Vanadium inhibits oxidative drug demethylation in vivo in mice

Abstract

Sodium vanadate inhibits the oxidative demethylation of substrates of the cytochrome P-450-dependent monooxygenase system in vivo in mice. [14C]Methacetin and 7-[methoxy-14C] coumarin were used as substrates, and the exhaled 14CO2 was monitored using the technique of the breath test. The inhibition is of short duration and begins to subside after about 10 min. The inhibition is dose-dependent; half-maximal effect is achieved at a dose of approximately 60 mumol/kg. The inhibition pattern is identical for both substrates, although 62% of the label of [14C] methacetin and only 10% of 7-[methoxy-14C] coumarin are enhaled within 1 h. Pretreatment with ascorbic acid (50 mg/kg p.o.) drastically diminishes the observed inhibitory effect of vanadate. Similarly, application of an equimolar dose of vanadyl sulphate produces a comparatively weak retardation of 14CO2 exhalation. The effect of vanadate is thought to occur by its competition for electrons normally transferred to cytochrome P-450.