Abstract
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 (Ks) with benzphetamine (type I substrate) but not with aniline (type II substrate). A study of enzyme kinetics (Km and Vmax) showed that Mg++ caused an increase in both the Km and Vmax with benzphetamine as the substrate, but with aniline as the substrate only Vmax was increased with no change in the Km. 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.
Footnotes
- Received September 16, 1969.
- Accepted February 19, 1970.
- © 1970 by The Williams & Wilkins Co.
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