A STUDY OF SOME POSSIBLE MECHANISMS BY WHICH MAGNESIUM ACTIVATES HEPATIC MICROSOMAL DRUG METABOLISM IN VITRO

¹ Department of Pharmacology, College of Medicine, The University of Iowa, Iowa City, Iowa

The activation in vitro of hepatic microsomal drug metabolism by Mg⁺⁺ is associated with increases in the activities of microsomal reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, NADPH-cytochrome c reductase and cytochrome P-450 reductase enzymes. There is also a slight but consistent alteration in the substrate-P-450 interaction as seen by a change in the spectral dissociation constant (K_s) with benzphetamine (type I substrate) but not with aniline (type II substrate). A study of enzyme kinetics (K_m and V_max) showed that Mg⁺⁺ caused an increase in both the K_m and V_max with benzphetamine as the substrate, but with aniline as the substrate only V_max was increased with no change in the K_m. High concentrations of Mg⁺⁺ (50 mM) inhibit microsomal NADPH oxidase but only further increase microsomal NADPH-cytochrome c and P-450 reductase activities. High concentrations of Mg⁺⁺ appear to offer in vitro conditions where cytochrome P-450 reductase is not the rate-limiting step in certain drug metabolisms by hepatic enzymes.