическая профилактика воздействий. М.: Медицина; 1998.Durnev AD, Seredenin SB. Mutagens: screening and pharmacological prevention of exposures. Moscow: Meditsina; 1998 (In Russ.)Дурнев АД, Середенин СБ. Комутагенез — новое направление исследований в генотоксикологии. Бюллетень экспериментальной биологии и медицины. 2003;135(6):604–12.Durnev AD, Seredenin SB. Co-mutagenesis as new vistas in genotoxicology. Bulleten eksperimentalnoy biologii i meditsiny = Bulletin of Experimental Biology and Medicine. 2003;135(6):604–12 (In Russ.)Дурнев АД, Даугель-Дауге НО, Середенин СБ. Комутагенное взаимодействие верапамила и рибавирина. Экспериментальная и клиническая фармакология. 2006;69(1):56–9.Durnev AD, Daugel’-Dauge NO, Seredenin SB. Comutagen interaction of verapamil and ribavirin. Eksperimental’naya i klinicheskaya farmakologiya = Experimental and Clinical Pharmacology. 2006;69(1):56–9 (In Russ.)Дурнев АД, Даугель-Дауге НО, Жанатаев АК, Лапицкая АС, Середенин СБ. Комутагенные эффекты валокордина. Экологическая генетика. 2012;10(3):53–8.Durnev AD, Daugel’-Dauge NO, Zhanataev AK, Lapitskaya AS, Seredenin SB. Comutagenic effects of valocordin. Ekologicheskaya genetika = Ecological Genetics. 2012;10(3):53–8 (In Russ.)Дурнев АД, Кулакова АВ, Жанатаев АК, Оганесянц ЛА. Оценка цитогенетической и мутаген-модифицирующей активности кофеина в клетках костного мозга мышей. Гигиена и санитария. 2015;94(3):106–10.Durnev AD, Kulakova AV, Zhanataev AK, Oganesyants LA. Evaluation of the cytogenetic and mutagen-modifying activity of caffeine in mouse bone marrow cells. Gigiena i sanitariya = Hygiene and Sanitation. 2015;94(3):106–10 (In Russ.)Brambilla G, Mattioli F, Robbiano L, Martelli A. Genotoxicity and carcinogenicity studies of bronchodilators and antiasthma drugs. Basic Clin Pharmacol Toxicol. 2013;112(5):302–13. https://doi.org/10.1111/bcpt.12054Brambilla G, Mattioli F, Robbiano L, Martelli A. Genotoxicity and carcinogenicity studies of bronchodilators and antiasthma drugs. Basic Clin Pharmacol Toxicol. 2013;112(5):302–13. https://doi.org/10.1111/bcpt.12054Еремина НВ, Жанатаев АК, Лисицын АА, Дурнев АД. Генотоксические свойства гипогликемических лекарств (систематический обзор). Экологическая генетика. 2021;19(3):219–40. https://doi.org/10.17816/ecogen70691Eremina NV, Zhanataev AK, Lisitsyn AA, Durnev AD. Genotoxic properties of hypoglycemic drugs (systematic review). Ekologicheskaya genetika = Ecological Genetics. 2021;19(3):219–40 (In Russ.) https://doi.org/10.17816/ecogen70691Дурнев АД, Еремина НВ, Жанатаев АК, Колик ЛГ. Генотоксичность психотропных лекарств в экспериментальных и клинических исследованиях (в печати).Durnev AD, Eremina NV, Zhanataev AK, Kolik LG. Genotoxicity of psychotropic drugs in experimental and clinical studies (article is being published) (In Russ.)

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