Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon.
Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon.
Int J Mol Sci. 2021 Jan 23;22(3):1106. doi: 10.3390/ijms22031106.
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, 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 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 mice through an NADPH-dependent pathway.
活性氧（ROS）的氧化损伤是导致地中海贫血患者细胞损伤和组织损伤的主要因素之一。最近的研究表明，非输血依赖型（NTDT）患者的 ROS 产生是由于铁过载所致。在不同的 ROS 来源中，烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶家族的酶和细胞色素 P450（CYP450）被认为是几种疾病中氧化应激的主要贡献者。然而，NTDT 患者的 ROS 来源仍知之甚少。在这项研究中，使用了一种β地中海贫血小鼠模型。与 C57BL/6 对照同窝仔相比，这些小鼠的主要 NOX 同工型（NOX1、NOX2 和 NOX4）的表达不变或降低。然而，与 C57BL/6 对照小鼠相比，在 小鼠中观察到 CYP4A 和 CYP4F 的蛋白合成显著增加。这些变化伴随着 CYP4A 和 CYP4F 代谢物 20-羟二十碳四烯酸（20-HETE）的产生增加。此外，这些变化与 ROS 产生与肝损伤同时发生相吻合。据我们所知，这是第一个表明 CYP450 4A 和 4F 诱导的 20-HETE 产生通过 NADPH 依赖性途径介导 小鼠中活性氧过度产生的报告。
