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Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses

Although Plasmodium vivax relapses are classically associated with hypnozoite activation, it has been proposed that a proportion of these cases are due to primaquine (PQ) treatment failure caused by polymorphisms in cytochrome P-450 2D6 (CYP2D6). Here, we present evidence that CYP2D6 polymorphisms a...

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Autores principales: Silvino, Ana Carolina Rios, Costa, Gabriel Luiz, de Araújo, Flávia Carolina Faustino, Ascher, David Benjamin, Pires, Douglas Eduardo Valente, Fontes, Cor Jesus Fernandes, Carvalho, Luzia Helena, de Brito, Cristiana Ferreira Alves, Sousa, Tais Nobrega
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965052/
https://www.ncbi.nlm.nih.gov/pubmed/27467145
http://dx.doi.org/10.1371/journal.pone.0160172
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author Silvino, Ana Carolina Rios
Costa, Gabriel Luiz
de Araújo, Flávia Carolina Faustino
Ascher, David Benjamin
Pires, Douglas Eduardo Valente
Fontes, Cor Jesus Fernandes
Carvalho, Luzia Helena
de Brito, Cristiana Ferreira Alves
Sousa, Tais Nobrega
author_facet Silvino, Ana Carolina Rios
Costa, Gabriel Luiz
de Araújo, Flávia Carolina Faustino
Ascher, David Benjamin
Pires, Douglas Eduardo Valente
Fontes, Cor Jesus Fernandes
Carvalho, Luzia Helena
de Brito, Cristiana Ferreira Alves
Sousa, Tais Nobrega
author_sort Silvino, Ana Carolina Rios
collection PubMed
description Although Plasmodium vivax relapses are classically associated with hypnozoite activation, it has been proposed that a proportion of these cases are due to primaquine (PQ) treatment failure caused by polymorphisms in cytochrome P-450 2D6 (CYP2D6). Here, we present evidence that CYP2D6 polymorphisms are implicated in PQ failure, which was reinforced by findings in genetically similar parasites, and may explain a number of vivax relapses. Using a computational approach, these polymorphisms were predicted to affect the activity of CYP2D6 through changes in the structural stability that could lead to disruption of the PQ-enzyme interactions. Furthermore, because PQ is co-administered with chloroquine (CQ), we investigated whether CQ-impaired metabolism by cytochrome P-450 2C8 (CYP2C8) could also contribute to vivax recurrences. Our results show that CYP2C8-mutated patients frequently relapsed early (<42 days) and had a higher proportion of genetically similar parasites, suggesting the possibility of recrudescence due to CQ therapeutic failure. These results highlight the importance of pharmacogenetic studies as a tool to monitor the efficacy of antimalarial therapy.
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spelling pubmed-49650522016-08-18 Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses Silvino, Ana Carolina Rios Costa, Gabriel Luiz de Araújo, Flávia Carolina Faustino Ascher, David Benjamin Pires, Douglas Eduardo Valente Fontes, Cor Jesus Fernandes Carvalho, Luzia Helena de Brito, Cristiana Ferreira Alves Sousa, Tais Nobrega PLoS One Research Article Although Plasmodium vivax relapses are classically associated with hypnozoite activation, it has been proposed that a proportion of these cases are due to primaquine (PQ) treatment failure caused by polymorphisms in cytochrome P-450 2D6 (CYP2D6). Here, we present evidence that CYP2D6 polymorphisms are implicated in PQ failure, which was reinforced by findings in genetically similar parasites, and may explain a number of vivax relapses. Using a computational approach, these polymorphisms were predicted to affect the activity of CYP2D6 through changes in the structural stability that could lead to disruption of the PQ-enzyme interactions. Furthermore, because PQ is co-administered with chloroquine (CQ), we investigated whether CQ-impaired metabolism by cytochrome P-450 2C8 (CYP2C8) could also contribute to vivax recurrences. Our results show that CYP2C8-mutated patients frequently relapsed early (<42 days) and had a higher proportion of genetically similar parasites, suggesting the possibility of recrudescence due to CQ therapeutic failure. These results highlight the importance of pharmacogenetic studies as a tool to monitor the efficacy of antimalarial therapy. Public Library of Science 2016-07-28 /pmc/articles/PMC4965052/ /pubmed/27467145 http://dx.doi.org/10.1371/journal.pone.0160172 Text en © 2016 Silvino et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Silvino, Ana Carolina Rios
Costa, Gabriel Luiz
de Araújo, Flávia Carolina Faustino
Ascher, David Benjamin
Pires, Douglas Eduardo Valente
Fontes, Cor Jesus Fernandes
Carvalho, Luzia Helena
de Brito, Cristiana Ferreira Alves
Sousa, Tais Nobrega
Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses
title Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses
title_full Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses
title_fullStr Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses
title_full_unstemmed Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses
title_short Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses
title_sort variation in human cytochrome p-450 drug-metabolism genes: a gateway to the understanding of plasmodium vivax relapses
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965052/
https://www.ncbi.nlm.nih.gov/pubmed/27467145
http://dx.doi.org/10.1371/journal.pone.0160172
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