Introduction

Magnesium is an element with an atomic number of 12 and a mass of 24.32 Da. It is the fourth most abundant cation in the body and the second most abundant cation in intracellular fluid. Nevertheless, the mechanisms involved in its regulation are still unknown. Magnesium is an essential cofactor for more than 300 cellular enzymes located in many intracellular compartments including nucleus, mitochondria, cytosol and microsomes. Magnesium is mainly involved in the activity of enzymes deputated to energy transfer through the action of adenosine nucleotides and also plays a role in protein and nucleic acid synthesis within the cell.

The knowledge of the detailed mechanisms regulating magnesium cellular homeostasis has been hampered by technical and methodological difficulties. In fact, until quite recently only the total magnesium concentration was measurable. Magnesium is present in three different states in most biological systems: freely coordinated to water, associated with anions and bound to protein. Because protein-bound and complexed magnesium are unavailable for biochemical processes, only ionized magnesium has biological activity. The synthesis of fluorescent probes quite specific for magnesium has greatly improved the knowledge about intracellular magnesium homeostasis.

Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine Edited by Gielen and Tiekink © 2005 John Wiley & Sons, Ltd

Cytosolic magnesium concentration is far from its electrochemical equilibrium. If cytosolic magnesium was at electrochemical equilibrium, assuming a membrane potential of — 70 mV and an extracellular magnesium concentration of about 0.8mmol/l, its concentration would be approximately 190mmol/l. The total intracellular magnesium concentration is about 12 mmol/l, thus it is evident that magnesium must be pumped out of the cell.1 4 The great majority of cellular magnesium is bound to intracellular constituents such as nucleic acids, phospholipids ATP and proteins, and ionized magnesium concentration is in the 0.3-1 mmol/l range.5,6

On average, the human body contains approximately 1 mol (24 g) of magnesium.7 About half the magnesium is present in the bone, and the other half is intracellular in soft tissue and muscle. Less than 1% of total body magnesium is present in plasma. This is particularly important to remember when interpreting laboratory data about magnesium. For example, plasma levels of magnesium reflect a very small fraction of total body magnesium and may not provide information on its status.

Recent studies indicate that the majority of magnesium is absorbed in the ilium and colon,8 and that there is an inverse curvilinear relationship between intake of magnesium and fractional absorption which ranges from 65 to 10% absorption at low and high intake, respectively.9 This suggests that for treating a magnesium deficiency a long oral supplementation period is required. The kidney is the major excretory organ for magnesium and is responsible for controlling plasma magnesium levels. The majority (70-80%) of plasma magnesium is filtered through the glomerular membrane. About 10-15% of the filtered magnesium is reabsorbed along the proximal tubule, about 60-70% is reabsorbed along the thick ascending limb of the Henle's loop and another 10-15% in the distal convoluted tubule.10

The majority of body magnesium is located in the bone and part of this magnesium is adsorbed to the surface and is in equilibrium with extracellular magnesium. At reduced plasma concentrations, magnesium can rapidly be released from the bone. Bone magnesium therefore represents a rapidly exchangeable pool that buffers magnesium extracellular concentration.11

The usual diet provides 2-7.5 mg of Mg2+ per kg of body weight. For adults the recommended intakes of magnesium are between 300 and 420mg/day.12 In animal models it has been shown that a reduction of total intracellular magnesium concentration can only be achieved by feeding animals with a severely deficient diet.13 Only if plasma magnesium is reduced below 0.2 mmol/l, a small decrease in intracellular magnesium concentration can be measured, indicating that the effects of magnesium deficiency are mainly restricted to extracellular magnesium.

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