Iron Manganese Interactions in

Manganese is an essential trace element at low concentrations, but at higher concentrations it is neurotoxic, accumulating particularly in the globus pallidus. While the clinical symptoms are typical of Parkinson's disease, with rhythmic tremor and muscular rigidity, there is an important psychiatric aspect associated with Mn intoxication, manifested by behavioural aggression. An increasingly popular hypothesis is that the continued degeneration of dopaminergic neurones in Parkinson's disease may be the consequence of aberrant oxidation of dopamine and resultant generation of DNA-reactive species in those patients receiving L-dopa therapy. Chronic occupational metal exposure, particularly to Mn and Cu, has been shown to be a risk factor for Parkinsonism (Gorell et al., 1999), and Mn has been shown to be a true catalyst for dopamine oxidation, lending support to this hypothesis. Studies in the rat have shown that Mn and Fe interact during transfer from the plasma to the brain and other organs, and that this transfer is synergistic rather than competitive in nature (Chua and Morgan, 1996), suggesting that excessive intake of Fe plus Mn may accentuate the risk of tissue damage by one metal alone, particularly in the brain. Chronic Mn exposure in rats alters iron homeostasis apparently by causing a unidirectional influx of iron from the systemic circulation across the blood-brain barrier (Zheng et al., 1999). Manganese intoxication in rhesus monkeys results in a Parkinsonian syndrome (in two of three animals), which did not respond to L-dopa (Olanow etal., 1996). Focal mineral deposits, primarily consisting of iron and aluminium, were found in both the globus pallidus and the substantia nigra pars reticularis. Both the cytotoxicity and clastogenicity of laevodopa and dopamine in cultured cell lines is enhanced by concomitant exposure to either Mn or Cu salts (Snyder and Friedman, 1998). Manganese was found to increase LPS-stimulated NO production from microglial cells (Chang and Liu, 1999), unlike other transition metals tested including iron, cobalt, copper and zinc. Mn appeared to exert its effect at the level of transcription of the inducible NO synthase (Chapter 10), and unlike other transition metals Mn did not appear to be cytotoxic to microglial cells. It is suggested that Mn could induce sustained production of neurotoxic NO by activated microglial cells, which might be detrimental to surrounding neurones.

The mitochondrial dysfunctionality seen in manganese neurotoxicity might be related to the accumulation of reactive oxygen species (Verity, 1999). Mitochondrial Mn superoxide dismutase (MnSOD) is found to be low or absent in tumour cells and may act as a tumour suppressor. It is induced by inflammatory cytokines like TNF, presumably to protect host cells. In a rat model, iron-rich diets were found to decrease MnSOD activity, although a recent study reported that in rat epithelial cell cultures iron supplementation increased MnSOD protein levels and activity, but did not compromise the ability of inflammatory mediators like TNF to further increase the enzyme activity (Kuratko, 1999).

While our present dietary heterogeneity (at least in the developed world) makes it unlikely that we will encounter many cases of Mn deficiency, the association of low Mn-dependent SOD activity with cancer susceptibility is a cause for concern (Finley and Davis, 1999). The dangers of Mn toxicity may be greater than we imagine. Vegetarian lifestyles are being adopted by an increasing number of young people, which may simultaneously increase Mn intake, and increase the risk of iron deficiency with concomitant increased dietary Mn absorption.ยง

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