The Clozapine-induced Toxicity via Induction of Oxidative Stress and Mitochondrial Dysfunction in Human Blood Lymphocytes and Protecting role of L-Carnitine Clozapine-induced Toxicity on Lymphocytes
International Pharmacy Acta,
Vol. 3 No. 1 (2020),
14 December 2020
,
Page 3e9:1-9
https://doi.org/10.22037/ipa.v3i1.32179
Abstract
Clozapine is a useful antipsychotic drug but with serious, life threatening toxicity effects. The aim of this study is to assess the direct cytotoxicity effect of clozapine (CLZ) on human blood lymphocytes and investigate the protective effect of L‐carnitine (LC) against clozapine‐induced cytotoxicity. Clozapine at 70 μM concentration induced cytotoxicity following 12 h. The Clozapine induced cytotoxicity was associated with intracellular reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) collapse, lysosomal membrane injury, lipid peroxidation, and depletion of glutathione (GSH) and raising of oxidized glutathione (GSSG). We showed that LC (1 mM) has a beneficial cytoprotective effect against clozapine-induced toxicity. Summery, clozapine causes organelles damages and triggers oxidative stress in lymphocytes. These data suggest that using of L‐carnitine could be useful for prevention and treatment of clozapine toxicity. Finally, it could be concluded that LC exerts a beneficial antioxidant and mitochondrial protective effects against oxidative stress induced by CLZ.
- Clozapine
- Cytotoxicity
- L‐carnitine
- Mitochondrial Damages
- Oxidative Stress
How to Cite
References
2. Voulgari C, Giannas R, Paterakis G, et al. Clozapine-induced late agranulocytosis and severe neutropenia complicated with Streptococcus pneumonia, venous thromboembolism, and allergic vasculitis in treatment-resistant female psychosis. Case Reports in Medicine. 2015;2015.
3. Alvir JMJ, Lieberman JA, Safferman AZ, et al. Clozapine-induced agranulocytosis--incidence and risk factors in the United States. New England Journal of Medicine. 1993;329(3):162-167.
4. Hummer M, Kurz M, Barnas C, et al. Clozapine-induced transient white blood count disorders. The Journal of clinical psychiatry. 1994;55(10):429-432.
5. Ahokas A, Elonen E. Circadian rhythm of white blood cells during clozapine treatment. Psychopharmacology. 1999;144(3):301-302.
6. Flanagan RJ, Dunk L. Haematological toxicity of drugs used in psychiatry. Human Psychopharmacology: Clinical and Experimental. 2008;23(S1):S27-S41.
7. Gerson SL. Clozapine--deciphering the risks. Mass Medical Soc; 1993.
8. Patel NC, Dorson PG, Bettinger TL. Sudden late onset of clozapine-induced agranulocytosis. Annals of Pharmacotherapy. 2002;36(6):1012-1015.
9. Harpaz S. L-carnitine and its attributed functions in fish culture and nutrition—a review. Aquaculture. 2005;249(1-4):3-21.
10. Gülçin İ. Antioxidant and antiradical activities of L-carnitine. Life sciences. 2006;78(8):803-811.
11. Wang Q, Ju X, Chen Y, et al. L‐carnitine exerts a cytoprotective effect against H2O2‐induced oxidative stress in the fathead minnow muscle cell line. Aquaculture research. 2017;48(3):941-954.
12. Augustyniak A, Skrzydlewska E. L-Carnitine in the lipid and protein protection against ethanol-induced oxidative stress. Alcohol. 2009;43(3):217-223.
13. Berni A, Meschini R, Filippi S, et al. L-carnitine enhances resistance to oxidative stress by reducing DNA damage in Ataxia telangiectasia cells. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2008;650(2):165-174.
14. Guzmán-Guillén R, Prieto A, Vázquez C, et al. The protective role of l-carnitine against cylindrospermopsin-induced oxidative stress in tilapia (Oreochromis niloticus). Aquatic toxicology. 2013;132:141-150.
15. Tonk EC, de Groot DM, Penninks AH, et al. Developmental immunotoxicity of di-n-octyltin dichloride (DOTC) in an extended one-generation reproductive toxicity study. Toxicology letters. 2011;204(2-3):156-163.
16. Salimi A, Vaghar-Moussavi M, Seydi E, et al. Toxicity of methyl tertiary-butyl ether on human blood lymphocytes. Environmental Science and Pollution Research. 2016;23(9):8556-8564.
17. Dikalov SI, Harrison DG. Methods for detection of mitochondrial and cellular reactive oxygen species. Antioxidants & redox signaling. 2014;20(2):372-382.
18. Nicholls DG. Fluorescence measurement of mitochondrial membrane potential changes in cultured cells. Mitochondrial Bioenergetics: Springer; 2012. p. 119-133.
19. Boya P, Kroemer G. Lysosomal membrane permeabilization in cell death. Oncogene. 2008;27(50):6434.
20. Beach DC, Giroux E. Inhibition of lipid peroxidation promoted by iron (III) and ascorbate. Archives of biochemistry and biophysics. 1992;297(2):258-264.
21. Kruger NJ. The Bradford method for protein quantitation. The protein protocols handbook: Springer; 2002. p. 15-21.
22. Hissin PJ, Hilf R. A fluorometric method for determination of oxidized and reduced glutathione in tissues. Analytical biochemistry. 1976;74(1):214-226.
23. Nielsen J, Young C, Ifteni P, et al. Worldwide differences in regulations of clozapine use. CNS drugs. 2016;30(2):149-161.
24. Rajagopal S. Clozapine, agranulocytosis, and benign ethnic neutropenia. The Fellowship of Postgraduate Medicine; 2005.
25. Wiciński M, Węclewicz MM. Clozapine-induced agranulocytosis/granulocytopenia: mechanisms and monitoring. Current opinion in hematology. 2018;25(1):22-28.
26. Regen F, Herzog I, Hahn E, et al. Clozapine-induced agranulocytosis: evidence for an immune-mediated mechanism from a patient-specific in-vitro approach. Toxicology and applied pharmacology. 2017;316:10-16.
27. Goto A, Mouri A, Nagai T, et al. Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells. Toxicology and applied pharmacology. 2016;306:8-16.
28. de With S, Pulit S, Staal W, et al. More than 25 years of genetic studies of clozapine-induced agranulocytosis. The pharmacogenomics journal. 2017;17(4):304.
29. You J, Lee J, Hyun S-H, et al. L-carnitine treatment during oocyte maturation improves in vitro development of cloned pig embryos by influencing intracellular glutathione synthesis and embryonic gene expression. Theriogenology. 2012;78(2):235-243.
30. Nooijen PM, Carvalho F, Flanagan RJ. Haematological toxicity of clozapine and some other drugs used in psychiatry. Human Psychopharmacology: Clinical and Experimental. 2011;26(2):112-119.
31. Gerson SL, Arce C, Meltzer HY. N‐desmethylclozapine: a clozapine metabolite that suppresses haemopoiesis. British journal of haematology. 1994;86(3):555-561.
32. Borges RS, Nagurniak GR, Queiroz LM, et al. Structure and toxicity of clozapine and olanzapine on agranulocytosis. Medicinal Chemistry Research. 2016;25(2):322-328.
33. Dragovic S, Gunness P, Ingelman-Sundberg M, et al. Characterization of human cytochrome P450s involved in the bioactivation of clozapine. Drug Metabolism and Disposition. 2013;41(3):651-658.
34. Abdelrazik H, Sharma R, Mahfouz R, et al. L-carnitine decreases DNA damage and improves the in vitro blastocyst development rate in mouse embryos. Fertility and sterility. 2009;91(2):589-596.
35. Wells PG, McCallum GP, Chen CS, et al. Oxidative stress in developmental origins of disease: teratogenesis, neurodevelopmental deficits, and cancer. Toxicological sciences. 2009;108(1):4-18.
36. Walss-Bass C, Weintraub ST, Hatch J, et al. Clozapine causes oxidation of proteins involved in energy metabolism: a possible mechanism for antipsychotic-induced metabolic alterations. International Journal of Neuropsychopharmacology. 2008;11(8):1097-1104.
37. Miljevic C, Nikolic M, Nikolic-Kokic A, et al. Lipid status, anti-oxidant enzyme defence and haemoglobin content in the blood of long-term clozapine-treated schizophrenic patients. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2010;34(2):303-307.
38. Kalogeris T, Bao Y, Korthuis RJ. Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox biology. 2014;2:702-714.
39. Park J, Chung S, An H, et al. Haloperidol and clozapine block formation of autophagolysosomes in rat primary neurons. Neuroscience. 2012;209:64-73.
40. Stone JR, Yang S. Hydrogen peroxide: a signaling messenger. Antioxidants & redox signaling. 2006;8(3-4):243-270.
41. Zdolsek JM, Svensson I. Effect of reactive oxygen species on lysosomal membrane integrity. Virchows Archiv B. 1993;64(1):401.
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