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).

Bioavailability and intestinal absorption of aluminum in rats: effects of aluminum compounds and some dietary constituents.

In the present investigation, the deposition of aluminum in intestinal fragment and the appearance in blood were studied in a perfused rat intestine in situ for 1 h with several aluminum forms (16 mM). We observed that aluminum absorption was positively correlated with the theoretic affinity of aluminum and the functional groups of the chelating agent. The absorption of aluminum after ingestion of organic compounds is more important than after ingestion of mineral compounds, with the following order: Al citrate > Al tartrate, Al gluconate, Al lactate > Al glutamate, Al chloride, Al sulfate, Al nitrate. Absorption depends on the nature of the ligands associated with the Al3+ ion in the gastrointestinal fluid. The higher the aluminum retention in intestinal fragment, the lower the absorption and appearance in blood. However, the higher aluminum concentration is always in the jejunal fragment because of the influence of pH variation on this fragment. Another objective of the present study was to determine the influence of several parameters on aluminum citrate absorption: with or without 0.1 mmol dinitrophenol/L, with aluminum concentration from 3.2, 16, 32, and 48, to 64 mmol/L, media containing 0, 3, or 6 mmol Ca/L, with or without phosphorus or glucose. It is concluded that aluminum is absorbed from the gastrointestinal tract by (1) a paracellular energy independent and nonsaturable route, mainly used for high aluminum concentration, which is modified by extracellular calcium, and (2) a transcellular and saturable route, the aluminum level was not modified with enhancement of aluminum quantity in intestinal lumen. This pathway can be similar with calcium transfer through the intestine and is energy dependent because of a decrease of aluminum absorption that follows the removal of glucose and phosphorus.

Reduction of dietary phosphorus absorption by oral phoshorus binders.

The aim of this study was to study a possible new non-aluminum phosphate-binder to limit hyperphosphatemia in patients with renal failure. Zirconyl chloride octahydrate was evaluated as a dietary phosphate binder in rats. Aluminum chloride hexahydrate was used as a reference. Animals were divided into six groups (6 animals per group): One - control group (C), two - aluminum groups (Al1 and Al2) and three - zirconium groups (Zr1, Zr2 and Zr3) receiving different doses of zirconyl chloride octahydrate. Urines were collected during the experimental period. At the end of the treatment, the animals were sacrified and plasma and different organs were collected (liver, spleen, kidneys, brain and femur). Determination of phosphorus and calcium levels in plasma indicated that zirconyl chloride octahydrate yielded as good results as aluminum chloride hexahydrate did. Zirconyl chloride octahydrate significantly (p<0.01) reduced bone phosphorus burden. Urinary excretion of phosphorus indicated a severe phosphorus depletion in all treatments. Not even traces of zirconium could be determined in the different tissues, in urines or in plasma. Consequently, it is important to carry out experiments with zirconium compounds in order to develop non-aluminum-containing phosphate binders.

A possible non-aluminum oral phosphate binder? A comparative study on dietary phosphorus absorption.

The aim of this study was to highlight a possible new non-aluminum phosphate-binder to limit hyperphosphatemia in patients with renal failure. Lanthanum chloride hydrate was evaluated as a dietary phosphate binder in rats. Aluminum chloride hexahydrate was evaluated as a reference. Animals were divided in five groups (6 animals per group): 1 control group (C), 2 aluminum groups (Al1 and Al2), receiving different doses of aluminum chloride hexahydrate and 2 lanthanum groups (La1 and La2), receiving different doses of lanthanum chloride hydrate. During the treatment, urine and stools were collected. At the end of the treatment animals were sacrificed and plasma and different organs were collected (liver, spleen, kidneys, brain and femur). To highlight the possible transfer of lanthanum in rat tissues, a long-term (100 days) study was carried with a high dose. At the end of the treatment, lanthanum determinations were carried out on several tissues (liver, spleen, kidneys, brain, femur and lungs). Determinations of phosphorus and calcium levels in plasma indicated that lanthanum chloride hydrate showed as good results as aluminum chloride hexahydrate. Lanthanum chloride hydrate significantly (p < 0.01) reduced the bone phosphorus burden. Decreases of urinary excretion and increases in fecal excretion of phosphorus indicated a severe phosphorus depletion in all treatments (Al and La). Unfortunately, in the long-term study, lanthanum traces could only be determined in the different tissues but not in plasma. However, in comparison with the equivalent aluminum treatment, the transfer of lanthanum was less important than aluminum transfer. Consequently, lanthanum could provide a possible alternative to aluminum.