Aluminum speciation studies in biological fluids. Part 7. A quantitative investigation of aluminum(III)-malate complex equilibria and their potential implications for aluminum metabolism and toxicity.

As a nonessential element, aluminum may be toxic at both environmental and therapeutic levels, depending on ligand interactions. Dietary acids that normally occur in fruits and vegetables and commonly serve as taste enhancers are good ligands of the Al(3+) ion. Malic acid is one of these and also one of the most predominant in food and beverages. The present paper reports an examination of its potential influence on aluminum bioavailability through speciation calculations based on Al(III)-malate complex formation constants especially determined for physiological conditions. According to the results obtained, malate appears to be extremely effective in maintaining Al(OH)(3) soluble over the whole pH range of the small intestine under normal dietary conditions. In addition, two neutral Al(III)--malate complexes are formed whose percentages are maximum from very low malate levels. When aluminum is administered therapeutically as its trihydroxide, the amount of metal neutralized by malate peaks as its solubility pH range regresses to its original limits in the absence of malate. The enhancing effect of malate towards aluminum absorption is therefore virtually independent of the aluminum level in the gastrointestinal tract. The presence of phosphate in the gastrointestinal juice is expected to limit the potential influence of malate on aluminum absorption. Under normal dietary conditions, phosphate effectively reduces the fraction of aluminum neutralized by malate but without nullifying it. Aluminum phosphate is predicted to precipitate when aluminum levels are raised as with the administration of aluminum hydroxide, but a significant amount of neutral aluminum malate still remains in solution. Even therapeutic aluminum phosphate is not totally safe in the presence of malate, even at low malate concentrations. As plasma simulations predict that no compensatory effect in favor of aluminum excretion may be expected from malate, simultaneous ingestion of malic acid with any therapeutic aluminum salt should preferably be avoided.

Aluminum speciation studies in biological fluids. Part 4. A new investigation of aluminum-succinate complex formation under physiological conditions, and possible implications for aluminum metabolism and toxicity.

Previous in vivo studies devoted to the capacity of succinate to influence aluminum metabolism have led to apparent contradictory results. Understanding the mechanisms that lie behind such discrepancies requires a knowledge of aluminum-succinate interactions at the molecular level. In the absence of possible direct analysis of the ultrafiltrable fraction of aluminum in vivo, computer simulations can help quantify the mobilizing power of succinate towards aluminum in the main biofluids. Based on this technique, a first attempt to elucidate the above issue was made using especially determined aluminum-succinate formation constants. However, further investigations have led to reconsider the stoichiometry of the aluminum-succinate complexes characterized on that occasion. The present work deals with these new investigations. The results obtained confirm the great complexity of the aluminum-succinate system. No less than seven species, among which five polynuclear complexes, have been characterized in two series of independent experiments. New simulations indicate that succinate is expected to facilitate aluminum gastrointestinal absorption to a greater extent than initially predicted when the metal is administered as its trihydroxide, especially at high concentrations of the metal. In contrast, succinate is not able to significantly increase aluminum absorption when ingested concomitantly with aluminum phosphate. It is also confirmed that succinate cannot influence the fate of aluminum in blood plasma, which supports the view that the protective effect of succinate against aluminum toxicity in mice is not due to aluminum complexation.

Aluminum-succinate complex equilibria and their potential implications for aluminum metabolism.

Apparent contradictory results have been reported about the effect of succinate on aluminum toxicity, distribution and excretion in mice. Investigating the influence of this ligand on aluminum speciation in the main biofluids may help understand the above observations at the molecular level. In the absence of experimental access to ultrafiltrable aluminum speciation, computer simulations have been used in the gastrointestinal fluid and blood plasma, based on Al-succinate complex formation constants determined under physiological conditions. Calculations run for gastrointestinal conditions show that Al-succinate soluble complexes are formed in the 2 to 6 pH range--especially the neutral M2L(OH)4--which may enhance aluminum absorption. This influence, however, should be limited by dietary phosphate. In blood plasma, there is no possibility for succinate to mobilize a significant aluminum fraction, which confirms a recent suggestion that the possible protective effect of succinate against aluminum toxicity in mice may not be due to aluminum complexation.