Effects of Aluminum on Bovine Parathyroid Adenylate Cyclase*

Abstract

It is known that the secretion of PTH is often impaired in association with aluminum (Al3+) accumulation in patients with renal failure. The mechanisms involved remain ill defined. Since adenylate cyclase plays a role in the regulation of PTH secretion, these studies examine the effects of Al3+ on parathyroid adenylate cyclase. In membranes from normal bovine parathyroid glands, basal adenylate cyclase activity, in the presence of 0.2 mM ATP and 20 mM Mg2+, increased by 22% as Al3+ was raised from 0-10 microM. Higher Al3+ concentrations caused a progressive decrease in adenylate cyclase activity, reaching 68% inhibition of control activity at 2 mM Al3+. Since adenylate cyclase activation is influenced by the interaction of multiple sites within the adenylate cyclase complex, the nature of the inhibition by Al3+ was explored by examining the interaction of Al3+ with substrate ATP and with Mg2+, an allosteric activating metal ion. In the presence of 20 mM Mg2+, Al3+ concentrations of 1-2 mM resulted in noncompetitive inhibition with respect to ATP [decrease in maximum velocity (Vmax) from 4176 in the absence of Al3+ to 1106 pmol cAMP/mg protein X 15 min; Michaelis Menten constant (Km) for ATP was unchanged]. In contrast, at fixed ATP (0.2 mM), 0.5 mM resulted in competitive inhibition of adenylate cyclase with respect to Mg2+, whereas at higher Al3+ concentrations the inhibition was noncompetitive. When Mg2+ was replaced by Mn2+ (enzyme activity reflects the activity of the catalytic unit), the inhibitory effect of Al3+ on adenylate cyclase activity was abolished. These data suggest that the inhibition of parathyroid adenylate cyclase by Al3+ occurs at the level of the allosteric metal activating site. These data provide a potential mechanism for the inhibition of PTH secretion by Al3+.

Substitution of Calcium Carbonate for Aluminum Hydroxide in Patients on Hemodialysis

“…First, it has been recently shown using in vitro techniques that the secretion of PTH by collagenase-dispersed bovine parathyroid cells or by tissue slices of porcine parathyroid glands is inhibited when these pre parations are incubated in media containing aluminum in concentrations comparable to those seen in patients on hemodialysis [22][23][24]. Furthermore, a decreased respon siveness of the parathyroid glands to hypocalcemia has been observed in patients with osteomalacia and evi dence of bone aluminum deposition [38].…”

“…We recognize that in our patients the simple discontinuation of aluminum intake for a period of 3 weeks is not likely to have caused a substantial decrement in total body aluminum content. However, the decrease in plasma aluminum levels may have been correlated with a decrease in the amount of readily ex changeable aluminum strategically located in the parath yroid glands where it exerts its suppressive action upon the activity of adenylate cyclase [23,39], This would then result in an increased secretion of PTH despite the con current increase in serum calcium concentration.…”

“…The consequences of the administration of CaCO? coupled with the discontinuation of Al(OH), on parathy roid function have not been explicitly assessed in clinical studies, despite some tantalizing evidence that aluminum inhibits parathyroid hormone (PTH) secretion in vitro [22][23][24]. We reasoned that if aluminum also inhibits par athyroid secretion in vivo, the discontinuation of Al(OH)j may be followed by a state of functional hyper parathyroidism that could contribute to the hypercal cemia seen with CaCOj administration.…”

The Influence of Aluminum on Resistance to <i>Listeria monocytogenes</i> in Swiss-Webster Mice

“…Such ef fects may inhibit molecular interactions on the sur face of lymphocytes, decrease the mobility of phago cytic cells and halt metabolic processes by making ATP unavailable for use, thereby increasing suscep tibility to bacterial challenge. However, Al may also decrease cAMP synthesis, increase cGMP produc tion, cause the release of intracellular calcium stores, stimulate the metabolism of phosphotidylinositols and initiate the phosphorylation of T cell receptors [5,7], These latter studies provide the basis for an understanding of how Al may increase immune re sponsiveness, including the means by which Al may act as an immunological adjuvant. In fact, Al has been shown to enhance antigen-presenting activ ity [27], suggesting that one effect of Al adjuvants in vaccines is to alter cellular function.…”

“…These clinical and environmental obser vations, combined with the knowledge that this metal is used as a component in many consumer products, motivated the initiation of studies on the biological consequences of excess Al exposure [1][2][3]. For exam ple, among 29 metals examined in vitro, only beryl lium and Al (1-5 pAf), complexed with fluoride ion, were able to activate G proteins and thereby regulate adenylate cyclase activity [4], At higher concentra tions (> 10 pi A/), Al was also shown to inactivate ad enylate cyclase [5]. Other work has pointed to the pos sible involvement of Al in the production of cyclic GMP [6] as well as the phosphatidylinositol secondmessenger pathway [7], Al hydroxide is well known as an immunological adjuvant and Al has been shown to activate lymphoid cell functions [7,8], Animal exposure studies have also shown that Al can modify mast cell function [9], induce splenic suppressor macrophages [10] and acti vate complement [11], We report herein that Al can af fect susceptibility of mice to infection by Listeria monocytogenes.…”