Regulation of xanthine oxidoreductase by intracellular iron.
Xanthine oxidoreductase (XOR) may produce reactive oxygen species and play a role in ischemia-reperfusion injury. Because tissue iron levels increase after ischemia, and because XOR contains functionally critical iron-sulfur clusters, we studied the effects of intracellular iron on XOR expression. Ferric ammonium citrate and FeSO(4) elevated intracellular iron levels and increased XOR activity up to twofold in mouse fibroblast and human bronchial epithelial cells. Iron increased XOR protein and mRNA levels, whereas protein and RNA synthesis inhibitors abolished the induction of XOR activity. A human XOR promoter construct (nucleotides +42 to -1937) was not induced by iron in human embryonic kidney cells. Hydroxyl radical scavengers did not block induction of XOR activity by iron. Iron chelation by deferoxamine (DFO) decreased XOR activity but did not lower endogenous XOR protein or mRNA levels. Furthermore, DFO reduced the activity of overexpressed human XOR but not the amount of immunoreactive protein. Our data show that XOR activity is transcriptionally induced by iron but posttranslationally inactivated by iron chelation.
Martelin
Eeva
E
Hospital for Children and Adolescents, Research Laboratory, University of Helsinki, Biomedicum Helsinki, 00014 University of Helsinki, Finland. eeva.martelin@hus.fi
Lapatto
Risto
R
Raivio
Kari O
KO
D016475:3T3 Cells; D000818:Animals; D003300:Copper / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D017665:Hydroxyl Radical / Q000037:antagonists & inhibitors; D007425:Intracellular Membranes / Q000378:metabolism*; D007501:Iron / Q000502:physiology*; D051379:Mice; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D019820:Xanthine / Q000378:metabolism*
D016166:Free Radical Scavengers; D019820:Xanthine; D017665:Hydroxyl Radical; D003300:Copper; D007501:Iron; D010088:Oxidoreductases; D003676:Deferoxamine