Is Dexmedetomidine Toxic on Kidney Cells (Hek-293)? Effects on Cytotoxicity, Reactive Oxygen Species (ROS) and Apoptosis
Abstract
Aim: Dexmedetomidine; it is widely used in anesthesia and intensive care. We aimed to examine and compare the cytotoxic, reactive oxygen species (ROS) and apoptotic effects of dexmedetomidine on kidney cells (Hek-293) in vitro at two different high and cumulative doses.
Material and Methods: The half-maximum inhibitory concentration (IC50) dose of dexmedetomidine on Hek-293 cells was determined using the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide (MTT) method. Then at two different doses of the drug; apoptotic effects were determined by Annexin-V Method, morphological examinations were determined by Acridine Orange Ethidium Bromide Method and intracellular ROS levels were determined by flow cytometry.
Results: The IC50 value of dexmedetomidine for Hek-293 cells was determined as 64.6559 μg/mL. Compared with the control group, doses of 50 and 100 µg/mL of dexmedetomidine tended to show cytotoxicity (p<0.05). dexmedetomidine was found to have a lower cytotoxic effect at a dose of 50 μg / mL than at a dose of 100 μg / mL (p<0.05).
Conclusion: In the study, it was determined that dexmedetomidine increased intracellular ROS more than clinical doses at two different concentrations on Hek-293 cells, cytotoxic doses caused an increase in ROS in cells and induced apoptosis. We think that the toxic effects of dexmedetomidine can be prevented with the data obtained from this study and further studies.
Keywords
Anesthesia apoptosis cytotoxicity dexmedetomidine human kidney cells (Hek-293) reactive oxygen species (ROS)
Supporting Institution
Harran University Scientific Research Projects Unit (HUBAK)
Project Number
19342
Thanks
The authors would like to express their sincere gratitude to the staff of Harran University Faculty of Medicine, Department of Biochemistry Laboratory and Hamza Erdoğdu for their support.
References
- Carollo DS, Nossaman BD, Ramadhyani U.Dexmedetomidine: a review of clinical applications.Curr Opin Anaesthesiol. 2008;21:457–61.
- Canakcı E, Karatas A, Coskun I, et al. Investigationof the nephroprotective effect of dexmedetomidineon colistin-induced nephrotoxicity in rats. BratislavaMed J. 2022;123:579–84.
- Wunsch H, Kahn JM, Kramer AA, et al.Dexmedetomidine in the Care of Critically IllPatients from 2001 to 2007. Anesthesiology.2010;113:386–94.
- Bae HB. Dexmedetomidine: an attractive adjunct toanesthesia. Korean J Anesthesiol. 2017;70:375.
- Liu X, Li T, Cao L, et al. Dexmedetomidineattenuates H2O2-induced neonatal ratcardiomyocytes apoptosis through mitochondria- and ER-medicated oxidative stress pathways. MolMed Rep. 2018.
- Yu X, Chi X, Wu S, et al. DexmedetomidinePretreatment Attenuates Kidney Injury andOxidative Stress during Orthotopic AutologousLiver Transplantation in Rats. Oxid Med CellLongev. 2016;2016:1–10.
- Tang C, Hu Y, Gao J, et al. Dexmedetomidinepretreatment attenuates myocardial ischemiareperfusion induced acute kidney injury andendoplasmic reticulum stress in human and rat. LifeSci. 2020;257:118004.
- Wu HH, Wang HT, Jin JJ, et al. DoesDexmedetomidine as a Neuraxial AdjuvantFacilitate Better Anesthesia and Analgesia? ASystematic Review and Meta-Analysis. PLoS One. 2014;9:e93114.
- Yuen VM, Irwin MG, Hui TW, et al. A Double-Blind, Crossover Assessment of the Sedative andAnalgesic Effects of Intranasal Dexmedetomidine.Anesth Analg. 2007;105:374–80.
- Billings FT, Chen SWC, Kim M, et al. α 2 -Adrenergic agonists protect against radiocontrast-induced nephropathy in mice. Am J Physiol Physiol.2008;295:741–8.
- Cho JS, Shim JK, Soh S, et al. Perioperativedexmedetomidine reduces the incidence and severityof acute kidney injury following valvular heartsurgery. Kidney Int. 2016;89:693–700.
- Koca U, Olguner ÇG, Ergür BU, et al. The Effects ofDexmedetomidine on Secondary Acute Lung andKidney Injuries in the Rat Model of Intra-AbdominalSepsis. Sci World J. 2013;2013:1–11.
- Armstrong R, Riaz S, Hasan S, et al. Mechanisms ofAnesthetic Action and Neurotoxicity: Lessons fromMolluscs. Front Physiol. 2017.01138.
- Perazella MA. Pharmacology behind Common DrugNephrotoxicities. Clin J Am Soc Nephrol. 2018;13:1897–908. Aleksa K, Matsell D, Krausz K, et al. CytochromeP450 3A and 2B6 in the developing kidney:implications for ifosfamide nephrotoxicity. PediatrNephrol. 2005;20:872–85.
- Fanos V, Cataldi L. Renal Transport of Antibioticsand Nephrotoxicity: a Review. J Chemother. 2001;13:461–72.
- Jang KJ, Mehr AP, Hamilton GA, et al. Humankidney proximal tubule-on-a-chip for drug transportand nephrotoxicity assessment. Integr Biol. 2013;5:1119–29.
- Mukai M, Tanaka S, Yamamoto K, et al. In vitroglucuronidation of propofol in microsomal fractionsfrom human liver, intestine and kidney: tissuedistribution and physiological role of UGT1A9. Pharmazie. 2014;69:829–32.
- Abarikwu SO, Simple G, Onuoha SC, et al.Evaluation of the protective effects of quercetin andgallic acid against oxidative toxicity in rat’s kidneyand HEK-293 cells. Toxicol Reports. 2020;7:955–62.
- Wang H, Li D, Hu Z, et al. Protective Effects ofGreen Tea Polyphenol Against Renal Injury ThroughROS-Mediated JNK-MAPK Pathway in LeadExposed Rats. Mol Cells. 2016;39:508–13.
- Pontén E, Viberg H, Gordh T, et al. Clonidineabolishes the adverse effects on apoptosis andbehaviour after neonatal ketamine exposure in mice.Acta Anaesthesiol Scand. 2012;56:1058–65.
- Hwang L, Cho IY, Kim SE, et al. Dexmedetomidine ameliorates intracerebral hemorrhage-induced memory impairment by inhibiting apoptosis and enhancing brain-derived neurotrophic factor expression in the rat hippocampus. Int J Mol Med. 2013;31:1047–56.
- Tang C, Huang X, Kang F, et al. Intranasal Dexmedetomidine on Stress Hormones, Inflammatory Markers, and Postoperative Analgesia after Functional Endoscopic Sinus Surgery. Mediators Inflamm. 2015;2015:1–9.
- Wei Q, Chen J, Xiao F, et al. High-Dose Dexmedetomidine Promotes Apoptosis in Fetal Rat Hippocampal Neurons. Drug Des Devel Ther. 2021;15:2433–44.
- Shehabi Y, Serpa Neto A, Howe BD, et al. Early sedation with dexmedetomidine in ventilated critically ill patients and heterogeneity of treatment effect in the SPICE III randomised controlled trial. Intensive Care Med. 2021;47:455–66.
- Pérez-Lara JL, Santana Y, Hernández-Torres J, Díaz-Fuentes G. Acute Colonic Pseudo-Obstruction Caused by Dexmedetomidine: A Case Report and Literature Review. Am J Case Rep. 2019;20:278–84.
- Nath S, Singh S, Pawar S. Dexmedetomidine overdosage: An unusual presentation. Indian J Anaesth. 2013;57:289.
- Liu JR, Yuki K, Baek C, et al. Dexmedetomidine-Induced Neuroapoptosis Is Dependent on Its Cumulative Dose. Anesth Analg. 2016;123:1008–17.
- Wang Z, Wu J, Hu Z, et al. Dexmedetomidine Alleviates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting p75NTR-Mediated Oxidative Stress and Apoptosis. Oxid Med Cell Longev. 2020;2020:1–13.
- Lavon H, Matzner P, Benbenishty A, et al. Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers. Br J Anaesth. 2018;120:188–96.
- Bao N, Tang B. Organ-Protective Effects and the Underlying Mechanism of Dexmedetomidine. Mediators Inflamm. 2020;2020:1–11.
- Song L, Shi S, Jiang W, et al. Protective role of propofol on the kidney during early unilateral ureteral obstruction through inhibition of epithelial-mesenchymal transition. Am J Transl Res. 2016;8:460–72.
- Ning Q, Liu Z, Wang X, et al. Neurodegenerative changes and neuroapoptosis induced by systemic lipopolysaccharide administration are reversed by dexmedetomidine treatment in mice. Neurol Res. 2017;39:357–66.
- Weng X, Zhang X, Lu X, et al. Reduced mitochondrial response sensitivity is involved in the anti apoptotic effect of dexmedetomidine pretreatment in cardiomyocytes. Int J Mol Med. 2018.
- Park JH, Ko IG, Kim SE, et al. Dexmedetomidine Oral Mucosa Patch for Sedation Suppresses Apoptosis in Hippocampus of Normal Rats. Int Neurourol J. 2017;21:S39-47.
- Chen Y, Feng X, Hu X, et al. Dexmedetomidine Ameliorates Acute Stress-Induced Kidney Injury by Attenuating Oxidative Stress and Apoptosis through Inhibition of the ROS/JNK Signaling Pathway. Oxid Med Cell Longev. 2018;2018:1–12.
- Hancı V, Yurdakan G, Yurtlu S, et al. Protective effect of dexmedetomidine in a rat model of α-naphthylthiourea–induced acute lung injury. J Surg Res. 2012;178:424–30.
- Lai YC, Tsai PS, Huang CJ. Effects of Dexmedetomidine on Regulating Endotoxin-Induced Up-Regulation of Inflammatory Molecules in Murine Macrophages. J Surg Res. 2009;154:212–9.
- Zhu S, Lu Y. Dexmedetomidine Suppressed the Biological Behavior of HK-2 Cells Treated with LPS by Down-Regulating ALKBH5. Inflammation. 2020;43:2256–63.
- Senoner T, Velik-Salchner C, Luckner G, Tauber H. Anesthesia-Induced Oxidative Stress: Are There Differences between Intravenous and Inhaled Anesthetics? Oxid Med Cell Longev. 2021;2021:1–11.
Deksmedetomidin Böbrek Hücreleri (Hek-293) Üzerinde Toksik midir ? Sitotoksisite, Reaktif Oksijen Türleri (ROS) ve Apoptoz Üzerine Etkileri
Abstract
Amaç: Deksmedetomidin; Anestezi ve yoğun bakımda yaygın olarak kullanılmaktadır. Amacımız Deksmedetomidinin böbrek hücreleri (Hek-293) üzerindeki sitotoksik, reaktif oksijen türleri (ROS) ve apoptotik etkilerini in vitro olarak iki farklı yüksek ve kümülatif dozda incelemek ve karşılaştırmak.
Gereç ve Yöntemler: Deksmedetomidinin Hek-293 hücreleri üzerindeki yarı maksimum inhibitör konsantrasyonu (IC50) dozu, 3-[4,5-dimetiltiazol-2il]-2,5-difeniltetrazolyum bromür (MTT) yöntemi kullanılarak belirlendi. Daha sonra ilacın iki farklı dozunda; apoptotik etkiler Annexin-V Yöntemi ile, morfolojik incelemeler Akridin Turuncu Ethidyum Bromür Yöntemi ile ve hücre içi reaktif oksijen türleri (ROS) seviyeleri akış sitometrisi ile belirlendi.
Bulgular: Deksmedetomidinin Hek-293 hücreleri için IC50 değeri 64,6559 μg/mL olarak belirlendi. Kontrol grubuyla karşılaştırıldığında, 50 ve 100 µg/mL deksmedetomidinin dozları sitotoksisite gösterme eğilimindeydi (p<0.05). deksmedetomidinin 50 μg/mL dozunda 100 μg/mL dozuna göre daha düşük sitotoksik etkiye sahip olduğu bulundu (p<0,05).
Sonuç: Bu çalışmada Hek-293 hücreleri üzerinde deksmedetomidin; İki farklı konsantrasyonda hücre içi ROS'u klinik dozlardan daha fazla artırarak toksik etkilere sahip olduğu bulunmuştur. Sitotoksik dozların hücrelerde ROS artışına neden olduğu ve apoptozu indüklediği belirlendi. Bu çalışmalardan elde edilen değerler ve ileride yapılacak çalışmaların sonuçları incelenerek bu ilaçların toksik etkilerinin önlenebileceği kanaatindeyiz.
Keywords
Anestezi Apoptozis Sitotoksite Dexmedetomidine İnsan Böbrek Epitel Hücreleri (Hek-293) Reaktif Oksijen Türleri (ROS)
Project Number
19342
References
- Carollo DS, Nossaman BD, Ramadhyani U.Dexmedetomidine: a review of clinical applications.Curr Opin Anaesthesiol. 2008;21:457–61.
- Canakcı E, Karatas A, Coskun I, et al. Investigationof the nephroprotective effect of dexmedetomidineon colistin-induced nephrotoxicity in rats. BratislavaMed J. 2022;123:579–84.
- Wunsch H, Kahn JM, Kramer AA, et al.Dexmedetomidine in the Care of Critically IllPatients from 2001 to 2007. Anesthesiology.2010;113:386–94.
- Bae HB. Dexmedetomidine: an attractive adjunct toanesthesia. Korean J Anesthesiol. 2017;70:375.
- Liu X, Li T, Cao L, et al. Dexmedetomidineattenuates H2O2-induced neonatal ratcardiomyocytes apoptosis through mitochondria- and ER-medicated oxidative stress pathways. MolMed Rep. 2018.
- Yu X, Chi X, Wu S, et al. DexmedetomidinePretreatment Attenuates Kidney Injury andOxidative Stress during Orthotopic AutologousLiver Transplantation in Rats. Oxid Med CellLongev. 2016;2016:1–10.
- Tang C, Hu Y, Gao J, et al. Dexmedetomidinepretreatment attenuates myocardial ischemiareperfusion induced acute kidney injury andendoplasmic reticulum stress in human and rat. LifeSci. 2020;257:118004.
- Wu HH, Wang HT, Jin JJ, et al. DoesDexmedetomidine as a Neuraxial AdjuvantFacilitate Better Anesthesia and Analgesia? ASystematic Review and Meta-Analysis. PLoS One. 2014;9:e93114.
- Yuen VM, Irwin MG, Hui TW, et al. A Double-Blind, Crossover Assessment of the Sedative andAnalgesic Effects of Intranasal Dexmedetomidine.Anesth Analg. 2007;105:374–80.
- Billings FT, Chen SWC, Kim M, et al. α 2 -Adrenergic agonists protect against radiocontrast-induced nephropathy in mice. Am J Physiol Physiol.2008;295:741–8.
- Cho JS, Shim JK, Soh S, et al. Perioperativedexmedetomidine reduces the incidence and severityof acute kidney injury following valvular heartsurgery. Kidney Int. 2016;89:693–700.
- Koca U, Olguner ÇG, Ergür BU, et al. The Effects ofDexmedetomidine on Secondary Acute Lung andKidney Injuries in the Rat Model of Intra-AbdominalSepsis. Sci World J. 2013;2013:1–11.
- Armstrong R, Riaz S, Hasan S, et al. Mechanisms ofAnesthetic Action and Neurotoxicity: Lessons fromMolluscs. Front Physiol. 2017.01138.
- Perazella MA. Pharmacology behind Common DrugNephrotoxicities. Clin J Am Soc Nephrol. 2018;13:1897–908. Aleksa K, Matsell D, Krausz K, et al. CytochromeP450 3A and 2B6 in the developing kidney:implications for ifosfamide nephrotoxicity. PediatrNephrol. 2005;20:872–85.
- Fanos V, Cataldi L. Renal Transport of Antibioticsand Nephrotoxicity: a Review. J Chemother. 2001;13:461–72.
- Jang KJ, Mehr AP, Hamilton GA, et al. Humankidney proximal tubule-on-a-chip for drug transportand nephrotoxicity assessment. Integr Biol. 2013;5:1119–29.
- Mukai M, Tanaka S, Yamamoto K, et al. In vitroglucuronidation of propofol in microsomal fractionsfrom human liver, intestine and kidney: tissuedistribution and physiological role of UGT1A9. Pharmazie. 2014;69:829–32.
- Abarikwu SO, Simple G, Onuoha SC, et al.Evaluation of the protective effects of quercetin andgallic acid against oxidative toxicity in rat’s kidneyand HEK-293 cells. Toxicol Reports. 2020;7:955–62.
- Wang H, Li D, Hu Z, et al. Protective Effects ofGreen Tea Polyphenol Against Renal Injury ThroughROS-Mediated JNK-MAPK Pathway in LeadExposed Rats. Mol Cells. 2016;39:508–13.
- Pontén E, Viberg H, Gordh T, et al. Clonidineabolishes the adverse effects on apoptosis andbehaviour after neonatal ketamine exposure in mice.Acta Anaesthesiol Scand. 2012;56:1058–65.
- Hwang L, Cho IY, Kim SE, et al. Dexmedetomidine ameliorates intracerebral hemorrhage-induced memory impairment by inhibiting apoptosis and enhancing brain-derived neurotrophic factor expression in the rat hippocampus. Int J Mol Med. 2013;31:1047–56.
- Tang C, Huang X, Kang F, et al. Intranasal Dexmedetomidine on Stress Hormones, Inflammatory Markers, and Postoperative Analgesia after Functional Endoscopic Sinus Surgery. Mediators Inflamm. 2015;2015:1–9.
- Wei Q, Chen J, Xiao F, et al. High-Dose Dexmedetomidine Promotes Apoptosis in Fetal Rat Hippocampal Neurons. Drug Des Devel Ther. 2021;15:2433–44.
- Shehabi Y, Serpa Neto A, Howe BD, et al. Early sedation with dexmedetomidine in ventilated critically ill patients and heterogeneity of treatment effect in the SPICE III randomised controlled trial. Intensive Care Med. 2021;47:455–66.
- Pérez-Lara JL, Santana Y, Hernández-Torres J, Díaz-Fuentes G. Acute Colonic Pseudo-Obstruction Caused by Dexmedetomidine: A Case Report and Literature Review. Am J Case Rep. 2019;20:278–84.
- Nath S, Singh S, Pawar S. Dexmedetomidine overdosage: An unusual presentation. Indian J Anaesth. 2013;57:289.
- Liu JR, Yuki K, Baek C, et al. Dexmedetomidine-Induced Neuroapoptosis Is Dependent on Its Cumulative Dose. Anesth Analg. 2016;123:1008–17.
- Wang Z, Wu J, Hu Z, et al. Dexmedetomidine Alleviates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting p75NTR-Mediated Oxidative Stress and Apoptosis. Oxid Med Cell Longev. 2020;2020:1–13.
- Lavon H, Matzner P, Benbenishty A, et al. Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers. Br J Anaesth. 2018;120:188–96.
- Bao N, Tang B. Organ-Protective Effects and the Underlying Mechanism of Dexmedetomidine. Mediators Inflamm. 2020;2020:1–11.
- Song L, Shi S, Jiang W, et al. Protective role of propofol on the kidney during early unilateral ureteral obstruction through inhibition of epithelial-mesenchymal transition. Am J Transl Res. 2016;8:460–72.
- Ning Q, Liu Z, Wang X, et al. Neurodegenerative changes and neuroapoptosis induced by systemic lipopolysaccharide administration are reversed by dexmedetomidine treatment in mice. Neurol Res. 2017;39:357–66.
- Weng X, Zhang X, Lu X, et al. Reduced mitochondrial response sensitivity is involved in the anti apoptotic effect of dexmedetomidine pretreatment in cardiomyocytes. Int J Mol Med. 2018.
- Park JH, Ko IG, Kim SE, et al. Dexmedetomidine Oral Mucosa Patch for Sedation Suppresses Apoptosis in Hippocampus of Normal Rats. Int Neurourol J. 2017;21:S39-47.
- Chen Y, Feng X, Hu X, et al. Dexmedetomidine Ameliorates Acute Stress-Induced Kidney Injury by Attenuating Oxidative Stress and Apoptosis through Inhibition of the ROS/JNK Signaling Pathway. Oxid Med Cell Longev. 2018;2018:1–12.
- Hancı V, Yurdakan G, Yurtlu S, et al. Protective effect of dexmedetomidine in a rat model of α-naphthylthiourea–induced acute lung injury. J Surg Res. 2012;178:424–30.
- Lai YC, Tsai PS, Huang CJ. Effects of Dexmedetomidine on Regulating Endotoxin-Induced Up-Regulation of Inflammatory Molecules in Murine Macrophages. J Surg Res. 2009;154:212–9.
- Zhu S, Lu Y. Dexmedetomidine Suppressed the Biological Behavior of HK-2 Cells Treated with LPS by Down-Regulating ALKBH5. Inflammation. 2020;43:2256–63.
- Senoner T, Velik-Salchner C, Luckner G, Tauber H. Anesthesia-Induced Oxidative Stress: Are There Differences between Intravenous and Inhaled Anesthetics? Oxid Med Cell Longev. 2021;2021:1–11.
Details
| Primary Language | English |
|---|---|
| Subjects | Surgery |
| Journal Section | Original Articles |
| Authors | |
| Project Number | 19342 |
| Early Pub Date | May 15, 2023 |
| Publication Date | May 15, 2023 |
| Acceptance Date | March 29, 2023 |
| Published in Issue | Year 2023 Volume: 5 Issue: 2 |
Chief Editors
Assoc. Prof. Zülal Öner
Address: İzmir Bakırçay University, Department of Anatomy, İzmir, Türkiye
Assoc. Prof. Deniz Şenol
Address: Düzce University, Department of Anatomy, Düzce, Türkiye
E-mail: medrecsjournal@gmail.com
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Medical Records Association (Tıbbi Kayıtlar Derneği)
Address: Düzce / Türkiye
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