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

Abstract

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, Hbbth3/+ 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 Hbbth3/+ 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 Hbbth3/+ mice through an NADPH-dependent pathway.

The interactions between ineffective erythropoiesis and ferroptosis in β-thalassemia

“…According to current studies, several molecular mechanisms may be involved in the promotion of ROS overproduction in erythrocytes by the oxidative system. Firstly, in the Hbbth3/+ mouse model of β-thal, 20-hydroxyeicosatetraenoic acid, a metabolite of Cytochrome P450 4A/F (CYP4A/F), mediates ROS overproduction through a NADPH-dependent pathway ( Bou-Fakhredin et al, 2021 ). Secondly, the generation of ROS and, IE is stimulated by the downregulation of isocitrate dehydrogenase 1 along with an increase in α-ketoglutarate ( Gonzalez-Menendez et al, 2021 ).…”

Bioinorganic Modulators of Ferroptosis: A Review of Recent Findings

“…There are up to 12 mitochondrial enzymes engaged in nutrient oxidation that also give rise to endogeneous ROS [ 25 ]. The production of ROS takes place in various cellular locations and involves the activity of proteins such as: the family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX), specialized in the physiological formation of superoxide or hydrogen peroxide, which play a role in various types of host defense and the promotion of inflammatory response [ 26 ]; several oxidases based in peroxisomes, where up to 35% of total hydrogen peroxide generation occurs in mammalian tissues [ 27 ]; or the cytochrome P450 (CYP) family of enzymes implicated in the metabolism of xenobiotics [ 28 ]. Overall, as many as 40 enzymes are known to contribute to the emergence of ROS in cells, alongside non-enzymatic processes like the mitochondrial electron transport chain with its 11 identified distinct sites of electron leak [ 29 ].…”

The Functions of Cytochrome P450 ω-hydroxylases and the Associated Eicosanoids in Inflammation-Related Diseases

“…Moreover, 20-HETE/GPR75 is involved in the activation of intracellular signaling in prostate cancer cells, leading to the more aggressive phenotypic differentiation of PC-3 cells ( Cárdenas et al, 2020 ). In endothelial cells, 20-HETE can promote reactive oxygen species (ROS) production through NADPH oxidase to activate the L-type Ca 2+ channel ( Medhora et al, 2008 ; Zeng et al, 2010 ; Bou-Fakhredin et al, 2021 ). In the ischemia-reperfusion injury, inhibition of 20-HETE synthesis reduced oxidative stress and the expression of vascular TNFα, IL-1β and IL-6 ( Regner et al, 2009 ; Hoff et al, 2011 ).…”