Document Type : Short Communication
Authors
1 Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, University of Mosul
2 Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, University of Mosul, Iraq
Abstract
Cadmium is a toxic metal that affects many organ systems in the body. Medetomidine is an alpha-2 adrenoceptor agonist reported to reduce glutathione (GSH) levels in tissues. We used the effect of medetomidine to determine GSH levels and turnover rates in the brain and liver of mice acutely treated with cadmium. Female mice were treated with either saline (control) or cadmium chloride at 2 mg cadmium/5 ml saline/kg of body weight, itraperitoneally (ip), followed one hour later with medetomidine at 0.2 mg/kg of body weight, ip. Five hours after the medetomidine administration, the mice were sacrificed using terminal ether anesthesia to obtain the whole brain and liver. GSH level was determined in the homogenized brain or liver spectrophotometrically. Turnover parameters (efflux rate constant-k, turnover time, and turnover rate) of GSH were estimated by a steady state kinetic relationship. The levels of GSH after medetomidine or cadmium + medetomidine treatments were reduced in the brain (12.4% and 11.4%, respectively) and liver (3.8% and 15.1%, respectively) of mice in comparison with respective control values. Cadmium reduced GSH trunover rate in the brain of mice by 8% with a corresponding decrease in k value by 8% and an increase of 9% in the turnover time. In the liver, it increased the turnover rate by 320% with a corresponding increase in k value by 319% and a reduction of turnover time by 76%. In conclusion, cadmium differentially affected GSH levels and turnover rates in the brain and liver of mice. Medetomidine administration was found to be a potential simple tool to determine GSH turnover and related parameters in tissues.
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Main Subjects
- Genchi G, Sinicropi MS, Lauria G, Carocci A, Catalano A. The Effects of Cadmium Toxicity. Int J Environ Res Public Health. 2020;17(11):3782. doi: 10.3390/ijerph17113782.
- Karmakar R, Roy S, Chatterjee M. The effects of cadmium on the hepatic and renal levels of reduced glutathione, the activity of glutathione S-transferase and gamma glutamyl transpeptidase. J Environ Pathol Toxicol Oncol. 1999;18(1):29-35. PMID: 9951837.
- Nemmiche S. Oxidative Signaling Response to Cadmium Exposure. Toxicol Sci. 2017 Mar 1;156(1):4-10. doi: 10.1093/toxsci/kfw222.
- Kumar A, Siddiqi NJ, Alrashood ST, Khan HA, Dubey A, Sharma B. Protective effect of eugenol on hepatic inflammation and oxidative stress induced by cadmium in male rats. Biomed Pharmacother. 2021;139:111588. doi: 10.1016/j.biopha.2021.111588.
- Valverde A, Skelding AM. Alternatives to opioid analgesia in small animal anesthesia: alpha-2 agonists. Vet Clin North Am Small Anim Pract. 2019;49(6):1013-1027. doi: 10.1016/j.cvsm.2019.07.010.
- Akpınar O, Nazıroğlu M, Akpınar H. Different doses of dexmedetomidine reduce plasma cytokine production, brain oxidative injury, PARP and caspase expression levels but increase liver oxidative toxicity in cerebral ischemia-induced rats. Brain Res Bull. 2017;130:1-9. doi: 10.1016/j.brainresbull.2016.12.005.
- Harbison RD, James RC, Roberts SM. Hepatic glutathione suppression by the alpha-adrenoreceptor stimulating agents phenylephrine and clonidine. Toxicology. 1991;69(3):279-90. doi: 10.1016/0300-483x(91)90187-6.
- Pizzorno J. Glutathione! Integr Med (Encinitas). 2014;13(1):8-12. PMID: 26770075.
- Averill-Bates DA. The antioxidant glutathione. Vitam Horm. 2023;121:109-141. doi: 10.1016/bs.vh.2022.09.002.
- Gasmi A, Noor S, Piscopo S, Menzel A. Toxic metal-mediated neurodegradation: a focus on glutathione and GST gene variants. Arch Razi Inst. 2022;77(2):525-536. doi: 10.22092/ARI.2021.356279.1816.
- Ramachandran A, Jaeschke H. Acetaminophen hepatotoxicity. Semin Liver Dis. 2019;39(2):221-234. doi: 10.1055/s-0039-1679919.
- Lv H, Zhen C, Liu J, Yang P, Hu L, Shang P. Unraveling the potential role of glutathione in multiple forms of cell death in cancer therapy. Oxid Med Cell Longev. 2019;2019:3150145. doi: 10.1155/2019/3150145.
- Yakoub LK, Mohammad FK. Medetomidine protection against diazinon-induced toxicosis in mice. Toxicol Lett. 1997;93(1):1-8. doi: 10.1016/s0378-4274(97)00070-2. PMID: 9381477.
- Mohammad FK, Yakoub LK. Neurobehavioral effects of medetomidine in mice. Ind J Anim Sci. 1997;97:33-34.
- Al-Baggou’ BKAF. Neurobehavioral and biochemical changes induced by interaction between cadmium and some insecticides in mice. PhD dissertation. Mosul: University of Mosul, 2002.
- Clarkson JM, Martin JE, McKeegan DEF. A review of methods used to kill laboratory rodents: issues and opportunities. Lab Anim. 2022;56(5):419-436. doi: 10.1177/00236772221097472.
- James RC, Goodman DR, Harbison RD. Hepatic glutathione and hepatotoxicity: changes induced by selected narcotics. J Pharmacol Exp Ther. 1982;221(3):708-14. PMID: 7086683.
- Brodie BB, Costa E, Dlabac A, Neff NH, Smookler HH. Application of steady state kinetics to the estimation of synthesis rate and turnover time of tissue catecholamines. J Pharmacol Exp Ther. 1966;154(3):493-8. PMID: 5928249.
- Reid WD, Volicer L, Brodie BB. Effect of phenoxybenzamine on the turnover rate of heart norepinephrine. Biochem Pharmacol. 1969;18(1):265-8. doi: 10.1016/0006-2952(69)90038-0. PMID: 5780996.
- Branca JJV, Morucci G, Pacini A. Cadmium-induced neurotoxicity: still much ado. Neural Regen Res. 2018;13(11):1879-1882. doi: 10.4103/1673-5374.239434. PMID: 30233056.
- Swiergosz-Kowalewska R. Cadmium distribution and toxicity in tissues of small rodents. Microsc Res Tech. 2001;55(3):208-22. doi: 10.1002/jemt.1171.
- Eaton DL, Stacey NH, Wong KL, Klaassen CD. Dose-response effects of various metal ions on rat liver metallothionein, glutathione, heme oxygenase, and cytochrome P-450. Toxicol Appl Pharmacol. 1980;55(2):393-402. doi: 10.1016/0041-008x(80)90101-5.
- Greń A, Barbasz A, Kreczmer B, Sieprawska A, Rudolphi-Skórska E, Filek M. Protective effect of ascorbic acid after single and repetitive administration of cadmium in Swiss mice. Toxicol Mech Methods. 2012;22(8):597-604. doi: 10.3109/15376516.2012.704957.
- Lauterburg BH, Smith CV, Hughes H, Mitchell JR. Determinants of hepatic glutathione turnover: toxicological significance. Trends Pharmacol Sci. 1982;3:245-248. https://doi.org/10.1016/0165-6147(82)91117-8.
- Skalska J, Dąbrowska-Bouta B, Strużyńska L. Oxidative stress in rat brain but not in liver following oral administration of a low dose of nanoparticulate silver. Food Chem Toxicol. 2016;97:307-315. doi: 10.1016/j.fct.2016.09.026.
- Choudhuri S, McKim JM Jr, Klaassen CD. Differential expression of the metallothionein gene in liver and brain of mice and rats. Toxicol Appl Pharmacol. 1993;119(1):1-10. doi: 10.1006/taap.1993.1037.
- Dringen R. Metabolism and functions of glutathione in brain. Prog Neurobiol. 2000;62(6):649-671. doi: 10.1016/s0301-0082(99)00060-x.
- Moraes TB, Dalazen GR, Jacques CE, de Freitas RS, Rosa AP, Dutra-Filho CS. Glutathione metabolism enzymes in brain and liver of hyperphenylalaninemic rats and the effect of lipoic acid treatment. Metab Brain Dis. 2014;29(3):609-15. doi: 10.1007/s11011-014-9491-x.
- Tateishi N, Higashi T. Turnover of glutathione in rat liver. In Functions of glutathione in liver and kidney. Proceedings in life sciences. Eds. Sies H, Wendel A., 1978. Berlin: Springer, pp. 3-7. https://doi.org/10.1007/978-3-642-67132-6_1
- Potter DW, Tran TB. Apparent rates of glutathione turnover in rat tissues. Toxicol Appl Pharmacol. 1993;120(2):186-92. doi: 10.1006/taap.1993.1102.
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