Oxidative renal tubular injuries induced by aminocarboxylate-type iron (III) coordination compounds as candidate renal carcinogens

Abstract

Oxidative renal tubular injuries and carcinogenesis induced by Fe(III)-nitrilotriacetate (NTA) and Fe(III)-ethylenediamine-N,N'-diacetate (EDDA) have been reported in rodent kidneys, but the identity of iron coordination structure essential for renal carcinogenesis, remains to be clarified. We compared renal tubular injuries caused by various low molecular weight aminocarboxylate type chelators with injuries due to NTA and EDDA. We found that Fe(III)-iminodiacetate (IDA), a novel iron-chelator, induced acute tubular injuries and lipid peroxidation to the same extent. We also prepared Fe(III)-IDA solutions at different pHs, and studied resultant oxidative injuries and physicochemical properties. The use of Fe(III)-IDA at pH 5.2, 6.2, and 7.2 resulted in renal tubular necrosis and apoptotic cell death, but neither tubular necrosis nor apoptosis was observed at pH 8.2. Spectrophotometric data suggested that Fe(III)-IDA had the same dimer structure from pH 6.2 to 7.2 as Fe(III)-NTA; but at a higher pH, iron polymerized and formed clusters. Fe(III)-IDA was crystallized, and this was confirmed by X-ray analysis and magnetic susceptibility measurements. These data indicated that Fe(III)-IDA possessed a linear mu-oxo bridged dinuclear iron (III) around neutral pH.

Model Reactions for the Formation of Iron Deposition

“…The K[Fe(ida) 2 ]3H 2 O complex is green in the crystalline state, but its color changed to orange when it dissolved in the buffer solution. The orange color thus found is frequently observed for the iron(III) species with -oxo bridged dimeric Fe(III) cores (Ito et al, 1996), and this color is very similar to that of K 4 [Fe 2 O(ida) 4 ]10H 2 O, its -oxo bridged dimeric core being confirmed by the crystal structure determination (Mizuno et al, 2006, and see Figure 3). These are implying that the -oxo Figure 6), and in the next step the formation of di--oxo bridged dimeric Fe(III) complex may occur through the attack by the iron(III) atom of the another iron(III) chelate.…”

The chemical mechanism of oxidative stress by copper(II) and iron(III) ions in several neurodegenerative disorders

“…We have determined the crystal structures of several iron (III) compounds including nta, pac, and ida [62][63][64]. As shown in Fig.…”

“…7), and injuries such as lipid peroxidation and protein oxidation are observed mainly in the renal proximal tubules [63,64], but no injury was observed in the distal position. It should be noted here that the glutathione cycle is highly active in the renal proximal position [69], and this may suggest that the glutathione cycle promotes the iron(III)-induced injuries.…”

“…On the basis of the above discussion, the tissue damage and renal carcinoma induced by the Fe(III)-(nta) chelate may be explained as follows (Scheme 7) [20,63,64]: when the binuclear Fe(III)-(nta) compound reacts with the glutathione cycle, the carbonato ions dissociate from the compound, leading to the interaction between two iron(III) atoms and the protein. At this stage, when oxygen is present, formation of peroxide ion is accelerated through the interaction with the glutathione cycle, and the peroxide adduct of the binuclear Fe(III)-(nta) complex formed shows high oxidative reactivity towards the proteins, leading to the tissue injuries and renal carcinoma.…”

“…In previous papers, the role of the hydroxyl radical in inducing tissue damage and renal carcinoma has been frequently pointed out, but this cannot explain the lower tissue-damaging activity exerted by the Fe(III)-(edda) chelate, nor the difference in the tissue damage exerted by the two alkoxo-bridged binuclear iron(III) complexes Fe 2 (hida) 2 (H 2 O) 2 (non-toxic) and Fe 2 (HPTP)Cl 4 (highly toxic), or by Fe(III)-(nta) and Fe(III)-(pac) chelates [20,63,64].…”