CYP450 mediates reactive oxygen species production in a mouse model of β-thalassemia through an increase in 20-hete activity

Rayan Bou-Fakhredin, Batoul Dia, Hilda E. Ghadieh, Stefano Rivella, Maria Domenica Cappellini, Assaad A. Eid, Ali T. Taher

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1106
Pages (from-to)1-14
Number of pages14
JournalInternational Journal of Molecular Sciences
Volume22
Issue number3
DOIs
Publication statusPublished - Feb 1 2021

Keywords

  • CYP450
  • NADPH oxidases
  • Non-transfusion-dependent thalassemia
  • Oxidative stress
  • Reactive oxygen species

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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