In vitro and in vivo studies on chelation of manganese.

This work deals with new chelating agents of manganese (Mn). Out of 24 compounds chosen for their chemical structure supposed to be favorable for Mn complexation, six polyaminopolycarboxylic acids proved to be efficient for displacing Mn bound to serum bovine proteins in vitro: TTHA, DTPA, DPTA, DPTA-OH, HBED, EDTA (mobilization > or =50%). The first five compounds were then tested in vivo on rats pretreated with MnCl2. They exhibited only slight to moderate efficacy to diminish Mn in tissues and were ineffective on increased Mn concentration in whole blood; in addition, they had different and specific mobilizing effects on other essential elements (Fe, Zn, Cu). Their limited efficacy in vivo could be due to the formation of very stable complexes between Mn2+ and different molecules such as hemoglobin and certain cytochromes, instead of Fe2+. This could disturb the functioning of the cellular respiratory chain, leading to an incomplete reduction of O2 with formation of free oxygenated radicals, reduction in the energy supply, and disturbance of the cytochromes renewal mechanism. All of these phenomena could accelerate cellular aging and explain the lack of efficacy of the chelating agents towards Mn neurotoxicity (Parkinson's syndrome).