Genotoxic effects of antiepileptic drugs. Literature review

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Abstract

Based on the selected criteria data from studies of the genotoxic activity of antiepileptic drugs in eukaryotic test systems in vitro and in vivo, performed by DNA comet assay, chromosomal aberrations and micronuclei assays, published in the period 1995–2022, were selected and summarized.

Among the 20 drugs reviewed, for one drug (N03AA05 Benzobarbital), there are no data on studies of genotoxic activity; for 7 drugs information is presented only as a summary on the FDA and EMA websites without primary data and information on experimental designs. Among the remaining 12 drugs, only three drugs (phenobarbital, valproic acid and levetiracetam) have information on in vivo studies, both by DNA damage assay and by cytogenetic methods. Based on known publications, it is impossible to draw reasonable conclusions about the genotoxic potential of individual drugs. The available data are fragmentary, incomplete and contradictory. It remains to state the facts of detection of genotoxic effects in individual drugs in separate studies. In general, there is no doubt about the potential genotoxic hazard of this group the drugs in.

Additional studies are needed to clarify the data on the genotoxicity of antiepileptic drugs including beyond the standard protocols. In the course of their implementation, one should take into account the possible tissue-specific manifestation of antiepileptics genotoxicity, as indicated by the facts of genotoxic effects detection in tissue cells that are not targets in classical genotoxic studies. The expediency of objectifying approaches when choosing a drug for safe therapy, taking into account information about its genotoxicity, is emphasized, and the prospects for possible studies on antigenotoxic prophylaxis in patients with epilepsy are pointed out.

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About the authors

Natalia V. Eremina

Research Zakusov Institute of Pharmacology

Author for correspondence.
Email: nnv1988@gmail.com
ORCID iD: 0000-0002-7226-5505
SPIN-code: 5224-1968

Cand, Sci. (Biol.), Senior Research Associate of the Laboratory of Drug Toxicology

Russian Federation, Moscow

Aliy K. Zhanataev

Research Zakusov Institute of Pharmacology

Email: zhanataev@academpharm.ru
ORCID iD: 0000-0002-7673-8672
SPIN-code: 7070-0510
Scopus Author ID: 6506103462

Cand. Sci. (Biol.), Leading Research Associate of the Laboratory of Mutagenesis Pharmacology

Russian Federation, Moscow

Andrey D. Durnev

Research Zakusov Institute of Pharmacology

Email: addurnev@mail.ru
ORCID iD: 0000-0003-0218-8580
SPIN-code: 8426-0380
Scopus Author ID: 7006060753

Dr. Sci. (Med.), Professor, Corresponding Member of RAS; Head of the Department of Drug Toxicology and Pharmacology of Mutagenesis

Russian Federation, Moscow

References

  1. World Health Organization. Epilepsy: a public health imperative. Summary. Geneva: World Health Organization, 2019 (WHO/MSD/MER/19.2). Licence: CC BY-NC-SA 3.0 IGO.
  2. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4): 475–482. doi: 10.1111/epi.12550
  3. Falco-Walter J. Epilepsy-definition, classification, pathophysiology, and epidemiology. Semin Neurol. 2020;40(6):617–623. doi: 10.1055/s-0040-1718719
  4. Chen Z, Brodie MJ, Kwan P. What has been the impact of new drug treatments on epilepsy? Curr Opin Neurol. 2020;33(2):185–190. doi: 10.1097/WCO.0000000000000803
  5. Singh G, Driever PH, Sander JW. Cancer risk in people with epilepsy: the role of antiepileptic drugs. Brain. 2005;128(1):7–17. doi: 10.1093/brain/awh363
  6. Durnev AD, Zhanataev AK, Eremina NV. Geneticheskaya toksikologiya. Moscow: Tipografiya Mittel’ Press, 2022. 286 p. (In Russ.)
  7. Steiblen G, van Benthem J, 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. doi: 10.1016/j.mrgentox.2020.503171
  8. oecd-ilibrary.org [Internet] OECD Guidelines for the Testing of Chemicals, Section 4. Health Effects. Available from: https://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788
  9. vidal.ru [Internet]. VIDAL. Spravochnik lekarstvennykh sredstv. Available from: https://www.vidal.ru/drugs/atc (In Russ.)
  10. Riedel L, Obe G. Mutagenicity of antiepileptic drugs. II. Phenytoin, primidone and phenobarbital. Mutat Res Genet Toxicol. 1984;138(1):71–74. doi: 10.1016/0165-1218(84)90087-9
  11. Müller-Tegethoff K, Kasper P, Müller L. Evaluation studies on the in vitro rat hepatocyte micronucleus assay. Mutat Res Sect Environ Mutagen Relat Subj. 1995;335(3):293–307. doi: 10.1016/0165-1161(95)00033-x
  12. Kindig D, Garriott ML, Parton JW, et al. Diphenylhydantoin is not genotoxic in a battery of short-term cytogenetic assays. Teratog Carcinog Mutagen. 1992;12(1):43–50. doi: 10.1002/tcm.1770120106
  13. International Agency for Research on Cancer (IARC) — Summaries and Evaluations [Internet]. Phenobarbital and its sodium salt (Group 2B). Available from: http://www.inchem.org/documents/iarc/vol79/79-06.html
  14. Deutsch WA, Kukreja A, Shane B, Hegde V. Phenobarbital, oxazepam and Wyeth 14,643 cause DNA damage as measured by the Comet assay. Mutagenesis. 2001;16(5):439–442. doi: 10.1093/mutage/16.5.439
  15. Biswas SJ, Pathak S, Khuda-Bukhsh AR. Assessment of the genotoxic and cytotoxic potential of an anti-epileptic drug, phenobarbital, in mice: a time course study. Mutat Res. 2004;563(1):1–11. doi: 10.1016/j.mrgentox.2004.05.016
  16. Sasaki YF, Izumiyama F, Nishidate E, et al. Detection of rodent liver carcinogen genotoxicity by the alkaline single-cell gel electrophoresis (Comet) assay in multiple mouse organs (liver, lung, spleen, kidney, and bone marrow). Mutat Res Genet Toxicol Environ Mutagen. 1997;391(3):201–214. doi: 10.1016/s1383-5718(97)00072-7
  17. Gonzales AJ, Christensen JG, Preston RJ, et al. Attenuation of G1 checkpoint function by the non-genotoxic carcinogen phenobarbital. Carcinogenesis. 1998;19(7):1173–1183. doi: 10.1093/carcin/19.7.1173
  18. La Vecchia C, Negri E. A review of epidemiological data on epilepsy, phenobarbital, and risk of liver cancer. Eur J Cancer Prev. 2014;23(1):1–7. doi: 10.1097/CEJ.0b013e32836014с8
  19. Durnev AD, Zhanataev AK. Relevant aspects of drug genetic toxicology. The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. Regulatory Research and Medicine Evaluation. 2022;12(1): 90–109. (In Russ.) doi: 10.30895/1991-2919-2022-12-1-90-109
  20. Stenchever MA, Allen M. The effect of selected antiepileptic drugs on the chromosomes of human lymphocytes in vitro. Am J Obstet Gynecol. 1973;116(6):867–870. doi: 10.1016/0002-9378(73)91022-3
  21. inchem.org [Internet]. Phenytoin. IARC Monograph. 1996. Vol. 66. 175 p. Available from: https://inchem.org/documents/iarc/vol66/phenytoin.html
  22. Erenberk U, Dundaroz R, Gok O, et al. Melatonin attenuates phenytoin sodium-induced DNA damage. Drug Chem Toxicol. 2014;37(2):233–239. doi: 10.3109/01480545.2013.838777
  23. Ghiraldini FG, Mello MLS. Micronucleus formation, proliferative status, cell death and DNA damage in ethosuximide-treated human lymphocytes. Cell Biol Int Rep. 2010;17(1):27–31. doi: 10.1042/CBR20100007
  24. Mironov AN, editor. Rukovodstvo po provedeniyu doklinicheskikh issledovanii lekarstvennykh sredstv. Chast’ pervaya. Moscow: Grif i K, 2012. 944 p. (In Russ.)
  25. Herha J, Obe G. Chromosomal damage in epileptics on monotherapy with carbamazepine and diphenylhydantoin. Hum Genet. 1976;34(3):255–263. doi: 10.1007/BF00295288
  26. Awara WM, El-Gohary M, El-Nabi SH, Fadel WA. In vivo and in vitro evaluation of the mutagenic potential of carbamazepine: does melatonin have anti-mutagenic activity? Toxicology. 1998;125(1): 45–52. doi: 10.1016/s0300-483x(97)00160-1
  27. Sinués B, Gazulla J, Bernal ML, et al. Six mutagenicity assays in exposure biomonitoring of patients receiving carbamazepine for epilepsy or trigeminal neuralgia. Mutat Res Sect Environ Mutagen Relat Subj. 1995;334(2):259–265. doi: 10.1016/0165-1161(95)90019-5
  28. Celik A. The assessment of genotoxicity of carbamazepine using cytokinesis-block (CB) micronucleus assay in cultured human blood lymphocytes. Drug Chem Toxicol. 2006;29(2):227–236. doi: 10.1080/01480540600566832
  29. Pavone A, Cardile V. An in vitro study of new antiepileptic drugs and astrocytes. Epilepsia. 2003;44(s10):34–39. doi: 10.1046/j.1528-1157.44.s10.5.x
  30. Atlı Şekeroğlu Z, Kefelioğlu H, Kontaş Yedier S, et al. Oxcarbazepine-induced cytotoxicity and genotoxicity in human lymphocyte cultures with or without metabolic activation. Toxicol Mech Methods. 2017;27(3):201–206. doi: 10.1080/15376516.2016.1273430
  31. Akbar H, Khan A, Mohammadzai I, et al. The genotoxic effect of oxcarbazepine on mice blood lymphocytes. Drug Chem Toxicol. 2018;41(2):135–140. doi: 10.1080/01480545.2017.1321011
  32. Novartis [Internet]. Trileptan label [cited 2022 Jun 6]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021014s026,021285s021lbl.pdf
  33. Suarez-Torres JD, Orozco CA, Ciangherotti CE. The numerical probability of carcinogenicity to humans of some pharmaceutical drugs: Alkylating agents, topoisomerase inhibitors or poisons, and DNA intercalators. Fundam Clin Pharmacol. 2021;35(6):1069–1089. doi: 10.1111/fcp.126
  34. Andreazza AC, Kauer-Sant’Anna M, Frey BN, et al. Effects of mood stabilizers on DNA damage in an animal model of mania. J Psychiatry Neurosci. 2008;33(6):516–524.
  35. Khan S, Jena G. Sodium valproate, a histone deacetylase inhibitor ameliorates cyclophosphamide-induced genotoxicity and cytotoxicity in the colon of mice. J Basic Clin Physiol Pharmacol. 2014;25(4):1–11. doi: 10.1515/jbcpp-2013-0134.
  36. Abdella EM, Galaly SR, Mohammed HM, Khadrawy SM. Protective role of vitamin E against valproic acid-induced cytogenotoxicity and hepatotoxicity in mice. J Basic Appl Zool. 2014;67(4):127–139. doi: 10.1016/j.jobaz.2014.03.003
  37. Ahmad T, Shekh K, Khan S, et al. Pretreatment with valproic acid, a histone deacetylase inhibitor, enhances the sensitivity of the peripheral blood micronucleus assay in rodents. Mutat Res Genet Toxicol Environ Mutagen. 2013;751(1):19–26. doi: 10.1016/j.mrgentox.2012.10.009
  38. Fucic A, Stojković R, Miškov S, et al. Transplacental genotoxicity of antiepileptic drugs: animal model and pilot study on mother/newborn cohort. Reprod Toxicol. 2010;30(4):613–618. doi: 10.1016/j.reprotox.2010.08.008
  39. Denli M, Aydin HI. Genotoxicity evaluation in female patients on valproic acid monotherapy using alkaline single cell gel electrophoresis (Comet assay). East J Med. 2000;5(2):61–65.
  40. Khan S, Ahmad T, Parekh CV, et al. Investigation on sodium valproate induced germ cell damage, oxidative stress and genotoxicity in male Swiss mice. Reprod Toxicol. 2011;32(4):385–394. doi: 10.1016/j.reprotox.2011.09.007.
  41. Luo Y, Wang H, Zhao X, et al. Valproic acid causes radiosensitivity of breast cancer cells via disrupting the DNA repair pathway. Toxicol Res (Camb). 2016;5(3):859–870. doi: 10.1039/c5tx00476d
  42. Tian Y, Liu G, Wang H, et al. Valproic acid sensitizes breast cancer cells to hydroxyurea through inhibiting RPA2 hyperphosphorylation-mediated DNA repair pathway. DNA Repair. 2017;58:1–12. doi: 10.1016/j.dnarep.2017.08.002
  43. Sakai A, Sasaki K, Muramatsu D, et al. A Bhas 42 cell transformation assay on 98 chemicals: the characteristics and performance for the prediction of chemical carcinogenicity. Mutat Res Genet Toxicol Environ Mutagen. 2010;702(1):100–122. doi: 10.1016/j.mrgentox.2010.07.007
  44. Lamictal [Internet]. Lamictal label [cited 2022 Jun 6]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020241s058,020764s051,022251s022lbl.pdf.
  45. Makawy AIE, Mabrouk DM, Ibrahim FA, Ahmed KA. Genotoxic, biochemical and histopathological studies to assessment the topiramate hepatorenal toxicity in mice. Drug Chem Toxicol. 2022;45(1):103–112. doi: 10.1080/014805
  46. NDA 020505-S-050 Topamax [Internet]. Topamax (topiramate) tablets label [cited 2022 Jun 6]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020844s041lbl.pdf
  47. Neurontin (gabapentin) [Internet]. Highlights of prescribing information [cited 2022 Jun 6]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020235s064_020882s047_021129s046lbl.pdf
  48. Neurontin and Associated names [Internet]. Annex I. List of the names, pharmaceutical forms, strengths of the medicinal products, route of administration, marketing authorisation holders in the member states [cited 2022 Jun 6]. Available from: https://www.ema.europa.eu/en/documents/referral/neurontin-article-30-referral-annex-i-ii-iii_en.pdf
  49. El-shorbagy H.M., Hamida H. Genotoxic and mutagenic studies of the antiepileptic drug levetiracetam in pregnant rats and their fetuses. Int J Pharm Pharm Sci. 2016;8(2):82–88.
  50. Baysal M, Ilgin S, Kilic G, et al. Reproductive toxicity after levetiracetam administration in male rats: Evidence for role of hormonal status and oxidative stress. PLoS One. 2017;12(4):e0175990. doi: 10.1371/journal.pone.0175990
  51. Tural S, Tekcan A, Elbistan M, et al. Genotoxic effects of prenatal exposure to levetiracetam during pregnancy on rat offsprings. In Vivo. 2015;29(1):77–81.
  52. Keppra, INN-Levetiracetam [Internet]. Scientific discussion [cited 2022 Jun 6]. Available from: https://www.ema.europa.eu/en/documents/scientific-discussion/keppra-epar-scientific-discussion_en.pdf
  53. Center for drug evaluation and research. Application number: 202834orig1s000 [Internet]. Pharmacology review(s) Perampanel. Tertiary Pharmacology Review [cited 2022 Jun 6]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202834Orig1s000PharmR.pdf
  54. Witczak M, Kociszewska I, Wilczyński J, et al. Evaluation of chromosome aberrations, sister chromatid exchange and micronuclei in cultured cord-blood lymphocytes of newborns of women treated for epilepsy during pregnancy. Mutat Res Genet Toxicol Environ Mutagen. 2010;701(2):111–117. doi: 10.1016/j.mrgentox.2010.05.003
  55. Klonopin [Internet]. KLONOPIN tablets label [cited 2022 Jun 6]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017533s059lbl.pdf
  56. Inovelon, INN-rufinamide [Internet]. Scientifec discussion [cited 2022 Jun 6]. Available from: https://www.ema.europa.eu/en/documents/scientific-discussion/inovelon-epar-scientific-discussion_en.pdf
  57. Europian Medicine Agency [Internet]. Zebinix EPAR Assessement report. Procedure No. EMEA/H/C/000988/X/0050/G [cited 2022 Jun 6]. Available from: https://www.ema.europa.eu/en/documents/variation-report/zebinix-h-c-988-x-0050-g-epar-assessment-report-extension_en.pdf
  58. Zonegran, INN-Zonisamide [Internet]. Scientific discussion [cited 2022 Jun 6]. Available from: https://www.ema.europa.eu/en/documents/scientific-discussion/zonegran-epar-scientific-discussion_en.pdf
  59. Lyrica, INN-Pregabalin [Internet]. Scientific discussion [cited 2022 Jun 6]. Available from: https://www.ema.europa.eu/en/documents/scientific-discussion/lyrica-epar-scientific-discussion_en.pdf
  60. Briviact, INN-brivaracetam [Internet]. Assessement report. Procedure No. EMEA/H/C/003898/0000 [cited 2022 Jun 6]. Available from: https://www.ema.europa.eu/en/documents/assessment-report/briviact-epar-public-assessment-report_en.pdf
  61. Brivaracetam [Internet]. Pharmacology review [cited 2022 Jun 6]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/205836Orig1s000_205837Orig1s000_205838Orig1s000PharmR.pdf
  62. Vimpat (lacosamide) [Internet]. Highlights of prescribing information [cited 2022 Jun 6]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022253s046s048,022254s036s038,022255s027s030lbl.pdf
  63. Vimpat, INN-lacosamide [Internet]. Assessment report [cited 2022 Jun 6]. Available from: https://www.ema.europa.eu/en/documents/assessment-report/vimpat-epar-public-assessment-report_en.pdf
  64. Aguiar CCT, Almeida AB, Araújo PVP, et al. Oxidative stress and epilepsy: literature review. Oxid Med Cell Longev. 2012;2012:795259. doi: 10.1155/2012/795259
  65. Adelöw C, Ahlbom A, Feychting M, et al. Epilepsy as a risk factor for cancer. J Neurol Neurosurg Psychiatry. 2006;77(6):784–786. doi: 10.1136/jnnp.2005.083931
  66. Kardoost M, Hajizadeh-Saffar E, Ghorbanian MT, et al. Genotoxicity assessment of antiepileptic drugs (AEDs) in human embryonic stem cells. Epilepsy Res. 2019;158:106232. doi: 10.1016/j.eplepsyres.2019.106232
  67. Reynolds EH, Green R. Valproate and folate: Congenital and developmental risks. Epilepsy Behav. 2020;108:107068. doi: 10.1016/j.yebeh.2020.107068
  68. Fenech M. Cytokinesis-block micronucleus assay evolves into a cytome assay of chromosomal instability, mitotic dysfunction and cell death. Mutat Res Fund Mol M. 2006;600(1–2):58–66. doi: 10.1016/j.mrfmmm.2006.05.028.
  69. de Oliveira PA, Lino FL, Cappelari SE, et al. Effects of gamma-decanolactone on seizures induced by PTZ-kindling in mice. Exp Brain Res. 2008;187(1):161–166. doi: 10.1007/s00221-008-1295-y
  70. Matos G, Ribeiro DA, Alvarenga TA, et al. Behavioral and genetic effects promoted by sleep deprivation in rats submitted to pilocarpine-induced status epilepticus. Neurosci Lett. 2012;515(2):137–140. doi: 10.1016/j.neulet.2012.03.030
  71. Coelho VR, Vieira CG, de Souza LP, et al. Antiepileptogenic, antioxidant and genotoxic evaluation of rosmarinic acid and its metabolite caffeic acid in mice. Life Sci. 2015;122:65–71. doi: 10.1016/j.lfs.2014.11.009
  72. Mahmoud A.N., Shata A., Kattawy H. Phenytoin: Is it genotoxic in isolated cultured human lymphocytes without metabolic activation by S9? African Journal of Pharmacy and Pharmacology, 2016;10(41):865–872
  73. Lazzarotto L, Pflüger P, Regner GG, et al. Lacosamide improves biochemical, genotoxic, and mitochondrial parameters after PTZ-kindling model in mice. Fundam Clin Pharmacol. 2020;35(2):351–363. doi: 10.1111/fcp.12598

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