Differential effects on cellular iron metabolism of the physiologically relevant diatomic effector molecules, NO and CO, that bind iron

Both nitrogen monoxide (NO) and carbon monoxide (CO) are biologically relevant diatomic effector molecules that mediate a variety of biological functions through their avid binding to iron (Fe). Previous studies showed that NO can inhibit Fe uptake from transferrin (Tf) and increase Fe mobilisation from cells [J. Biol. Chem. 276 (2001) 4724]. We used CO gas, a CO-generating agent ([Ru(CO)(3)Cl-2](2)), and cells stably transfected with the CO-producing enzyme, haem oxygenase 1 (HO1), to assess the effect of CO on Fe metabolism. These results were compared to the effects of NO produced by a variety of NO-generating agents, including S-nitrosoglutathione (GSNO), spermine-NONOate (SperNO) and S-nitroso-N-acetylpenicillamine (SNAP). Incubation of cells with CO inhibited Fe-59 uptake from Fe-59-Tf by cells, and like NO, reduced ATP levels. Hence, the ability of both agents to inhibit Fe-59 uptake may be partially mediated by inhibition of energy-dependent processes. These results showing a CO-mediated decrease in Fe-59 uptake from Fe-59-Tf using exogenous CO were in agreement with studies implementing cells transfected with HO1. Like NO, CO markedly prevented Fe-59 uptake into ferritin. In comparison to the avid ability of exogenous CO to inhibit Fe-59 uptake, it had less effect on cellular Fe-59 mobilisation. Experiments with HO1-transfected cells compared to control cells showed that Fe-59 mobilisation was slightly enhanced. In contrast to NO, CO did not affect the RNA-binding activity of the iron regulatory protein 1 that plays an important role in Fe homeostasis. Our studies demonstrate that subtle differences in the chemistry of NO and CO results in divergence of their ability to affect Fe metabolism. (C) 2004 Elsevier B.V. All rights reserved.