Consider Magnesium Homeostasis: III: Cytochrome P450 Enzymes and Drug Toxicity*

Abstract

The serum contains only 0.3% of the body's magnesium (sMg). More than half is in bone and nearly half is intracellular. The bone Mg is in equilibrium with sMg, whereas red blood cell Mg (rbcMg) reflects sMg concentration while each cell is maturing. The kidney controls the sMg by reabsorption up to a serum level of 3mg/dL, and the amount saved varies with the Mg balance. Normal humans retain less than 25% of an intravenous Mg load test. When the sMg is normal and the load test and/or rbcMg values are abnormal, normomagnesemia Mg deficiency (MgD), Type I, exists. The earliest stage is latent MgD, which has been defined as more than 25% but less than 50% retention of Mg in a load test. In those with more severe stages of MgD, the Mg retention is more than 50%. Occult MgD is when there is more than 50% retention. Whenever the rbcMg level is also decreased, subclinical MgD is present. Type II MgD is clearly understood by everyone, because of the presence of hypomagnesemia. There are multiple causes of minimal urinary Mg wasting, plus other causes of MgD, and there are many subtle symptoms of MgD. Over 300 enzyme systems require Mg to function optimally, including the cytochrome P450 enzymes (CYP450). In vitro evaluation of CYP450 metabolism of drugs require a NADPH-generating system, which contains MgCl2 and requires NADPH cytochrome P450 reductase. NADPH-CYP450-reductase also requires Mg. Drug toxicity might well be due, in part, to CYP450 enzymes not being in an adequate environment when MgD is present. Symptoms and signs of both noncardiac and cardiotoxic drug reactions to theophylline and some of the second-generation antihistamines are similar to those found in MgD. MgD is a known risk factor for torsades de pointes TdP, which has been treated with Mg sulfate. Moreover, many of the causes of MgD are present in patients with drug intolerance. A comprehensive evaluation of Mg status should be done in all patients with drug reactions when CYP450 enzymes are involved, before, during and after intervention. This should include a sMg, rbcMg, and a 24-hour urine Mg levels. A urine creatinine/Mg ratio should be calculated using 24-hour urine concentrations. The metabolism of these drugs need to be studied in a population of patients with known normomagnesemia MgD.