Can tolvaptan usage cause cytotoxicity? An in vitro study

Objectives: Tolvaptan is a nonpeptide V2 (vasopressin) receptor antagonist which is commonly used for treatment of hypernatremia. Besides it is mostly used for rescue strategies of mutant V2 receptors which are responsible for congenital type of Nephrogenic Diabetes insipidus (NDI) as a pharmacological chaperone (PC) treatment. Tolvaptan is metabolized by CYP3A4 and usage of tolvaptan may cause cytotoxicity which can be prevented by antioxidants. The aim of this study is investigating cytotoxic effect of tolvaptan on COS-1 cells and preventing it via antioxidants such as Vitamin C and N-acetyl cysteine (NAC). Methods: To measure cytotoxicity of tolvaptan, COS-1 cells were separated in three groups; tolvaptan, tolvaptan+Vitamin C and tolvaptan+NAC. 24 h after cells were seeded in 96-well plates, they were treated with different concentrations of tolvaptan, tolvaptan+Vitamin C and tolvaptan+NAC. After 24 h incubation, the (3-(4,5-Dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide) [MTT] analysis were performed and GraphPad Prism 5.01 for Windows was used for statistical analysis. Results: According to results of MTT assay, treatment with tolvaptan did not decrease cell viability except that treatment of 10-5 M tolvaptan showed significantly decrase on cell viability compared to control group. At the concentration of 10-9 M, there was significantly different cell viability between treated with tolvaptan and tolvaptan+Vitamin C. Conclusions: Tolvaptan may show its cytotoxic effects when it is used for the treatment of hyponatremia than its usage of as a PC. Since low concentrations of tolvaptan for a short time treatment is enough for its PC role, it may not show any cytotoxic effect on cells which is coherent with our results.

Keywords:

Tolvaptan, cytotoxicity, cell culture, hyponatremia, nephrogenic diabetes indipidus pharmacological chaperone,

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1. Ali F, Guglin M, Vaitkevicius P, Ghali JK. Therapeutic potential of vasopressin receptor antagonists. Drugs 2007;67:847-58.
2. Torres VE. Vasopressin receptor antagonists, heart failure, and polycystic kidney disease. Annu Rev Med 2015;66:195-210.
3. Yi JH, Shin HJ, Kim HJ. V2 receptor antagonist; tolvaptan. Electrolyte Blood Press 2011;9:50-4.
4. Bichet DG. What is the role of vaptans in routine clinical nephrology? Clin J Am Soc Nephrol 2012;7:700-3.
5. Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, et al. Tolvaptan a selective oral vasopressin v2 receptor antagonist for hyponatremia. N Engl J Med 2006;355:2099-112.
6. Bhardwaj A. Neurological impact of vasopressin dysregulation and hyponatremia. Ann Neurol 2006;59:229-36.
7. De Luca L, Klein L, Udelson JE, Orlandi C, Sardella G, Fedele F, et al. Hyponatremia in patients with heart failure. Am J Cardiol 2005;96:19L-23L.
8. Goldberg A, Hammerman H, Petcherski S, Nassar M, Zdorovyak A, Yalonetsky S, et al. Hyponatremia and long-term mortality in survivors of acute ST-elevation myocardial infarction. Arch Intern Med 2006;166:781-6.
9. Wu Y, Beland FA, Chen S, Liu F, Guo L, Fang JL. Mechanisms of tolvaptan-induced toxicity in HepG2 cells. Biochem Pharmacol 2015;95:324-36.
10. Zmily HD, Daifallah S, Ghali JK. Tolvaptan, hyponatremia, and heart failure. Int J Nephrol Renovasc Dis 2011;4:57-71.
11. Rangarajan B, Binoy V, Hingmire SS, Noronha V. Tolvaptan. South Asian J Cancer 2014;3:182-4.
12. Gheorghiade M, Konstam MA, Burnett JC, Grinfeld L, Maggioni A, Swedberg K, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA 2007;297:1332-43.
13. Gheorghiade M, Orlandi C, Burnett JC, Demets D, Grinfeld L, Maggioni A, et al. Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the Efficacy of Vasopressin antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST). J Card Fail 2005;11:260-9.
14. Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007;297:1319-31.
15. Erdem Tuncdemir B, Mergen H, Saglar Ozer E. Evaluation of pharmacochaperone mediated rescue of mutant V2 receptor proteins. Eur J Pharmacol 2019;865:172803.
16. Tao YX, Conn PM. Pharmacoperones as novel therapeutics for diverse protein conformational diseases. Physiol Rev 2018;98:697-725.
17. Prosperi F, Suzumoto Y, Marzuillo P, Costanzo V, Jelen S, Iervolino A, et al. Characterization of five novel vasopressin V2 receptor mutants causing nephrogenic diabetes insipidus reveals a role of tolvaptan for M272R-V2R mutation. Sci Rep 2020;10:16383.
18. Robben JH, Sze M, Knoers NV, Deen PM. Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 2007;292:F253-60.
19. Takahashi K, Makita N, Manaka K, Hisano M, Akioka Y, Miura K, et al. V2 vasopressin receptor (V2R) mutations in partial nephrogenic diabetes insipidus highlight protean agonism of V2R antagonists. J Biol Chem 2012;287:2099-106.
20. Eichel K, Jullié D, Barsi-Rhyne B, Latorraca NR, Masureel M, Sibarita J-B, et al. Catalytic activation of β-arrestin by GPCRs. Nature 2018;557:381-6.
21. Schulz A, Sangkuhl K, Lennert T, Wigger M, Price DA, Nuuja A, et al. Aminoglycoside pretreatment partially restores the function of truncated V(2) vasopressin receptors found in patients with nephrogenic diabetes insipidus. J Clin Endocrinol Metab 2002;87:5247-57.
22. Sangkuhl K, Schulz A, Rompler H, Yun J, Wess J, Schoneberg T. Aminoglycoside mediated rescue of a disease-causing nonsense mutation in the V2 vasopressin receptor gene in vitro and in vivo. Hum Mol Genet 2004;13:893-903.
23. Groeneweg S, van den Berge A, Meima ME, Peeters RP, Visser TJ, Visser WE. Effects of chemical chaperones on thyroid hormone transport by MCT8 mutants in patient-derived fibroblasts. Endocrinology 2018;159:1290-302.
24. Kamijima S, Sekiya A, Takata M, Nakano H, Murakami M, Nakazato T, et al. Gene analysis of inherited antithrombin deficiency and functional analysis of abnormal antithrombin protein (N87D). Int J Hematol 2018;107:490-4.
25. Leanos-Miranda A, Ulloa-Aguirre A, Janovick JA, Conn PM. In vitro coexpression and pharmacological rescue of mutant gonadotropin-releasing hormone receptors causing hypogonadotropic hypogonadism in humans expressing compound heterozygous alleles. J Clinndocrinol Metab 2005;90:3001-8.
26. Janovick JA, Goulet M, Bush E, Greer J, Wettlaufer DG, Conn PM. Structure-activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropin-releasing hormone receptor. J Pharmacol Exp Ther 2003;305:608-14.
27. Gunderson EG, Lillyblad MP, Fine M, Vardeny O, Berei TJ. Tolvaptan for volume management in heart failure. Pharmacotherapy 2019;39:473-85.
28. Hitomi Y, Nagatomo Y, Yukino M, Yumita Y, Kagami K, Yasuda R, et al. Characterization of tolvaptan response and its impact on the outcome for patients with heart failure. J Cardiol 2021;78:285-93.
29. Beaudoin JJ, Brock WJ, Watkins PB, Brouwer KLR. Quantitative systems toxicology modeling predicts that reduced biliary efflux contributes to tolvaptan hepatotoxicity. Clin Pharmacol Ther 2021;109:433-42.
30. Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 1987;47:936-42.
31. Costello-Boerrigter LC, Boerrigter G, and Burnett JC, Jr. Pharmacology of vasopressin antagonists. Heart Fail Rev 2009;14:75-82.
32. Gheorghiade M, Niazi I, Ouyang J, Czerwiec F, Kambayashi J, Zampino M, et al. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Circulation 2003;107:2690-6.
33. Reilly T, Chavez B. Tolvaptan (Samsca) for hyponatremia: is it worth its salt? PT 2009;34:543-547.
34. Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W, Greenberg BH, O'Connor CM, et al. Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry. Eur Heart J 2007;28:980-8.
35. Gheorghiade M, Rossi JS, Cotts W, Shin DD, Hellkamp AS, Pina IL, et al. Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the escape trial. Arch Intern Med 2007;167:1998-2005.
36. Konstam MA, Kiernan M, Chandler A, Dhingra R, Mody FV, Eisen H, et al. Short-term effects of tolvaptan in patients with acute heart failure and volume overload. J Am Coll Cardiol 2017;69:1409-19.
37. Bellos I. Safety profile of tolvaptan in the treatment of autosomal dominant polycystic kidney disease. Ther Clin Risk Manag 2021;17:649-56.
38. Szalai L, Sziraki A, Erdelyi LS, Kovacs KB, Toth M, Toth AD, et al. Functional rescue of a nephrogenic diabetes insipidus causing mutation in the V2 vasopressin receptor by specific antagonist and agonist pharmacochaperones. Front Pharmacol 2022;13:811836.
39. Feldman BJ, Rosenthal SM, Vargas GA, Fenwick RG, Huang EA, Matsuda-Abedini M, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 2005;352:1884-90.
40. Erdelyi LS, Mann WA, Morris-Rosendahl DJ, Gross U, Nagel M, Varnai P, et al. Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis. Kidney Int 2015;88:1070-8.
41. Morello JP, Bichet DG. Nephrogenic diabetes insipidus. Annu. Rev. Physiol 2001;63:607-30.
42. Mubeen MF. Pharmacoperones role in nephrogenic diabetes insipidus. Glob Acad J Pharm Drug Res 2020;2:34-28.
43. Bernier V, Bichet DG, Bouvier M. Pharmacological chaperone action on G-protein coupled receptors. Curr Opin Pharmacol 2004;4:528-33.
44. Ulloa-Aguirre A, Janovick JA, Brothers SP, Conn PM. Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease. Traffic 2004;5:821-37.
45. Durukan AB, Erdem B, Durukan E, Sevim H, Karaduman T, Gurbuz HA, et al. May toxicity of amiodarone be prevented by antioxidants? A cell culture study. J Cardiothorac Surg 2012;7:61.
46. Fujiki T, Ando F, Murakami K, Isobe K, Mori T, Susa K, et al. Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation. Sci Rep 2019;9:9245.