Effective Pharmacogenetic Model for Analyzing N-Acetylation of Hydrazine-Class Toxicants
https://doi.org/10.33647/2074-5982-22-1-25-37
Abstract
The widespread use of hydrazine derivatives in industry and pharmacy necessitates the development of an effective toxicogenetic model to analyze their N-acetylation and associated toxic effects. Transgenic humanized mice carrying the human NAT2 gene have been shown to model key aspects of hydrazine toxicity in humans. We present these mice as a pharmacogenetic extrapolation platform for assessing and predicting the toxic effects of hydrazine-class compounds during the targeted screening of new nontoxic hydrazine hydrochloride-based pharmaceuticals. The toxicogenetic effects of these compounds can be assessed by analyzing the transcriptional levels of the human NAT2 gene, which encodes the human cytosolic protein NAT2 in a transgenic mouse, as well as those of the genes of nuclear proteins SIRT1 and HMGB1.
About the Authors
N. V. Petrova
Scientific Center of Biomedical Technologies of the Federal Medical and Biological Agency of Russia
Russian Federation
Russian Federation
Natalia V. Petrova
143442, Russian Federation, Moscow Region, Krasnogorsk District, Svetlye Gory Village, 1
N. N. Karkischenko
Scientific Center of Biomedical Technologies of the Federal Medical and Biological Agency of Russia
Russian Federation
Russian Federation
Nikolay N. Karkischenko, Dr. Sci. (Med.), Prof., Acad. of the Russian Academy of Rocket and Artillery Sciences, Corr. Member of the Russian Academy of Sciences
143442, Russian Federation, Moscow Region, Krasnogorsk District, Svetlye Gory Village, 1
R. A. Klesov
Scientific Center of Biomedical Technologies of the Federal Medical and Biological Agency of Russia
Russian Federation
Russian Federation
Roman A. Klesov
143442, Russian Federation, Moscow Region, Krasnogorsk District, Svetlye Gory Village, 1
References
1. Bugaev P.A., Antushevich A.E., Reinyuk V.L., Basharin V.A., Zatsepin V.V. [Gidrazin i ego proizvodniye: toksikologicheskaya harakteristika [Hydrazine and its derivatives: toxicological characteristics]. Setevoye nauchnoye izdaniye. Sovremenniye problemy nauki i obrazovaniya [Network scientific publication. Modern problems of science and education]. 2017;4. (In Russian).
2. Kazakov A.V. Optimizatsiya gepatoprotektivnoj terapii u bolnykh tuberkulezom organov dykhaniya s uchetom otsenki geneticheskogo polimorfizma genov fermentov biotransformatsii ksenobiotikov s pomoshchyu biologicheskikh chipov [Optimization of Hepatoprotective Therapy in Patients with Respiratory Tuberculosis, Taking into Account the Assessment of Genetic Polymorphism of Xenobiotic Biotransformation Enzyme Genes Using Biological Chips]. Dissertation … Dr. Sci. (Med.). Moscow: I.M. Sechenov First Moscow State Medical University of the Ministry of Health Care of Russian Federation (Sechenov University), 2021:176. (In Russian).
3. Karkischenko V.N., Dulya M.S., Khvostov D.V., Petrova N.V., Pronina G.I., Koryagina N.Yu. [Regulyaciya aktivnosti sistem acetilirovaniya v processah kancerogeneza: ot fenotipa k epigenetike [Regulation of acetylation system activity in carcinogenesis: from phenotype to epigenetics]. Biomedicina [Journal Biomed]. 2016;4:4–21. (In Russian).
4. Karkischenko V.N., Ryabykh V.P., Karkischenko N.N., Dulya M.S., Ezerskiy V.A., Koloskova E.M, Lazarev V.N., Maksimenko S.V., Petrova N.V., Stolyarova V.N., Trubitsyna T.P. [Molekulyarno-geneticheskie aspecty tehnologii poluchenia transgennih mishey s integrirovannimy genamy N-acetiltrensferazy (NAT1 I NAT2) cheloveka [Molecular and genetic aspects of the technology for producing transgenic mice with integrated human N-acetyltransferase (NAT1 and NAT2) genes]. Biomedicina [Journal Biomed]. 2016;1:4–17. (In Russian).
5. Karkishenko N.N., Kapanadze G.D., Petrova N.V. Novaya model ocenki izbiratelnoy toksichnosti antiblastomnyh sredstv na transgennyh myshah s genami Nat1hom cheloveka [New Model for Assessing the Selective Toxicity of Antineoplastic Agents on Transgenic Mice with Human Nat1hom Genes]. Biomedicina [Journal Biomed]. 2015;3:4–19. (In Russian).
6. Karkischenko N.N., Ryabykh V.P., Karkischenko V.N., Koloskova E.M. Sozdanie gumanizirovannyh myshej dlya farmakotoksikologicheskih issledovaniy (uspehi, neudachi i perspektivy) [Creation of humanized mice for pharmacotoxicological research (successes, failures, and prospects)]. Biomedicina[Journal Biomed]. 2014;3:4–22. (In Russian).
7. Krasnova N.M., Nikolaev V.M. Izoniazid-inducirovannoye porazhenie pecheni: farmakogeneticheskie aspekty [Isoniazidinduced liver damage: pharmacogenetic aspects]. Russian J. of Personalized Medicine. 2022;2(3):38–51. (In Russian).
8. Rukovodstvo po laboratornym zhivotnym i al’ternativnym modelyam v biomedicinskih issledovaniyah [Guide to Laboratory Animals and Alternative Models in Biomedical Research]. Ed. by N.N. Karkischenko, S.V. Grachev. Moscow: Profil-2C Publ., 2010:358. (In Russian).
9. Stepanova O.I., Klesov R.A., Semenov Kh.Kh., Pomytkin I.A., Karkischenko V.N. Novij diagnosticheskij podhod dlya ocenki tkanevyh izmenenij pri saharnom diabete tipa 2 u mishej s pomoshchyu pribora “LAZMA ST” [A new diagnostic approach for assessing tissue changes in type 2 diabetes mellitus in mice using the LASMA ST device]. Biomedicina [Journal Biomed]. 2022;18(3):37–44. (In Russian). DOI: 10.33647/2074-5982-18-3-37-44.
10. Al-Habsi M., Chamoto K., Matsumoto K., Nomura N., Zhang B., Sugiura Y., Sonomura K., Maharani A., Nakajima Y., Wu Y., Nomura Y., Menzies R., Tajima M., Kitaoka K., Haku Y., Delghandi S., Yurimoto K., Matsuda F., Iwata S., Ogura T., Fagarasan S., Honjo T. Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. Science. 2022;378(6618):eabj3510. DOI: 10.1126/science.abj3510.
11. Badrinath M., Chen R.J., John S. Isoniazid Toxicity. StatPearls Publ., 2025.
12. Conway L.P., Rendo V., Correia M.S.P., Bergdahl I.A., Sjöblom T., Globisch D. Unexpected Acetylation of Endogenous Aliphatic Amines by Arylamine N-Acetyltransferase NAT2. Angew Chem. Int. Ed. Engl. 2020;59(34):14342–14346. DOI: 10.1002/anie.202005915.
13. Gutiérrez-Virgen J.E., Piña-Pozas M., HernándezTobías E.A., Taja-Chayeb L., López-González M.L., Meraz-Ríos M.A., Gómez R. NAT2 global landscape: Genetic diversity and acetylation statuses from a systematic review. PLoS One. 2023;18(4):e0283726. DOI: 10.1371/journal.pone.0283726.
14. Hein D.W., Millner L.M. Arylamine N-acetyltransferase acetylation polymorphisms: paradigm for pharmacogenomic-guided therapy- a focused review. Expert Opin Drug Metab Toxicol. 2021;17(1):9–21. DOI: 10.1080/17425255.2021.1840551.
15. Kang R., Chen R., Zhang Q., Hou W., Wu S., Cao L., Huang J., Yu Y., Fan X.G., Yan Z., Sun X., Wang H., Wang Q., Tsung A., Billiar T.R., Zeh H.J. 3rd, Lotze M.T., Tang D. HMGB1 in health and disease. Mol. Aspects Med. 2014;40:1–116.
16. Kolenc O.I., Quinn K.P. Evaluating Cell Metabolism Through Autofluorescence Imaging of NAD(P)H and FAD. Antioxid Redox Signal. 2019;30(6):875–889. DOI: 10.1089/ars.2017.7451.
17. Madeo F., Eisenberg T., Pietrocola F., Kroemer G. Spermidine in health and disease. Science. 2018;359(6374):eaan2788. DOI: 10.1126/science.aan2788.
18. Mahajan R., Tyagi A.K. Pharmacogenomic insights into tuberculosis treatment shows the NAT2 genetic variants linked to hepatotoxicity risk: a systematic review and meta-analysis. BMC Genom Data. 2024;25(1):103. DOI: 10.1186/s12863-024-01286-y.
19. Sim E., Abuhammad A., Ryan A. Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery. Br. J. Pharmacol. 2014;171(11):2705–2725. DOI: 10.1111/bph.12598.
20. Teixeira S., Castanheira E.M.S., Carvalho M.A. Hydrazides as Powerful Tools in Medicinal Chemistry: Synthesis, Reactivity, and Biological Applications. Molecules. 2025;30(13):2852. DOI: 10.3390/molecules30132852.
21. Wang M., Zhao J., Chen J., Long T., Xu M., Luo T., Che Q., He Y., Xu D. The role of sirtuin1 in liver injury: molecular mechanisms and novel therapeutic target. PeerJ. 2024;12:e17094. DOI: 10.7717/peerj.17094.
22. Wang Y., Mohsen A.W., Mihalik S.J., Goetzman E.S., Vockley J. Evidence for physical association of mitochondrial fatty acid oxidation and oxidative phosphorylation complexes. J. Biol. Chem. 2010;285(39):29834–29841. DOI: 10.1074/jbc.M110.139493.
23. Yang Y., Liu Y., Wang Y., Chao Y., Zhang J., Jia Y., Tie J., Hu D. Regulation of SIRT1 and Its Roles in Inflammation. Front Immunol. 2022;13:831168. DOI: 10.3389/fimmu.2022.831168.
24. Yang Y., Peng W., Su X., Yue B., Shu S., Wang J., Fu C., Zhong J., Wang H. Epigenomics Analysis of the Suppression Role of SIRT1 via H3K9 Deacetylation in Preadipocyte Differentiation. Int. J. Mol. Sci. 2023;24(14):11281. DOI: 10.3390/ijms241411281.
Review
For citations:
Petrova N.V., Karkischenko N.N., Klesov R.A. Effective Pharmacogenetic Model for Analyzing N-Acetylation of Hydrazine-Class Toxicants. Journal Biomed. 2026;22(1):25-37. (In Russ.) https://doi.org/10.33647/2074-5982-22-1-25-37
Views:
45
JATS XML
Email this article 
