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.
