Effect of Glutathione on Pyruvate Levels in Colistin-Induced Nephropathy in Rats
DOI:
https://doi.org/10.57125/FEM.2026.06.30.03Abstract
Colistin (polymyxin E) is a last-line antibiotic widely used for the treatment of multidrug-resistant Gram-negative infections; however, its clinical application is limited by severe nephrotoxicity. Accumulating evidence suggests that colistin-induced renal injury is closely associated with mitochondrial dysfunction and oxidative stress. Pyruvate, a key intermediate of glycolysis and mitochondrial energy metabolism, may serve as a sensitive marker of impaired mitochondrial function due to its dependence on the activity of the pyruvate dehydrogenase complex (PDH). Glutathione (GSH), the principal intracellular antioxidant, plays a crucial role in maintaining redox homeostasis and mitochondrial integrity.
The aim of this study was to evaluate plasma pyruvate levels as a metabolic marker of nephrotoxicity and to assess the effect of glutathione administration on pyruvate metabolism in a rat model of colistin-induced nephropathy. Nephropathy was induced by daily intravenous administration of colistin at a dose of 15 mg/kg for seven days. Rats were divided into five experimental groups: colistin alone, colistin combined with GSH (100 mg/kg), control, colistin with saline, and colistin followed by prolonged GSH treatment. Plasma pyruvate concentration was determined spectrophotometrically using a dinitrophenylhydrazine-based colorimetric method.
Colistin administration resulted in a significant increase in plasma pyruvate levels compared with controls, indicating impaired mitochondrial utilization of pyruvate. In contrast, glutathione treatment markedly reduced pyruvate concentrations, restoring them toward physiological values. These findings suggest that colistin disrupts pyruvate metabolism, likely through inhibition of PDH activity caused by oxidative stress and mitochondrial dysfunction. Glutathione supplementation appears to counteract these effects by preserving mitochondrial function and redox regulation of PDH.
In conclusion, plasma pyruvate may serve as a useful metabolic marker of colistin-induced nephropathy, while glutathione demonstrates a protective effect against metabolic and mitochondrial disturbances associated with colistin toxicity.
References
Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, et al. Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative infections. Lancet Infect Dis. 2006;6(9):589–601. doi:10.1016/S1473-3099(06)70580-1
Falagas ME, Kasiakou SK. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care. 2006;10(1):R27. doi:10.1186/cc3995
Nation RL, Velkov T, Li J. Polymyxins and nephrotoxicity. Clin Infect Dis. 2014;59(Suppl 7):S649–S655. doi:10.1093/cid/ciu264
Dalfino L, Puntillo F, Mosca A, Monno R, Spada ML, Coppolecchia S, et al. High-dose, extended-interval colistin administration in critically ill patients: is this the right dosing strategy? Clin Infect Dis. 2012;54(12):1720–1726. doi:10.1093/cid/cis286
Dai C, Li J, Tang S, Li J, Xiao X. Colistin-induced nephrotoxicity in mice involves the mitochondrial, death receptor and endoplasmic reticulum stress pathways. Antimicrob Agents Chemother. 2014;58(7):4075–4085. doi:10.1128/AAC.00070-14
Mahmoud MA, Alharbi M. Molecular mechanisms attributed to colistin renal proximal tubular epithelial cytotoxicity. Toxicol Appl Pharmacol. 2025;33:45. doi:10.1007/s44446-025-00049-9
Forman HJ, Zhang H. Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med. 2009;30(1-2):1–12. doi:10.1016/j.mam.2008.08.006
Mari M, Morales A, Colell A, García-Ruiz C, Fernández-Checa JC. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal. 2009;11(11):2685–2700. doi:10.1089/ars.2009.2695
Hall AM, Unwin RJ. The not so 'mighty chondrion': kidney disease and mitochondrial dysfunction. Nephron Physiol. 2007;105(1):1–10. doi:10.1159/000096860
Patel MS, Korotchkina LG. Regulation of the pyruvate dehydrogenase complex. Biochem Soc Trans. 2006;34(Pt 2):217–222. doi:10.1042/BST0340217
Adeva-Andany MM, Pérez-Felpete N, Fernández-Fernández C, Donapetry-García C, Pazos-García C. Liver glucose metabolism in humans. Biosci Rep. 2016;36(6):e00416. doi:10.1042/BSR20160385
Roche TE, Hiromasa Y. Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci. 2007;64(7-8):830–849. doi:10.1007/s00018-007-6380-z
Mailloux RJ, Jin X, Willmore WG. Redox regulation of mitochondrial function with emphasis on cysteine oxidation reactions. Redox Biol. 2013;2:123–139. doi:10.1016/j.redox.2013.12.011
Pedraza-Chaverri J, Maldonado PD, Medina-Campos ON. Garlic ameliorates gentamicin nephrotoxicity: relation to antioxidant enzymes. Free Radic Biol Med. 2000;29(7):602–611. doi:10.1016/s0891-5849(00)00354-3
Stacpoole PW. The pyruvate dehydrogenase complex as a therapeutic target for age-related diseases. Aging Cell. 2012;11(3):371–377. doi:10.1111/j.1474-9726.2012.00805.x
Grégoire N, Aranzana-Climent V, Magréault S, Marchand S, Couet W. Clinical pharmacokinetics and pharmacodynamics of colistin. Clin Pharmacokinet. 2017;56(12):1441–1460. doi:10.1007/s40262-017-0561-1
Friedemann TE, Haugen GE. Pyruvic acid: II. The determination of keto acids in blood and urine by 2,4-dinitrophenylhydrazine and organic solvent extraction. J Biol Chem. 1943;147:415–442.
Velkov T, Roberts KD, Nation RL, Thompson PE, Li J. Pharmacology of polymyxins: new insights into an old class of antibiotics. Future Microbiol. 2013;8(6):711–724. doi:10.2217/fmb.13.39
Ozkan G, Ulusoy S, Orem A, Alkanat M, Mungan S, Yulug E, et al. How does colistin-induced nephrotoxicity develop and can it be treated? Antimicrob Agents Chemother. 2013;57(8):3463–3469. doi:10.1128/AAC.00343-13
Jeoung NH, Harris RA. Role of pyruvate dehydrogenase kinase 4 in regulation of blood glucose levels. Korean Diabetes J. 2010;34(5):274–283. doi:10.4093/kdj.2010.34.5.274
Andersen LW, Mackenhauer J, Roberts JC, Berg KM, Cocchi MN, Donnino MW. Etiology and therapeutic approach to elevated lactate. Mayo Clin Proc. 2013;88(10):1127–1140. doi:10.1016/j.mayocp.2013.06.012
Ruiz-Andres O, Suarez-Alvarez B, Sanchez-Niño MD, Ruiz-Ortega M, Egido J, Ortiz A, et al. The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury. Kidney Int. 2016;89(2):399–410. doi:10.1038/ki.2015.332
Szibor M, Holtz J. Mitochondrial ageing. Redox control of mitochondrial function. Antioxid Redox Signal. 2001;3(3):515–523. doi:10.1089/15230860152409149
Kirby DM, Thorburn DR, Turnbull DM, Taylor RW. Biochemical assays of respiratory chain complex activity. Methods Cell Biol. 2007;80:93–119. doi:10.1016/S0091-679X(06)80004-X
Fisher-Wellman KH, Neufer PD. Linking mitochondrial bioenergetics to insulin resistance via redox biology. Trends Endocrinol Metab. 2012;23(3):142–153. doi:10.1016/j.tem.2011.12.008
Stacpoole PW, Henderson GN, Yan Z, James MO. Clinical pharmacology and toxicology of dichloroacetate. Environ Health Perspect. 1998;106(Suppl 4):989–994. doi:10.1289/ehp.98106s4989
Dai C, Tang S, Velkov T, Xiao X. Lycopene attenuates colistin-induced nephrotoxicity in mice via activation of the Nrf2/HO-1 pathway. Antimicrob Agents Chemother. 2015;59(1):579–585. doi:10.1128/AAC.03925-14
Yousef JM, Chen G, Hill PA, Nation RL, Li J. Melatonin attenuates colistin-induced nephrotoxicity in rats. Antimicrob Agents Chemother. 2011;55(9):4044–4049. doi:10.1128/AAC.00328-11
Samsami M, Shabani M. The effects of vitamin E on colistin-induced nephrotoxicity in treatment of drug-resistant gram-negative bacterial infections: a randomized clinical trial. J Infect Chemother. 2021;27(8):1181–1185. doi:10.1016/j.jiac.2021.03.013
Gai Z, Samodelov SL, Kullak-Ublick GA, Visentin M. Molecular mechanisms of colistin-induced nephrotoxicity. Molecules. 2019;24(3):653. doi:10.3390/molecules24030653
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 authors
This work is licensed under a Creative Commons Attribution 4.0 International License.
