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CYP450 Mediates Reactive Oxygen Species Production in a Mouse Model of β-Thalassemia through an Increase in 20-HETE Activity

Oxidative damage by reactive oxygen species (ROS) is one of the main contributors to cell injury and tissue damage in thalassemia patients. Recent studies suggest that ROS generation in non-transfusion-dependent (NTDT) patients occurs as a result of iron overload. Among the different sources of ROS,...

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Autores principales: Bou-Fakhredin, Rayan, Dia, Batoul, Ghadieh, Hilda E., Rivella, Stefano, Cappellini, Maria Domenica, Eid, Assaad A., Taher, Ali T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865490/
https://www.ncbi.nlm.nih.gov/pubmed/33498614
http://dx.doi.org/10.3390/ijms22031106
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author Bou-Fakhredin, Rayan
Dia, Batoul
Ghadieh, Hilda E.
Rivella, Stefano
Cappellini, Maria Domenica
Eid, Assaad A.
Taher, Ali T.
author_facet Bou-Fakhredin, Rayan
Dia, Batoul
Ghadieh, Hilda E.
Rivella, Stefano
Cappellini, Maria Domenica
Eid, Assaad A.
Taher, Ali T.
author_sort Bou-Fakhredin, Rayan
collection PubMed
description Oxidative damage by reactive oxygen species (ROS) is one of the main contributors to cell injury and tissue damage in thalassemia patients. Recent studies suggest that ROS generation in non-transfusion-dependent (NTDT) patients occurs as a result of iron overload. Among the different sources of ROS, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes and cytochrome P450 (CYP450) have been proposed to be major contributors for oxidative stress in several diseases. However, the sources of ROS in patients with NTDT remain poorly understood. In this study, Hbb(th3/+) mice, a mouse model for β-thalassemia, were used. These mice exhibit an unchanged or decreased expression of the major NOX isoforms, NOX1, NOX2 and NOX4, when compared to their C57BL/6 control littermates. However, a significant increase in the protein synthesis of CYP4A and CYP4F was observed in the Hbb(th3/+) mice when compared to the C57BL/6 control mice. These changes were paralleled by an increased production of 20-hydroxyeicosatetraenoic acid (20-HETE), a CYP4A and CYP4F metabolite. Furthermore, these changes corroborate with onset of ROS production concomitant with liver injury. To our knowledge, this is the first report indicating that CYP450 4A and 4F-induced 20-HETE production mediates reactive oxygen species overgeneration in Hbb(th3/+) mice through an NADPH-dependent pathway.
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spelling pubmed-78654902021-02-07 CYP450 Mediates Reactive Oxygen Species Production in a Mouse Model of β-Thalassemia through an Increase in 20-HETE Activity Bou-Fakhredin, Rayan Dia, Batoul Ghadieh, Hilda E. Rivella, Stefano Cappellini, Maria Domenica Eid, Assaad A. Taher, Ali T. Int J Mol Sci Article Oxidative damage by reactive oxygen species (ROS) is one of the main contributors to cell injury and tissue damage in thalassemia patients. Recent studies suggest that ROS generation in non-transfusion-dependent (NTDT) patients occurs as a result of iron overload. Among the different sources of ROS, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes and cytochrome P450 (CYP450) have been proposed to be major contributors for oxidative stress in several diseases. However, the sources of ROS in patients with NTDT remain poorly understood. In this study, Hbb(th3/+) mice, a mouse model for β-thalassemia, were used. These mice exhibit an unchanged or decreased expression of the major NOX isoforms, NOX1, NOX2 and NOX4, when compared to their C57BL/6 control littermates. However, a significant increase in the protein synthesis of CYP4A and CYP4F was observed in the Hbb(th3/+) mice when compared to the C57BL/6 control mice. These changes were paralleled by an increased production of 20-hydroxyeicosatetraenoic acid (20-HETE), a CYP4A and CYP4F metabolite. Furthermore, these changes corroborate with onset of ROS production concomitant with liver injury. To our knowledge, this is the first report indicating that CYP450 4A and 4F-induced 20-HETE production mediates reactive oxygen species overgeneration in Hbb(th3/+) mice through an NADPH-dependent pathway. MDPI 2021-01-23 /pmc/articles/PMC7865490/ /pubmed/33498614 http://dx.doi.org/10.3390/ijms22031106 Text en © 2021 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bou-Fakhredin, Rayan
Dia, Batoul
Ghadieh, Hilda E.
Rivella, Stefano
Cappellini, Maria Domenica
Eid, Assaad A.
Taher, Ali T.
CYP450 Mediates Reactive Oxygen Species Production in a Mouse Model of β-Thalassemia through an Increase in 20-HETE Activity
title CYP450 Mediates Reactive Oxygen Species Production in a Mouse Model of β-Thalassemia through an Increase in 20-HETE Activity
title_full CYP450 Mediates Reactive Oxygen Species Production in a Mouse Model of β-Thalassemia through an Increase in 20-HETE Activity
title_fullStr CYP450 Mediates Reactive Oxygen Species Production in a Mouse Model of β-Thalassemia through an Increase in 20-HETE Activity
title_full_unstemmed CYP450 Mediates Reactive Oxygen Species Production in a Mouse Model of β-Thalassemia through an Increase in 20-HETE Activity
title_short CYP450 Mediates Reactive Oxygen Species Production in a Mouse Model of β-Thalassemia through an Increase in 20-HETE Activity
title_sort cyp450 mediates reactive oxygen species production in a mouse model of β-thalassemia through an increase in 20-hete activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865490/
https://www.ncbi.nlm.nih.gov/pubmed/33498614
http://dx.doi.org/10.3390/ijms22031106
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