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

International Journal of Molecular Sciences

Rayan Bou-Fakhredin¹  HildaE. Ghadieh¹  Batoul Dia¹  AssaadA. Eid¹  Stefano Rivella²  AliT. Taher³  MariaDomenica Cappellini⁴ 

[1] Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon;Department of Pediatrics, Division of Hematology, The Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA 19104, USA;Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon;Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Internal Medicine, 20122 Milan, Italy;

关键词: oxidative stress;    reactive oxygen species;    CYP450;    non-transfusion-dependent thalassemia;    NADPH oxidases;   

DOI  :  10.3390/ijms22031106

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown