1st International Conference on Chemo and BioInformatics, ICCBIKG 2021, (427-430)
AUTHOR(S) / АУТОР(И): Sanja Lj. Matić, Snežana M. Stanić, Nevena M. Tomašević, Rino Ragno, Milan P. Mladenović
E-ADRESS / Е-АДРЕСА: sanjamatic@kg.ac.rs, stanic@kg.ac.rs, nevena.stankovic@pmf.kg.ac.rs; milan.mladenovic@pmf.kg.ac.rs
DOI: 10.46793/ICCBI21.427M
ABSTRACT / САЖЕТАК:
Previously unreported genotoxic and antigenotoxic potentials of hesperetin (Hes) were revealed by treating the Drosophila melanogaster (dm) whose DNA has been altered by means of O6-ethylguanine (dmGO6-Et) and O4-ethylthymine (dmTO4-Et) lesions appearance, caused by ethyl methanesulfonate (EMS), a proven alkylating agent and mutagen. Therefore, Hes potencies were determined by means of the comet assay on somatic cells level, where compound exerted no genotoxic effects but acted genotoxically as a Topoisomerase IIα (dmTopIIα) catalytic inhibitor by invading the Binding and Cleavage Domain and stabilizing the noncovalent dmTopIIα-plasmid DNA (dmPDNA) complex, as verified by the kinetoplast DNA (dmK-DNA) decatenation assays. Hes’s structure-based alignment caused compound’s A and C rings to occupy the area normally invaded by EMS, thus making a spatial barrier for the dmGO6-Et or dmTO4-Et lesions formation: the A ring C7-OH group formed hydrogen bonds (HBs) with either dmGO6 (dHB = 2.576 Å) or guanine’s N7 nitrogen (dmGN7, dHB = 2.737 Å), whereas the A ring C5-OH group formed an HB with dmTO4 (dHB = 3.548 Å). Furthermore, Hes likewise acted as a mixed-type competitive inhibitor of dmATPase, as verified by the catalytic, FRET, and structure-based studies where it affected the dmATPase dimerization and the hydrolysis of ATP, denying the metabolic energy for the catenation of ethylated G-dmDNA segment, the formation of dmTO4-Et-G-dmDNA phosphotyrosine intermediate (dmTO4-Et-G- dmDNA-PTyr785I), and the passage of ethylated T-dmDNA segment through the temporarily broken dmTO4-Et-G-dmDNA-PTyr785I, processes seen as comets. Conclusively, Hes may be used in anticancer therapy controlling the effects of alkylating agents.
KEY WORDS / КЉУЧНЕ РЕЧИ:
Hesperetin, Drosophila melanogaster, molecular modelling, comet assay
REFERENCES / ЛИТЕРАТУРА:
- N. M. Borradaile, K.K. Carroll, E.M. Kurowska., Regulation of HepG2 cell apolipoprotein B metabolism by the citrus flavanones hesperetin and naringenin, Lipids, 34 (1999) 591- 598.
- H. L. Yang, S.C. Chen, K.J. Senthil Kumar, K.N. Yu, P.D. Lee Chao, S.Y. Tsai, Y.C. Hou, Y.C. Hseu., Antioxidant and anti-inflammatory potential of hesperetin metabolites obtained from Hes-administered rat serum: an ex vivo approach, Journal of Agricultural and Food Chemistry, 60 (2012) 522-532.
- S. T. Rahideh, F. Shidfar, M. Nourbakhsh, M. Hoseini, F. Koohdani, M. Entezam, M. Keramatipour., The individual or combinational effects of hesperetin and letrozole on the activity and expression of aromatase in MCF-7 cells, Cellular and Molecular Biology, 62 (2016) 38-43.
- J. A. Kang, S.H. Yoon, J.K. Rho, B. Jang, D.S. Choi, D.-E. Lee, E.-B. Byun, J. Jeon, S.H. Park., Radioprotective effect of hesperetin against γ-irradiation induced DNA damage and immune dysfunction in murine splenocytes, Food Science and Biotechnology, 25(S) (2016) 163-168.
- P. P. Trivedi, D.N. Tripathi, G.B. Jena., Hesperetin protects testicular toxicity of doxorubicin in rat: Role of NF-κB, p38 and caspase-3, Food and Chemical Toxicology, 49 (2011) 838-847.
- N. P. Singh, M.T. McCoy, R.R. Tice, E.L. Schneider., A simple technique for quantitation of low levels of DNA damage in individual cells, Experimental Cell Research, 175 (1988) 184–191.
- M. Mladenović, S. Matić, S. Stanić, S. Solujić, V. Mihailović, N. Stanković, J. Katanić., Combining molecular docking and 3-D pharmacophore generation to enclose the in vivo antigenotoxic activity of naturally occurring aromatic compounds: Myricetin, quercetin, rutin, and rosmarinic acid, Biochemical Pharmacology, 86 (2013) 1376–1396.
- J.H. Lee, T.J. Wendorff , J.M. Berger., Resveratrol: A novel type of topoisomerase II inhibitor, Journal of Biological Chemistry, 292 (2017) 21011-21022.