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Front. Mol. Biosci.
Sec. Metabolomics
Volume 11 - 2024 | doi: 10.3389/fmolb.2024.1338497

Metabolomics highlights biochemical perturbations occurring in kidney and liver of mice administered with human dose of colistin Provisionally Accepted

 Ioanna Barla1 Ioanna V. Dagla2 Aikaterini M. Daskalopoulou3 Maria Panagiotopoulou3 Maria Kritikaki3 Panagiotis Dalezis4  Nikolaos S. Thomaidis1 Antony Tsarbopoulos4 Dimitrios Trafalis4  Evagelos Gikas1*
  • 1Laboratory of Analytical Chemistry, School of Science, Department of Chemistry, National and Kapodistrian University of Athens, Greece
  • 2GAIA Research Center, The Goulandris Natural History Museum, Greece
  • 3Laboratory of Pharmaceutical Analysis, School of Health Science, Department of Pharmacy, National and Kapodistrian University of Athens, Greece
  • 4Laboratory of Pharmacology, School of Medicine, National and Kapodistrian University of Athens, Greece

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Colistin (CMS) is used for the curation of infections caused by multidrug-resistant bacteria. CMS is constrained by toxicity, particularly in kidney and neuronal cells. The recommended human doses are 2.5-5 mg/kg/day, and the toxicity is linked to higher doses. So far, the in vivo toxicity studies have used doses even 10-fold higher than human doses. It is essential to investigate the impact of metabolic response of doses, that are comparable to human doses, to identify biomarkers of latent toxicity. The innovation of the current study is the in vivo CMS impact using a range of CMS doses that have never been investigated before, i.e., 1 mg/kg and 1.5 mg/kg. The 1 mg/kg and 1.5 mg/kg, administered in mice, correspond to the therapeutic and toxic human doses, based on previous expertise of our team, regarding the human exposure. The study mainly focused on the biochemical impact of CMS on the metabolome, and on the alterations provoked by 50%-fold of dose increase. The main objectives were (i) the comprehension of the biochemical changes resulting after CMS administration and (ii) from its dose increase; and (iii) the determination of dose-related metabolites that could be considered as toxicity monitoring biomarkers. The in vivo experiment employed two doses of CMS versus a control group treated with normal saline, and samples of plasma, kidney, and liver were analyzed with a UPLC-MS-based metabolomics protocol. Both univariate and multivariate statistical approaches (PCA, OPLS-DA, PLS regression, ROC) and pathway analysis were combined for the data interpretation. The results pointed out six dose-responding metabolites (PAA, DA4S, 2,8-DHA, etc.), dysregulation of renal dopamine , and extended perturbations in renal purine metabolism. Also, the study determined altered levels of liver suberylglycine, a metabolite linked to hepatic steatosis. One of the most intriguing findings was detection of elevated levels of renal xanthine and uric acid, that act as AChE activators, leading to the rapid degradation of acetylcholine. This evidence provides a naïve hypothesis, for the potential association between the CMS induced nephrotoxicity and CMS induced neurotoxicity, that should be further investigated.

Keywords: Metabolomics, Colistin, Drug-toxicity, pathway analysis, dopamine-metabolism, purine-metabolism

Received: 14 Nov 2023; Accepted: 23 May 2024.

Copyright: © 2024 Barla, Dagla, Daskalopoulou, Panagiotopoulou, Kritikaki, Dalezis, Thomaidis, Tsarbopoulos, Trafalis and Gikas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Evagelos Gikas, Laboratory of Analytical Chemistry, School of Science, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece