Non-heme induction of heme oxygenase-1 does not alter cellular iron metabolism.
The catabolism of heme is carried out by members of the heme oxygenase (HO) family. The products of heme catabolism by HO-1 are ferrous iron, biliverdin (subsequently converted to bilirubin), and carbon monoxide. In addition to its function in the recycling of hemoglobin iron, this microsomal enzyme has been shown to protect cells in various stress models. Implicit in the reports of HO-1 cytoprotection to date are its effects on the cellular handling of heme/iron. However, the limited amount of uncommitted heme in non-erythroid cells brings to question the source of substrate for this enzyme in non-hemolytic circumstances. In the present study, HO-1 was induced by either sodium arsenite (reactive oxygen species producer) or hemin or overexpressed in the murine macrophage-like cell line, RAW 264.7. Both of the inducers elicited an increase in active HO-1; however, only hemin exposure caused an increase in the synthesis rate of the iron storage protein, ferritin. This effect of hemin was the direct result of the liberation of iron from heme by HO. Cells stably overexpressing HO-1, although protected from oxidative stress, did not display elevated basal ferritin synthesis. However, these cells did exhibit an increase in ferritin synthesis, compared with untransfected controls, in response to hemin treatment, suggesting that heme levels, and not HO-1, limit cellular heme catabolism. Our results suggest that the protection of cells from oxidative insult afforded by HO-1 is not due to the catabolism of significant amounts of cellular heme as thought previously.
Sheftel
Alex D
AD
Lady Davis Institute for Medical Research, Montréal, Québec H3T 1E2, Canada.
Kim
Sangwon F
SF
Ponka
Prem
P
D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005293:Ferritins / Q000096:biosynthesis*; D015870:Gene Expression; D006418:Heme / Q000378:metabolism / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D007501:Iron / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D017670:Sodium Compounds / Q000494:pharmacology
D018053:Arsenites; D004791:Enzyme Inhibitors; D017670:Sodium Compounds; D006418:Heme; C017947:sodium arsenite; D005293:Ferritins; D007501:Iron; D051547:Heme Oxygenase-1