Iron-mediated oxidant production under conditions relevant to both natural aquatic and neurological environments

Abstract

As a result of the participation in a multitude of biological processes, including photosynthesis, respiration and oxygen transportation, iron is an indispensable micronutrient for all living organisms. However, the redox cycling between the two oxidation states of this critical metal is closely related to the severe damage in proteins, DNA and lipids as a result of the concomitant generation of reactive oxygen species (ROS), including superoxide, hydrogen peroxide or even hydroxyl radical. In the natural environment, as a consequence of the ready precipitation of ferric iron following the rapid oxidation of the active ferrous iron, the bioavailability of iron is one of the key limiting factors for the growth of marine lives. In humans, while an important co-factor for many enzymes, the aging related iron accumulation within the substantial nigra has long been proposed to associate with the progression of Parkinson’s disease (PD) as a result of the iron induced oxidative stress. In general, both the bioavailability and toxicity of iron largely depends on the form present with the iron oxides being most inactive. As such, the presence of oxidants, reductants and/or iron chelators exert a significant influence on the reactivity of iron, thereby altering the bioavailability and toxicity of iron. Given the interest in the role of iron both in the natural environment and PD, this work is divided into two sub-units with the first part focusing on the bioavailability of iron to microorganisms and the second part emphasizing the relationships between iron and PD. The transformation and redox cycling of iron in this work are investigated by employing spectrophotometric techniques with high sensitivity and temporal resolution. Given that thermodynamic equilibrium will be unlikely attained and, in order to assist the better understanding and the elucidation of the mechanisms of iron redox cycling under different conditions, kinetic models are developed in this work. In the first section, the effects of Cu(II) (a naturally existing metal) and dopamine (DA, a bio-active compound released by a prominent macroalgae of green tides) on the transformation of iron are investigated. Results of this part indicate that i) the oxidation of the most bioavailable iron, Fe(II), can be dramatically accelerated in the presence of Cu(II) with this process being significantly pH and chloride concentration dependent; ii) the benefits gained by the macroalgae via the release of substantial concentrations of DA possibly involving the DA induced iron and light stress alleviation as well as iron induced oxidative stress to local communities and iii) biotic input of H2O2 to the coastal waters as a result of seasonal blooms of macroalgae may be more significant than previous expected with this process possibly relating to harmful algae blooms induced human health problem. In the second section, the interactions between iron and dopamine (a well-known neurotransmitter, which is closely related to the progression of PD) are examined with emphasis on the iron induced oxidative stress and generation of toxic metabolites. The mechanism of the utilization of deferiprone (a clinically used iron chelator) and the possibility of the application of ascorbate (a widely-distributed reductant) as a therapeutic strategy to attenuate the progression of PD are also investigated. Results of this part indicate that i) the oxidation of DA is accompanied by the generation of considerable amounts of H2O2 and aminochrome (DAC) with this process being accelerated dramatically in the presence of both Fe(II) and Fe(III); ii) in addition to the commonly used pFe3+ value, low pKa values and low electron density on the functional groups within the chelator may be an important design and selection criteria to clinically used chelators, which is closely associated with the iron removal efficiency and chelator induced toxicity and iii) while a reduction in a generation and accumulation of both DAC and H2O2 is evident as a result of ascorbate induced scavenging of radicals, an elevated Fe(II) concentrations is observed, especially in the presence of high concentrations of ascorbate. As such, instead of the single treatment with ascorbate, a combination therapy including both ascorbate and strong iron chelator might be a promising direction in view of the future treatment.