Chemical properties of aluminium pertinent to biological interloping

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Quelling itself aloof from the biological utility functions, in spite of being ubiquitous in the environment, aluminium establishes its uniqueness as an element. Literally, aluminium is omnipresent, throughout the macrocosm (Table 1). As per abundance in the Earth’s crust, aluminium comes third as an element (after oxygen and silicon), and first as a metal. It is believed that approximately 8% (w/w) of Earth’s solid surface is contributed by aluminium. Being the most frequently encountered metal in nature, in 270 different mineral forms, undoubtedly, aluminium is the most operable element on the Earth’s surface. Interestingly, on the contrary, no aluminium compound is cognised to be used naturally by any life form.

Despite of pervasiveness, evolution has bypassed aluminium possibly because of – (i) its supererogatory reactivity and non-availability in free form in the environment, (ii) high aqueous insolubility at physiological pH along with incompatibility with other biologically active systems1, (iii) its efficient cycling within the lithosphere2 and (iv) negligence or tolerance of living organisms towards its presence.

This torpid attitude of aluminium towards the biota allowed it to be considered as ‘biologically inert’ for long. The unique physic-chemical properties (Table 2) of this metal might be instrumental for this attitude of aluminium towards the biological system. However, omnipresence of aluminium possesses the problem of being included in the cellular microenvironment; even though, it does not have any proven beneficial function in the biological system3-6. Contrary to this notion of ‘biological inertness’, aluminium is found to be used with medicinal values in varied occasions7; as follows –

  • Aluminium carbonate in antacids.
  • Aluminium chloride anhydrous as antiperspirant.
  • Aluminium chloride hexahydrate as disinfectant in stables and slaughterhouses, in deodorants and antiperspirants, as astringent (in cosmetics).
  • Aluminium chlorohydrate in deodorants and antiperspirants.
  • Aluminium hydroxide as stomach antacid, in antiperspirants and dentifrices, as phosphate binder in renal failure patients.
  • Aluminium nitrate in antiperspirants.
  • Aluminium phosphate in stomach antacids.
  • Aluminium silicate in dental cement, antacids and food additives.
  • Aluminium sulphate in antiperspirants, in agricultural pesticides, in aluminium acetate ear drops, to arrest foul discharges from mucous surfaces locally applied on ulcers as 5-10% solution.
  • Aluminium trioxide as abrasive.
  • Aluminium phthalocyanine-polymer conjugates are used as photosensitizers for photodynamic therapy of cancer.

The metal has a long history of being used for water purification and in medications. For example, in ancient Rome, aluminium salts were used for the purification of water, and in the Middle Ages it was combined with honey for the treatment of ulcers8. There are many medicinal uses of Alum (Potash Alum, Soda Alum, and Ammonium Alum), complex salts of aluminium. Some of them are listed below9:

  • As adjuvant, alum is used in many vaccine preparations. Thus, alum increase the bodily responses for the vaccination in which it is used.
  • As anti-hemorrhagic agent.
  • Being astringent, alum is useful against abrasions and venial injuries, for human (as aftershave) as well as for animals (improper nail clipping).
  • The antibiotic nature against malodours bacteria, credited alum as deodorant.
  • For canker sores, as domestic curative, powdered alum is commonly used.
  • To stop bleeding and discharge from haemorrhoids, dissolved alum powder (20%) is used to shrivel them.
  • In oral poison case, alum is also used as an emetic agent.

In homeopathic system also, alumina, a medicine prepared from aluminium, is used in treatments for chronic fatigue syndrome, dementia, nervous disorders, constipation, and appetite disorders10.

Therefore, exogenous aluminium is not really indifferent towards biological system, however, still now no beneficial role of endogenous aluminium is reported. This also unfolds the vulnerability of biological system for the metal’s untoward implications. Recently, Exley mentioned that the ‘biological reactivity of aluminium is such that there are myriad potential ligands which upon binding Al3+(aq) could induce neurotoxicity’ and explored the possibility of its coordination within a biomolecule to impart biological effect of aluminium11.

Biological Chemistry of Aluminium

Chemical properties of aluminium pertinent to biological interloping

The element aluminium is unique in respect of its many chemical properties. As a metal it is highly reactive; and, in nature never aluminium is found in its free form12. Commonly, natural existence of aluminium is as compound of oxygen, silica and fluorine. As aluminium is a hard acid, it readily reacts with hard bases like silica, oxides, phosphates and carboxylates13. Normally, aluminium exhibits only one oxidation state (Al3+) and does not undergo any oxidation-reduction reactions. However, a very small fraction of aluminium is found as the simple Al3+ ion in most natural systems14. Utilizing the physiochemical parameters of aluminium, limited predictions can be made as to the biological fate of aluminium in man15. Ligands available in biological system can interact with Al3+ to form wide-ranging complexes and limit the availability of free Al3+. Even, if no biological ligand is available, with time Al3+ salts form different hydroxy compounds. On the basis of high charge to radius ratio, thermodynamic preference of electrostatic interactions by aluminium was predicted16. The high charge and small size give Al3+ a strong polarizing effect on adjacent atoms17. Krewski et al18 rightly identified that the chemistry and biochemistry of the aluminium ion (Al3+) dominate the pathways that lead to toxic outcomes.

It has been suggested that in general, the toxic effects of aluminium result from its contention to bind with sites within biological ligands meant for other metal ions. Not being the best fit on the site specific for some other ion, aluminium ion cannot match the affinity or avidity of the specified ion. However, the competition created by presence of aluminium may have formidable impacts. Though, aluminium is a very good Lewis acid catalyst, it exchanges ligands very slowly19. With the available information about the ligand exchange process, it can be suggested that binding of aluminium with available biological structures, which are acting as ligand for aluminium complex or capable of using aluminium as ligand for them, would construct a strong interlinking bond. However, as already mentioned, the slow exchange rate for ligands would slacken the reaction process.

Solubility of aluminium in biological fluid

Limited water solubility of aluminium and its compounds is believed to be the reason of its restricted use in the biological system. The solubility of Al3+ is lowest at pH 6.2 but increases with acidic or alkaline solutions and by some complexing ligands20. In nature, most of aluminium is in the complex form. However, easy transition of it from solid to liquid phase and high solubility of the metal in acid environs are decisive factors for its harmful impacts21. Aluminium also forms numerous mineral and organic complexes characterized by different degrees of hydration.

The forms of aluminium occurrence and their solubility are crucially determined by the pH of the solution. If pH is less than five, aluminium in water occurs as [A1(H2O)6]3+ ion, a simple form. Hydrocomplex ions, like [A1(H2O)5(OH)]2+ and [A1(H2O)4(OH)2]+, start appearing in the solution with the increase of pH. In combination with organic and inorganic ligands, [A1(H2O)6]3+ ions form numerous complexes which can be further polymerized into multimolecular structures when the pH ranges from 4.5 to 5.5. Soluble A1(OH)3 begins to occur when the pH is approximating 6 and more soluble ionic forms like [A1(H2O)2(OH)4]- and [A1(H2O)(OH)5]2 come along when pH is 6.2 or more22.

Acidity and alkalinity of solutions greatly promote the solubility of aluminium12, 13. Highly differentiated concentrations of aluminium (range: 0.001 – 1.0 mg/dm3 in neutral to alkaline pH; may reach to 100 mg/dm3 in acid pH) in water is the result of change in solubility accompanied with change in chemical forms22. In near neutral pH, as in most biological systems, aluminium complexes undergo extensive hydrolysis and generate hydroxides [Al(OH)3] that precipitate out of solutions12, 13. At pH ~4.0, where the presence of [A1(H2O)6]3+ ion is reported, the conditions are best suited for aluminium absorption. Interestingly, this ion and its hydrolytic forms i.e. [A1(OH)]2+, [A1(OH)2]+ are considered as toxic22.

Aluminium speciation in biological fluid

Trivalent hexa-aqua cation of aluminium is the biologically reactive form11. Solubility, bioavailability, tissue uptake, excretion and toxicity of aluminium are influenced by the form or chemical speciation of aluminium in environment and body fluid23, 24. Recently, Liang et al25 have reemphasized the same and mentioned that speciation is also important for transfer of aluminium into the brain. Aluminium is present in blood as ionic species, although, complexes with low molecular weight organic molecules, such as citrate and bicarbonate, are formed. As mentioned earlier, at physiological pH aluminium undergoes hydrolysis and forms polymeric species, such speciation is precluded. The highly polarising power of the aluminium ion dictates its fastidious affinity for oxygen donors that exist in large quantity within the dietary substances and eventually diversify its chemical attaractions towards the essential biomolecules26. On the other hand, presence of complexing anions and/or other binding species in blood inhibit the aforementioned hydrolytic reactions of aluminium. Consequently, in blood and tissue fluids aluminium ions are found complexed with organic molecules12. Interaction with organic molecules is also substantiated by substitution of magnesium and iron by aluminium in mammalian system and also can alter the metabolic processes22.

There are three main categories of aluminium species relevant to biological availability. These are monomeric, polymeric (formed through activation of coordinated OH groups becoming deprotonated and bridging between the metal centres), and metastable polynuclear aluminium complexes, which grow in size and ultimately form microcrystalline gibbsite27. At neutral pH, the salt undergoes extensive hydrolysis and Al(OH)3 is produced. As the solution ages, Al3+ salts form monomeric hydroxy compounds, which form polymeric hydroxy compounds and later colloidal particles14. The pH of a solution determines the aluminium species and ionic forms present28. Thus, in basic media, aluminium exists as the anionic form while in acidic solutions it is found in the cationic form14. Since aluminium is a very strong oxygen acceptor, it also tends to bind to other oxygen donors such as citrate, phosphate, lactic acid, oxalic acid, citric acid and catecholamines29. Because of the formation of these insoluble aluminium species, it was taken for granted that limited absorption would render innocuity to aluminium14. Besides, the dominant form of aluminium in physiological pH is Al(OH)4­¯ and this form of aluminium does not react with ligands or proteins in aqueous media2. Therefore, this self-precipitation and non-reactivity of aluminium species may be the hindrance of the element’s involvement in biological evolution and regarded as ‘biologically inert’.

Taking together – the speciation and ligand binding (Figure 1) – it has been suggested that the concentrations of hydrogen (pH) and suspension (buoyancy) of a solution influence the availability of monomeric form of inorganic aluminium (Al3+). In addition, accessibility of active ligands also plays important role in discerning this toxic fraction of aluminium in the solution22.

There are two major groups of biological ligands reacting / binding with aluminium – (a) high molecular masses like transferrin, and (b) low molecular masses like citrate. As these interactions influence the bioavailability and speciation of aluminium, on the other hand, structural and chemical alterations of these ligands are also highly possible under the influence of interactions with aluminium. Thus, aluminium has the potential of bifacial impacts on the biological interactions.

In spite of growing information and concern regarding the aluminium-borne health issues, till the end of twentieth century, the concept of limited bioavailability prevailed. Release of aluminium into the environment was regarded as harmless and human interventions continued to increase the biologically reactive aluminium in environment. Complexation and interactions of aluminium with wide range of neuroactive biomolecules like high-energy phosphate compounds, substrate and cofactors of various enzymes, phospholipids, etc. are reported for long. Recently, aluminium’s derivatization with superoxides is drawing attention as putative agent involved in neurodegeneration.

Are superoxide species also possible for aluminium?

Possibilities of complexation between aluminium and superoxide have been suggested for long30. In spite of several indirect evidences in support of the concept, till now the aluminium-superoxide species is not identified. With the help of electron paramagnetic resonance (EPR) study, Exley31 predicted that possible aluminium-superoxide complex would be a strong one and associated with high oxidizing power. Confirmation of putative aluminium superoxide semi-reduced radical ion [AlO2]2+ might explain the prooxidant activity of aluminium, as well as bridge the catalytic activity of this redox-inactive metal and both superoxide-driven and iron-driven biological oxidation32. However, to explain the association of oxidant imbalances with aluminium exposure while aluminium itself is a redox-inactive metal, existence of Al3+-superoxide complexes (Figure 2) have been hypothesized and theoretical (simulative) testings are being carried out2.

Observing strong affinities and exoergonicity of Al3+ toward the superoxide, Mujika et al2 suggested that even small concentrations of Al3+ free species would be relevant for oxidant activity. They have also suggested that low molecular mass ligands may have dual impact on the oxidation capacity of aluminium. One way low molecular mass ligands may augment the [AlO2]2+ formation by enhancing the bioavailability of Al3+ species, while these ligands may also influence the thermodynamic equilibrium of [AlO2]2+ formation. Once an [AlO2]2+ species is formed, how this radical ion leads to oxidative damage is still speculative.