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High-Dose Primaquine Induces Proximal Tubular Degeneration and Ventricular Cardiomyopathy Linked to Host Cells Mitochondrial Dysregulation

Primaquine (PQ) is the only antimalarial medication used to eradicate many species of Plasmodium gametocytes and prevent relapse in vivax and ovale malarias. PQ metabolites induce oxidative stress and impair parasitic mitochondria, leading to protozoal growth retardation and death. Collateral damage...

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Autores principales: Rabiablok, Atthasit, Hanboonkunupakarn, Borimas, Tuentam, Khwanchanok, Fongsodsri, Kamonpan, Kanjanapruthipong, Tapanee, Ampawong, Sumate
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9962680/
https://www.ncbi.nlm.nih.gov/pubmed/36851021
http://dx.doi.org/10.3390/toxics11020146
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author Rabiablok, Atthasit
Hanboonkunupakarn, Borimas
Tuentam, Khwanchanok
Fongsodsri, Kamonpan
Kanjanapruthipong, Tapanee
Ampawong, Sumate
author_facet Rabiablok, Atthasit
Hanboonkunupakarn, Borimas
Tuentam, Khwanchanok
Fongsodsri, Kamonpan
Kanjanapruthipong, Tapanee
Ampawong, Sumate
author_sort Rabiablok, Atthasit
collection PubMed
description Primaquine (PQ) is the only antimalarial medication used to eradicate many species of Plasmodium gametocytes and prevent relapse in vivax and ovale malarias. PQ metabolites induce oxidative stress and impair parasitic mitochondria, leading to protozoal growth retardation and death. Collateral damage is also presented in mammalian host cells, particularly erythrocytes, resulting in hemolysis and tissue destruction. However, the underlying mechanisms of these complications, particularly the mitochondria-mediated cell death of the host, are poorly understood. In the present study, toxicopathological studies were conducted on a rat model to determine the effect of PQ on affected tissues and mitochondrial toxicity. The results indicated that the LD(50) for PQ is 200 mg/kg. A high dose of PQ induced hemolytic anemia, elevated a hepatic enzyme (SGPT), and induced proximal tubular degeneration, ventricular cardiomyopathy, and mitochondrial dysregulation. In addition, PQ induced the upregulation of apoptosis-related proteins Drp-1 and caspase-3, with a positive correlation, as well as the pro-apoptotic mitochondrial gene expression of Bax, reflecting the toxic effect of high doses of PQ on cellular damage and mitochondrial apoptosis in terms of hepatotoxicity, nephrotoxicity, and cardiotoxicity. Regarding the risk/benefit ratio of drug administration, our research provides caution for the use of PQ in the treatment of malaria based on its toxicopathological effects.
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spelling pubmed-99626802023-02-26 High-Dose Primaquine Induces Proximal Tubular Degeneration and Ventricular Cardiomyopathy Linked to Host Cells Mitochondrial Dysregulation Rabiablok, Atthasit Hanboonkunupakarn, Borimas Tuentam, Khwanchanok Fongsodsri, Kamonpan Kanjanapruthipong, Tapanee Ampawong, Sumate Toxics Article Primaquine (PQ) is the only antimalarial medication used to eradicate many species of Plasmodium gametocytes and prevent relapse in vivax and ovale malarias. PQ metabolites induce oxidative stress and impair parasitic mitochondria, leading to protozoal growth retardation and death. Collateral damage is also presented in mammalian host cells, particularly erythrocytes, resulting in hemolysis and tissue destruction. However, the underlying mechanisms of these complications, particularly the mitochondria-mediated cell death of the host, are poorly understood. In the present study, toxicopathological studies were conducted on a rat model to determine the effect of PQ on affected tissues and mitochondrial toxicity. The results indicated that the LD(50) for PQ is 200 mg/kg. A high dose of PQ induced hemolytic anemia, elevated a hepatic enzyme (SGPT), and induced proximal tubular degeneration, ventricular cardiomyopathy, and mitochondrial dysregulation. In addition, PQ induced the upregulation of apoptosis-related proteins Drp-1 and caspase-3, with a positive correlation, as well as the pro-apoptotic mitochondrial gene expression of Bax, reflecting the toxic effect of high doses of PQ on cellular damage and mitochondrial apoptosis in terms of hepatotoxicity, nephrotoxicity, and cardiotoxicity. Regarding the risk/benefit ratio of drug administration, our research provides caution for the use of PQ in the treatment of malaria based on its toxicopathological effects. MDPI 2023-02-02 /pmc/articles/PMC9962680/ /pubmed/36851021 http://dx.doi.org/10.3390/toxics11020146 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rabiablok, Atthasit
Hanboonkunupakarn, Borimas
Tuentam, Khwanchanok
Fongsodsri, Kamonpan
Kanjanapruthipong, Tapanee
Ampawong, Sumate
High-Dose Primaquine Induces Proximal Tubular Degeneration and Ventricular Cardiomyopathy Linked to Host Cells Mitochondrial Dysregulation
title High-Dose Primaquine Induces Proximal Tubular Degeneration and Ventricular Cardiomyopathy Linked to Host Cells Mitochondrial Dysregulation
title_full High-Dose Primaquine Induces Proximal Tubular Degeneration and Ventricular Cardiomyopathy Linked to Host Cells Mitochondrial Dysregulation
title_fullStr High-Dose Primaquine Induces Proximal Tubular Degeneration and Ventricular Cardiomyopathy Linked to Host Cells Mitochondrial Dysregulation
title_full_unstemmed High-Dose Primaquine Induces Proximal Tubular Degeneration and Ventricular Cardiomyopathy Linked to Host Cells Mitochondrial Dysregulation
title_short High-Dose Primaquine Induces Proximal Tubular Degeneration and Ventricular Cardiomyopathy Linked to Host Cells Mitochondrial Dysregulation
title_sort high-dose primaquine induces proximal tubular degeneration and ventricular cardiomyopathy linked to host cells mitochondrial dysregulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9962680/
https://www.ncbi.nlm.nih.gov/pubmed/36851021
http://dx.doi.org/10.3390/toxics11020146
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