Cytotoxicity and Mode of Cell Death of Dimethylarsinothionic acid (DMAS) in MDCK Canine Cocker Spaniel kidney Cells

  • M Elmustafa Faculty of Pharmacy, University of Gezira, Sudan
  • H Wallace University of Aberdeen, Scotland


Background: Exposure to arsenical compounds from natural or industrial sources is a global health problem which is associated with renal damage resulting from exposure to the parent arsenical or its metabolites. The metabolism of arsenicals plays a main role in their toxicity and previous studies have shown trivalent metabolites to be many folds more toxic than their pentavalent counterparts. Objectives: To investigate the toxicity and mode of cell death produced by the newly identified pentavalent metabolite, dimethylarsinothionic acid DMAS. Methods:  The toxicity and mode of cell death induced by DMAS was compared with other arsenicals in canine cocker kidney MDCK cells using the MTT (3(4,5-dimethylthiazole-2-yl)-2-5- diphenyl tetrazolium bromide) cytotoxicity and DAPI (4'-6-diamidino-2-phenylindole) assays respectively. Results:  DMAS produced toxicity levels (IC50 35 µM) at both 24 and 48 hours which was much higher than those of pentavalent, but lower, yet comparable, to those of trivalent arsenicals. The toxicity of DMAS was reduced in a dose dependant manner in the presence of the reactive oxygen scavenger dimethylsulphoxide DMSO suggesting a role of reactive oxygen species or oxidative stress in its toxicity. The levels of apoptosis induced by DMAS in the MDCK cells were much higher than those induced by the other arsenical compounds which suggest the possible involvement of a different or more profound mechanism in its toxicity. Conclusion: These results question the concept of valence dependant toxicity and suggest that other factors may influence arsenical induced toxicity such as functional groups or substitution of the arsenical compound in question.


1. Gebel TW. Genotoxicity of arsenical compounds. Int J Hyg Environ Health [Internet]. 2001;203(3):249–62. Available from:
2. World Health Organisation. Fact sheet on Arsenic [Internet]. Fact sheet on arsenic. 2020 [cited 2020 Apr 10]. Available from:
3. Andrewes P, DeMarini DM, Funasaka K, Wallace K, Lai VWM, Sun H, et al. Do Arsenosugars Pose a Risk to Human Health? The Comparative Toxicities of a Trivalent and Pentavalent Arsenosugar. Environ Sci Technol [Internet]. 2004 Aug 1;38(15):4140–8. Available from:
4. Mass MJ, Tennant A, Roop BC, Cullen WR, Styblo M, Thomas DJ, et al. Methylated Trivalent Arsenic Species Are Genotoxic. Chem Res Toxicol [Internet]. 2001 Apr 1;14(4):355–61. Available from:
5. Chakraborti D, Rahman MM, Paul K, Chowdhury UK, Sengupta MK, Lodh D, et al. Arsenic calamity in the Indian subcontinent: What lessons have been learned? Talanta [Internet]. 2002;58(1):3–22. Available from:
6. Antman KH. Introduction: The History of Arsenic Trioxide in Cancer Therapy. Oncologist [Internet]. 2001 Apr;6(S2):1–2. Available from:
7. Morales KH, Ryan L, Kuo TL, Wu MM, Chen CJ. Risk of internal cancers from arsenic in drinking water. Environ Health Perspect [Internet]. 2000 Jul 1;108(7):655–61. Available from:
8. Styblo M, Del Razo LM, Vega L, Germolec DR, LeCluyse EL, Hamilton GA, et al. Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells. Arch Toxicol [Internet]. 2000 Aug 18;74(6):289–99. Available from:
9. Hansen HR, Raab A, Jaspars M, Milne BF, Feldmann J. Sulfur-Containing Arsenical Mistaken for Dimethylarsinous Acid [DMA(III)] and Identified as a Natural Metabolite in Urine:  Major Implications for Studies on Arsenic Metabolism and Toxicity. Chem Res Toxicol [Internet]. 2004 Aug 1;17(8):1086–91. Available from:
10. Petrick JS, Ayala-Fierro F, Cullen WR, Carter DE, Vasken Aposhian H. Monomethylarsonous Acid (MMAIII) Is More Toxic Than Arsenite in Chang Human Hepatocytes. Toxicol Appl Pharmacol [Internet]. 2000;163(2):203–7. Available from:
11. Vega L, Styblo M, Patterson R, Cullen W, Wang C, Germolec D. Differential Effects of Trivalent and Pentavalent Arsenicals on Cell Proliferation and Cytokine Secretion in Normal Human Epidermal Keratinocytes. Toxicol Appl Pharmacol [Internet]. 2001;172(3):225–32. Available from:
12. Hansen HR, Pickford R, Thomas-Oates J, Jaspars M, Feldmann J. 2-Dimethylarsinothioyl Acetic Acid Identified in a Biological Sample: The First Occurrence of a Mammalian Arsinothioyl Metabolite. Angew Chemie Int Ed [Internet]. 2004 Jan 5;43(3):337–40. Available from:
13. Raab A, Feldmann J. Arsenic speciation in hair extracts. Anal Bioanal Chem [Internet]. 2005 Jan 31;381(2):332–8. Available from:
14. Leffers L, Ebert F, Taleshi MS, Francesconi KA, Schwerdtle T. In vitro toxicological characterization of two arsenosugars and their metabolites. Mol Nutr Food Res [Internet]. 2013 Jul;57(7):1270–82. Available from:
15. Bartel M, Ebert F, Leffers L, Karst U, Schwerdtle T. Toxicological Characterization of the Inorganic and Organic Arsenic Metabolite Thio- DMA V in Cultured Human Lung Cells. J Toxicol [Internet]. 2011;2011(December 2014):1–9. Available from:
16. Moe B, Peng H, Lu X, Chen B, Chen LWL, Gabos S, et al. Comparative cytotoxicity of fourteen trivalent and pentavalent arsenic species determined using real-time cell sensing. J Environ Sci [Internet]. 2016 Nov;49:113–24. Available from:
17. Madden EF, Fowler BA. MECHANISMS OF NEPHROTOXICITY FROM METAL COMBINATIONS: A REVIEW. Drug Chem Toxicol [Internet]. 2000 Jan 1;23(1):1–12. Available from:
18. Le XC, Ma M, Cullen WR, Aposhian HV, Lu X, Zheng B. Determination of monomethylarsonous acid, a key arsenic methylation intermediate, in human urine. Environ Health Perspect [Internet]. 2000 Nov;108(11):1015–8. Available from:
19. Vasken Aposhian H, Zakharyan RA, Avram MD, Sampayo-Reyes A, Wollenberg ML. A review of the enzymology of arsenic metabolism and a new potential role of hydrogen peroxide in the detoxication of the trivalent arsenic species. Toxicol Appl Pharmacol [Internet]. 2004;198(3):327–35. Available from:
20. Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods [Internet]. 1983 Dec;65(1–2):55–63. Available from:
21. Ochi T, Kinoshita K, Suzuki T, Miyazaki K, Noguchi A, Kaise T. The role of glutathione on the cytotoxic effects and cellular uptake of diphenylarsinic acid, a degradation product of chemical warfare agents. Arch Toxicol [Internet]. 2006;80(8):486–91. Available from:
22. Pérez-Pastén R, Martínez-Galero E, Garduño-Siciliano L, Lara IC, Cevallos GC. Effects of dimethylsulphoxide on mice arsenite-induced dysmorphogenesis in embryo culture and cytotoxicity in embryo cells. Toxicol Lett [Internet]. 2006;161(3):167–73. Available from:
23. Ding W, Hudson LG, Liu KJ. Inorganic arsenic compounds cause oxidative damage to DNA and protein by inducing ROS and RNS generation in human keratinocytes. Mol Cell Biochem [Internet]. 2005;279(1):105–12. Available from:
24. Corsini E, Asti L, Viviani B, Marinovich M, Galli CL. Sodium Arsenate Induces Overproduction of Interleukin-1α in Murine Keratinocytes: Role of Mitochondria. J Invest Dermatol [Internet]. 1999;113(5):760–5. Available from:
25. Barchowsky A, Klei LR, Dudek EJ, Swartz HM, James PE. Stimulation of reactive oxygen, but not reactive nitrogen species, in vascular endothelial cells exposed to low levels of arsenite. Free Radic Biol Med [Internet]. 1999;27(11):1405–12. Available from:
How to Cite
ELMUSTAFA, M; WALLACE, H. Cytotoxicity and Mode of Cell Death of Dimethylarsinothionic acid (DMAS) in MDCK Canine Cocker Spaniel kidney Cells. Gezira Journal of Health Sciences, [S.l.], v. 16, n. 1, p. 21-32, sep. 2020. ISSN 1810-5386. Available at: <>. Date accessed: 25 jan. 2021.