Lactobionic and gluconic acid complexes of Fe II and Fe III; control of oxidation pathways by an organ transplantation preservant

Abstract

Lactobionic acid, [4-β-(galactosido)-D-gluconic acid] = LBA, is the major component of the Wisconsin organ transplantation preservant fluid and may suppress oxygen radical-induced tissue damage upon reperfusion by the control of Fe II autoxidation. Fe II and Fe III complexes of LBA and the related gluconic acid (GLC) have been studied herein by titrimetric, infrared, and electrochemical methods (CV; DPP). Fe II(GLC) forms quickly at pH 7, but Fe II(LBA) reacts in two steps, the second requiring 4 hr. The initial complex lacks coordination of the LBA carboxylate (C-1) and is bound by the “2,3,5” hydroxyl groups. The slow rearrangement forms a “1,2,3,6” chelate which Fe II(LBA) shares in common with the donor set of the Fe III(LBA) complex. Titration data shows the removal of three protons from LBA through pH 5 and an additional proton from pH 6 to 9 which is indicative of the [Fe III(LBA)(OH)(H 2O)] − formulation with LBA donating at the “1,2,3,6” positions. The more stable, second form of Fe II(LBA) has been investigated in its oxidation mechanisms with H 2O 2 and O 2 using selected trapping agents for HO · and ferryl intermediates. Eighty-six percent of the oxidation events of Fe II(LBA)/H 2O 2 occurs in steps involving formation and reduction of freely diffusible HO ·. These pathways are altered by the known HO · traps t-butanol, dmso, ethanol, and methanol in the manner predictable for β-oxidizing radicals (from t-butanol or dmso) and α-reducing radicals (from ethanol and methanol). Fourteen percent of the Fe II(LBA)/H 2O 2 reaction occurs via Fe IVO intermediates not trapped by t-butanol or dmso, but intercepted by primary and secondary alcohols. The HO · generating pathways are responsible for a competitive LBA ligand oxidation at the C-2 position via HO ·, formed from Fe II(LBA) and H 2O 2 within the original reaction cage. Competitive ligand oxidation at C-2 is absent for the Fe II(LBA)/O 2 autoxidation, indicative of a different redox mechanism. The Fe II(LBA)/O 2 reaction rate is first-order in each component and is insensitive to the presence of t-butanol as an HO · trap. These observations support a ferryl intermediate in the autoxidation pathway and the absence of HO · or free H 2O 2 during autoxidation. Although chelation of Fe II by hard ligand donors such as edta 4−, Cl −, or HPO 4 2− accelerate the rate of autoxidation of Fe II, chelation of carboxylate, alkoxy, and hydroxyl donors of LBA does not accelerate autoxidation. The implications of these findings, and the absence of an inner-sphere coordination role of the 4-β-(galactosido) functionality toward the action of LBA in organ preservant fluids, are discussed.