A novel iron chelator that does not induce HIF-1 activity.
Human skin cells (FEK-4) have been shown to undergo an immediate and transient release of low molecular mass iron (LMrFe) when subjected to UVA (320-380 nm) irradiation and this iron may act as a pro-oxidant and increase tissue injury. In order to decrease this transient release of LMrFe, cells were treated with the iron chelators desferrioxamine (DFO) and salicylaldehyde isonicotinoyl hydrazone (SIH). However, although the iron pool decreased, an increase in the DNA binding activity of the hypoxia inducible factor-1 (HIF-1) was observed when DFO and SIH were administered to normal growing FEK-4 cells. The induction of HIF-1 activates the expression of several genes associated with hypoxia and iron homeostasis. HIF-1 induction has also been associated with protection against certain forms of oxidative stress. Therefore, it is difficult to use a conventional HIF-1 activating iron chelator (such as DFO) for mechanistic studies of protection against iron-mediated oxidative stress since any protection observed could be a consequence of either the chelation of LMrFe or the induction of protective genes associated with the hypoxic response. In order to observe the effect of iron chelation on cell function without the induction of hypoxia responsive genes, cells were treated with the novel iron chelator N-(2-hydroxybenzyl)-L-serine (HBSer). Although this compound is an effective iron chelator under the conditions employed in this experiment, it does have a lower iron-binding constant than either DFO or SIH. This may be the major determinant of the observation that the compound does not induce HIF-1 binding or activate HIF-1 responsive transcriptional promoters.
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, UK.
Mark
M
Creighton-Gutteridge
Rex M
RM
Tyrrell
D000447:Aldehydes / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors
D000447:Aldehydes; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D006835:Hydrazones; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; C403766:N-(2-hydroxybenzyl)serine; D009687:Nuclear Proteins; D010636:Phenols; D012333:RNA, Messenger; D014157:Transcription Factors; C413684:salicylaldehyde isonicotinoyl hydrazone; D012694:Serine; D007501:Iron; D003676:Deferoxamine