The influence of magnesium and some other divalent cations on hepatic microsomal drug metabolism in vitro

Abstract

The addition of Mg 2+ caused marked increases in rat liver microsomal metabolism in vitro of several drug substrates. The substrates studied have been grouped according to the responses seen with increasing concentrations of Mg 2+: (1) no effect or a decrease in enzyme activity; (2) increased enzyme activity with increased Mg 2+ concentrations; and (3) peak enzyme activity with 6 mM Mg 2+ or less, followed by a decreased activity with higher concentrations of Mg 2+. Enhanced drug metabolism appeared to be caused by the Mg 2+ ion rather than by ionic strength or associated anion. Although Mg 2+ may affect the NADPH-generating system, it also enhanced the microsomal drug-metabolizing enzyme systems directly (Mg 2+ enhanced activity in the absence of an NADPH-generating system). Other divalent cations (Mn 2+, Ca 2+ and Sr 2+) caused a marked enhancement of hepatic microsomal metabolism similar to that caused by Mg 2+ with all substrates studied. Divalent cobalt in low concentration caused enhanced microsomal metabolism of hexobarbital, but was inhibitory with other substrates. Ferrous ion, Cu 2+ and Zn 2+ did not enhance any of the microsomal drug metabolisms studied. The monovalent cations, K + and Na +, had little if any effect on drug metabolism. The effects of the various cations studied were qualitatively the same with hepatic microsomal preparations from both control and phenobarbital-treated rats.