Pharmacological implications of aluminofluoride complexes.

A review of the evidence for pathophysiological effects of aluminium and fluoride on living organism

Aluminofluoride complexes: new phosphate analogues for laboratory investigations and potential danger for living organisms. by ©Anna Strunecká^a & Jiří Patočka^b
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^aCharles University, Faculty of Sciences, Department of Physiology and Developmental Physiology, Prague
^bDepartment of Toxicology, Purkyn Military Medical Academy, Hradec Králové, Czech Republic

Running title: Pharmacological implications of aluminofluoride complexes

Corresponding author: Anna Strunecká
Department of Physiology and Developmental Physiology,
Faculty of Sciences, Charles University, Vininá
7, 128 00, Prague 2, Czech Republic
Telephone: (42) - 02/21953239
Fax no.: (42) - 02/299713
E-mail: astrun@cesnet.cz

A list of non-standard abbreviations used in the paper: AD, Alzheimer´s disease; [AlF₄]^–, aluminofluoride complexes; cAMP, cyclic adenosine monophosphate; G proteins, guanine nucleotide binding proteins; GDP, guanosine diphosphate; GTP, guanosine triphosphate; 1,4,5-IP₃, inositol-1,4,5-trisphosphate; PIP₂, phosphatidylinositol 4,5-bis-phosphate.

Abstract

Aluminofluoride complexes have been widely used in laboratory investigations for stimulation of various guanine nucleotide binding proteins. These fluorometallic complexes cannot be obtained through any catalogue or drug store. They are formed in water solutions containing fluoride and traces of aluminium in the form of the soluble ionic complexes, Aluminofluoride complexes have been recognised to act as phosphate analogues. Reflecting many studies which utilise aluminofluoride complexes in laboratory investigations, the effects of these fluorometallic complexes on various cells and tissues as observed, can be reviewed. With the appearance of acid rain and the use of aluminium in industry, there has been a dramatic increase in the amount of uncomplexed aluminium in ecosystems. In view of the ubiquity of phosphate in cell metabolism, aluminofluoride complexes represent a strong potential danger for living organisms including humans. The possibility of pathophysiological consequences of their long-term action is not fully recognised at this point.

INTRODUCTION

During the last decade aluminofluoride complexes have been widely used in laboratory investigations as the tool for stimulation of various guanine nucleotide binding proteins (G proteins). Knowledge about the role of G proteins in signal transduction has expanded enormously , as over one hundred G protein-coupled receptors have been described (Gilman, 1987). Physiological agonists of these receptors include neurotransmitters and hormones, such as dopamine, epinephrine, norepinephrine, serotonin, acetylcholine, glucagon, vasopressin, neuropeptides, opioids, excitatory aminoacids, prostanoids, purines, photons and odorants. Fluoride anions had been recognised as the activators of the purified guanine nucleotide-binding regulatory component of adenylate cyclase (Rall & Sutherland 1958). Later Sternweis & Gilman (1982) reported that fluoride activation of adenylate cyclase depends on the presence of aluminium traces. The requirement for aluminium is highly specific; of 28 other metal tested, only Be²⁺ promoted activation of the guanine nucleotide-binding regulatory component of adenylate cyclase by fluoride. [AlF₄]^– mimics the role of the phosphate only if the phosphate is present and remained unsubstituted. These metallofluoride complexes are only active in conjuction with a bound nucleoside diphosphate. Their effect is more readily seen with G proteins because guanosine diphosphate (GDP) is always tightly bound in the site after the hydrolysis of guanosine triphosphate (GTP). In aqueous solutions, the fluoride anions bind to metal cation and are exchangeable with free fluoride or hydroxyl ions. The complexes are not permanent; equilibria exist between the various possible complexes, and the proportions of multifluorinated species such as AlF₃, AlF₃(OH) and [AlF₄]^–, depend on the excess concentration of free F^– ions and on the pH of the solution (Bigay et al. 1987; Martin 1988; Chabre 1990).

Chabre (1990) explained an important "functional" difference between a phosphate group and the structurally analogous aluminofluoride complexes. In phosphate, oxygen is covalently bound to the phosphorus and does not exchange with oxygen from solvent. In aluminofluoride complexes, ionic bonds are formed between the electropositive aluminium and the highly electronegative fluorine. While the reaction of a bound phosphate compound with orthophosphate is endergonic and slow, the corresponding reaction with [AlF₄]^– is rapid and spontaneous. Aluminofluoride complexes bind ionically to the terminal oxygen of GDP -phosphate. Enzyme-bound GDP or ADP could therefore form a complex with [AlF₄]^– that imitates ATP or GTP in its effect on protein conformation. This effect often causes a structural change that locks the site and prevents the dissociation of the trisphosphate. Free phosphates and nucleotides, when present at milimolar concentrations, do bind ionically to all the fluoride complexes. The action of [AlF₄]^– is not therefore restricted only to guanine nucleotides. These fluorometallic complexes influence the activity of a variety of phosphatases, phosphorylases and kinases (Bigay et al. 1987). In view of the ubiquity of phosphate in cell metabolism, aluminofluoride complexes can represent a strong potential danger for living organisms including humans. The possibility of pathophysiological consequences of their long-term action is not fully recognised at this point. But, reflecting many studies which utilise aluminofluoride complexes in laboratory investigations, the effects of these fluorometallic complexes on various cells and tissues as observed, can be reviewed. It might seem difficult to decide if these experiments present a potential toxicological risk for the human population in the future. In this article we review some of the evidence for pathophysiological effects of aluminium and fluoride on living organism.

II. PHYSIOLOGICAL AND BIOCHEMICAL ACTION OF [AlF₄]^–
IN VARIOUS CELLS AND TISSUES

Liver. Isolated parenchymal cells, hepatocytes, maintain responsiveness to hormones and serve as model cells equipped with very complex biochemical pathways. The stimulation of glycolysis by vasopressin, angiotensin II, and ₁-adrenergic agonists is mediated in the liver through the increase of the Ca²⁺ cytosolic level. It has been demonstrated that the phosphoinositide signaling second messenger system is activated and involved in these events (Werve et al. 1985). Blackmore et al. (1985; 1988) demonstrated in their studies that the treatment of isolated hepatocytes with NaF produced the efflux of Ca²⁺, the rise in free cytosolic Ca²⁺, the decrease in phosphatidylinositol 4,5-bis-phosphate (PIP₂)content and the increase in inositol-1,4,5-trisphosphate (1,4,5-IP₃) and diacylglycerol. The level of intracellular cyclic adenosine monophosphate (cAMP) was decreased. All these changes were concentration dependent. The effects of low doses of NaF (2-15 mM) were potentiated by AlCl₃and this potentiation was abolished by Al³⁺ chelator desferoxamine. Fluoride anions in the presence of aluminium thus mimicked the action of Ca²⁺-mobilizing hormones glucagon and vasopressin in hepatocytes. The effects of submaximal doses of [AlF₄]^– were potentiated by submaximal doses of vasopressin, angiotensin II, and ₁-adrenergic agonists. Using phorbol myristate acetate, the activator of protein kinase C, the conclusion was made that [AlF₄]^– mimics the effects of Ca²⁺ mobilizing hormones by activating the G protein which couples the hormone receptor to phospholipase C specific to PIP₂ (Blackmore & Exton 1986). The phosphate-analogue model of [AlF₄]^– action is not restricted to guanine nucleotides in the liver. Blackmore et al. (1985) observed the activation of phosphorylase and inactivation of glycogen synthase after the activation of fluoride in the presence of AlCl₃ in hepatocytes. [AlF₄]^– transforms the liver to the organ involved in glycogenolysis, fatty acid oxidation and lipolysis.

Brain. G protein-coupled receptors and G protein-mediated cell responses are of key importance in the processes of neurotransmission and intercellular signaling in the brain. Phosphoinositide metabolism is coupled to several neurotransmitter receptors in the central nervous system including cholinergic, adrenergic, dopaminergic and histaminergic receptors. [AlF₄]^– has been widely used to stimulate phosphoinositide hydrolysis. The ability of [AlF₄]^– to mimic the effects of Ca²⁺-mobilizing hormones suggests the coupling of hormone receptors to phosphoinositide breakdown through G proteins (Rana & Hokin 1990).

Candura et al. (1991) observed that aluminium salts and NaF mimicked the action of GTP(S) in stimulating phosphoinositide turnover and generation of inositol phosphates in rat cerebral cortical membranes. A much greater hydrolysis of phosphoinositides was observed when AlCl₃ and NaF were present together, supporting the concept that [AlF₄]^– is the active stimulatory species. Nadakavukaren et al. (1990) demonstrated accumulation of inositol phosphates in the suprachiasmatic nuclei region of rat hypothalamus over a 40 min incubation with [AlF₄]^–. Hypothalamic suprachiasmatic nuclei were suggested as the site of a biological clock responsible for generation of circadian rhythms. Melatonin receptors are involved in this function. Melatonin can facilitate secretion via a cholera and pertussis toxins-insensitive mechanism which can be inhibited by aluminum fluoride. [AlF₄]^– blocked the increase in cAMP stimulation by forskolin, being as effective as melatonin and increased intracellular calcium ( Morgan et al. 1991).

When rat hippocampal slices were exposed to 10 mM NaF and 10 µM AlCl₃ for a brief period of time (12-15 min), spike amplitude fell to very low levels. Upon washout, spike amplitude recovered beyond control values and in half of the preparations a prolonged enhancement of spike amplitude (greater than 2 hours) occurred. If AlCl₃ was omitted from fluoride-containing saline, enhancement of spike amplitude, when observed, was brief. These experiments show that brief exposure to [AlF₄]^– induces prolonged enhancement of synaptic transmission in rat hippocampal slices (Publicover 1991).

Tremendous possibilities of multiple molecular interactions of aluminium, fluoride and aluminofluoride complexes probably exist in the brain. Understanding the action of [AlF₄]^– in the brain warrants further investigation.

Kidney. The effects of aluminofluoride complexes on the kidney were studied using glomerular mesangial cells, proximal tubular cells, and inner medullary collecting tubule cells of rat kidney.

The ion transporting processes are affected by [AlF₄]^– in kidney tubular cells. [AlF₄]^– stimulates adenylate cyclase, inhibits amiloride-sensitive Na/H exchange regulated by cAMP-dependent protein kinase, enhances epidermal growth factor-stimulated prostaglandin production, and mimics vasopressin and bradykinin induced Ca²⁺ mobilisation. It is suggested that [AlF₄]^–can affect the activity of many other ion channels and enzymes in the kidney (Zhou et al.1990).

Cells of blood. [AlF₄]^– induces shape changes and aggregation in platelets ( Rendu et al. 1990). Incubation of platelets with NaF (5-10 mM) induced only slight morphological changes. Addition of 10 µM AlCl₃ resulted in aggregation. One min after addition of AlCl₃, most of the granules were concentrated in the center of the cell, but some were extruding their contents by direct exocytosis. No myosin light-chain phosphorylation typical for the platelet response was observed after fluoride activation in the presence of aluminium. It has been reported that [AlF₄]^– impairs the polymerisation-depolymerisation cycle of tubulin (Chabre 1990).

Rapid and dynamic changes of the actin network are of vital importance for the motility of human neutrophils. Bengtsson et al. (1990) observed [AlF₄]^– induction of a pronounced and sustained increase in a filamentous form of actin in intact human neutrophils. This effect parallels an increase in cytosolic Ca²⁺ level, indicating that phospholipase C (PLC) is activated.

Shape changes and disorganisation of the spectrin network were observed after addition of 1 mM NaF and 10 µM AlCl₃in human red blood cells (Strunecká et al. 1991). Cells lost their membrane material and became smaller.

Osteoblasts and osteoclasts. Caverzasio et al. (1996) found that traces of aluminium markedly enhanced the stimulation of inorganic phosphate transport induced by fluoride in osteoblasts, suggesting that a fluoroaluminium complex might be responsible for fluoride -induced regulatory pathway. Analysis of the role of tyrosine phosphorylation in mediating this cellular response indicates that this signal transduction pathway is also involved in the stimulation of inorganic phosphate transport activity by fluoride. Aluminium potentiates the effect of fluoride on tyrosine phosphorylation and osteoblast replication in vitro and bone mass in vivo. The combination of fluoride and aluminium modulates a growth factor-dependent tyrosine kinase pathway enhancing mitogen-activated protein kinase and osteoblastic proliferation. Studies in ewes show that at a low dose fluoride stimulates the recruitment and lifespan of osteoblasts; at higher doses, fluoride decreases osteoblast activity (Chavassieux et al. 1991). The hormone calcitonin inhibits osteoclastic bone resorption. The activation of calcitonin involves two separate effects on the osteoclast: abolition of cell motility and marked cellular retraction. [AlF₄]^– produces both effects. Calcitonin elicited a biphasic elevation of cytosolic calcium level in isolated osteoclasts. Exposure of osteoclasts to [AlF₄]^–resulted in a marked concentration-dependent inhibition of bone resorption (Moonga et al. 1993).

Energy metabolism. ATP generation in mitochondria requires the association of F₁ subunit with F₀ transmembrane subunit transporting protons. The binding of ADP and P_i in a catalytic site of F₁ triggers conformational changes which lock both of them into the site and induce the formation of pyrophosphate bonds by eliminating a water molecule (Chabre 1990). Lunardi et al. (1988) reported the inhibition of mitochondrial ATPase activity in the presence of [AlF₄]^–. This inhibition is not reversed by elution of fluoride from solution or by addition of strong chelators of aluminium. No significant release of the complex occured over a period of days. [AlF₄]^– inhibits many ATPases, phosphatases and phosphorylases. The intervention of aluminofluoride complexes in the energy transformation processes may thus affect the energy metabolism of the entire organism.

III. EVIDENCE FOR IMPLICATION OF ALUMINIUM, FLUORIDE
AND ALUMINOFLUORIDE COMPLEXES IN PATHOLOGY

Elevated aluminium levels have been implicated as the cause of dialysis encephalopathy or dementia in renal failure patients after three to seven years of hemodialysis treatment (Alfrey et al. 1976; Meiri et al. 1991). Speech disorders precede dementia and convulsions. The mode of death has been reported as sudden cardiac arrest usually associated with acute pulmonary oedema (Elliot et al. 1978).

Increased serum fluoride concentration and fluoride intoxication have been also observed in chronic hemodialysis patients (Chaleil et al. 1986 ). Arnow et al. (1994) reported that 12 of 15 patients receiving dialysis treatment in one room became acutely ill, with severe pruritus, multiple nonspecific symptoms, and/or fatal ventricular fibrillation (3 patients). Death was associated with longer hemodialysis time and increased age compared with other patients who became ill. Serum concentrations of fluoride in the sick patients were markedly increased to as high as 716 µM. The source of fluoride was the temporary deionization system used to purify water for hemodialysis.

NaF is so far clinically used as the potent stimulator of bone formation. However, there are conflicting reports on the effect of fluoride on trabecular bone formation and bone strength. Osteosclerosis in workers exposed to fluoride and aluminium (industrial fluorosis) led to the use of fluoride as a treatment to increase bone mass in osteoporosis patients. Caverzasio et al. (1996) administered fluoride and aluminium subcutaneously to rats for 8 months. Their results suggest that the combination of fluoride and aluminium modulates a growth factor-dependent tyrosine kinase pathway enhancing mitogen-activated protein kinase and osteoblastic proliferation and bone mass. The authors concluded that these effects are consistent with the crucial role of aluminium in osteosclerosis observed in industrial fluorosis.

Soyseth et al. (1994) investigated the relation between plasma fluoride levels and bronchial responsiveness in a longitudinal study in aluminium potroom workers who reported work-related asthmatic symptoms. A positive association was found between bronchial responsiveness and plasma fluoride levels. Plasma fluoride levels were associated with the total atmospheric fluoride concentration.

The effects of aluminofluoride complexes have been also studied in connection with impairment of blood circulation. As a model for G protein-induced cardiopulmonary dysfunction, fluoride infusion (0.9 mol/l in 0.9% NaCl at 15 µl.kg^-1.min^-1 for 3 h i.v.) in the presence and absence of AlCl₃ (0.6 µg.kg^-1.min^-1) into pigs anaesthetised with pentobarbital sodium was used (Dodam & Olson, 1995). NaF, with or without AlCl₃, induced progressive deterioration of cardiopulmonary function after 1 h of infusion. Recent studies provide evidence that apoptosis of pancreatic cells is important in the early etiology of both type I and type II diabetes mellitus. Loweth et al. (1996) employed fluoride and show that this agent induces apoptosis in clonal pancreatic cells and also in the cells of normal rat islets of Langerhans. The process may reflect the formation of [AlF₄]^– since it was inhibited by the aluminum chelator deferoxamine.

Conroy et al. (1995) reported that treatment of thymic lobes cells with fluoroaluminate provoked apoptosis of a wider range of thymocyte subtypes. Oguro et al. (1990) studied the cytotoxicity of NaF on fibroblast-like cells from 5 Japanese whole foetuses and found that the growth of the cells was markedly impaired by fluoride. In a living organism, fibroblasts must be able to move into areas of newly forming tissue and to secrete molecules that helps glue together the tissue. Laboratory investigations clearly indicate that both production of extracellular matrix and cell movement can be affected by the action of [AlF₄]^–.

Because a higher amount of aluminium was found in the human brain with Alzheimer's disease (AD) than in brains of age-matched healthy controls, the hypothesis that the accumulation of toxic amounts of aluminium in the brain is the cause of neurofibrillary changes and dementia has been discussed very often (McDermott et al. 1979; Zatta et al. 1988; Patočka et al. 1996). A positive correlation between the incidence of Alzheimer's disease and concentrations of aluminium in drinking water was reported by some authors (Martyn et al. 1989; Flaten 1990). Neither the increased content of aluminium in the brain nor the results of ecological studies can explain why aluminium constitutes a risk. Aluminium is currently regarded as the putative risk factor for the etiology of this disease. The recent fundamental research of pathogenesis of AD has brought evidence that this disease is connected with the alterations in neurotransmission, -amyloid production, plaque formation, and cytoskeletal abnormalities in brain tissue. We suggest that some of pathologic changes are not raised by aluminium alone, but by the aluminofluoride complexes (Strunecká 1999). AD could be an example demonstrating the diversified and multidimensional nature of the integration of the nervous system. However, aluminofluoride complexes may act as the initial signal stimulating impairment of homeostasis, degeneration and death of the cells. By influencing energy metabolism these complexes can accelerate the aging and impair the functions of the nervous system. In respect to the etiology of AD, the long term action of [AlF₄]^– may represent a serious and powerful risk factor for the development of this devastating disease.

IV. CONCLUSIONS

Aluminofluoride complexes appear as a new class of phosphate analogues for laboratory investigations. Experimental data clearly indicate that aluminofluoride complexes may mimic or potentiate the action of numerous extracellular signals and significantly affect many cellular responses. The principle of amplification of the initial signal during its conversion into the functional response has been a widely accepted tenet in cell physiology. Aluminofluoride complexes may therefore act with powerful pharmacological efficacy. The interpretation of laboratory investigations using isolated animal and human cells or tissues on the intact human organism could be discussed. It seems that, in an evolutionary sense, the natural barrier systems such as low aluminium absorption in the gastrointestinal tract, and various physiological ligands, such as transferrin, citrate, phosphate and silicic acid, were efficient buffers preventing the increased intake of this metal in natural conditions (Wilhelm et al. 1990). With the appearance of acid rains and due to the use of aluminium in industry, there has been a dramatic increase in the amount of aluminium appearing in ecosystems, nourishment and water sources (Cooke & Gould 1991). The increasing content of aluminium and fluorides in environment and food chains has raised the possibility that the near future will supply us with more data about the danger of aluminofluoride complexes for the human race.

Supported by Grant Agency of Charles University, Prague (Grant No. 113/1998/BBio/PřF).

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