Effects of vanadate on intracellular reduction equivalents in mouse liver and the fate of vanadium in plasma, erythrocytes and liver.
Intraperitoneal injection of 180 mumol sodium vanadate/kg body wt in mice inhibits the in vivo metabolism of drugs by the hepatic monooxygenase, as measured by exhalation of 14CO2 after treatment with appropriately labeled [14C]methacetin. Determinations of hepatic GSH, NADPH and NADH after vanadate injection show an initial and transient decrease of GSH (10 min, 20%), followed by a transient decrease of NADPH (30 min, 23%), followed by a decrease of NADH (40 min, 23% and 60 min, 26%). Rat liver organ spectrophotometry in the dual-wavelength mode shows an immediate response of the NAD(P)H level, which decreases transiently after addition of vanadate. Furthermore, EPR and AAS measurements indicate that vanadium occurs in the plasma in the oxidation states +IV and +V, whereas in intracellular compartments in liver and erythrocytes vanadium exists practically only in the +IV form (vanadyl). The duration of the inhibition for about 2 h coincides well with the transient concentration of vanadate in plasma, which decreases more rapidly than vanadyl. Maximal drug inhibition is associated with the phase of rapid formation of vanadyl in the liver. The experiments are in accordance with the hypothesis that vanadate inhibits the cytochrome P-450 dependent oxidative drug metabolism by diversion of reducing equivalents away from cytochrome P-450. Further evidence for such a hypothesis is provided by in vitro experiments in microsomes. Vanadate causes a dose dependent decrease of ethoxyresorufin deethylation which is reversible by the addition of NADPH.
D000081:Acetamides / Q000378:metabolism; D000818:Animals; D003640:Dealkylation; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009243:NAD / Q000032:analysis; D009249:NADP / Q000032:analysis; D010084:Oxidation-Reduction; D051381:Rats; D014638:Vanadates; D014639:Vanadium / Q000378:metabolism* / Q000494:pharmacology*
D000081:Acetamides; D014639:Vanadium; D009243:NAD; C035495:methacetin; D014638:Vanadates; D009249:NADP; D005978:Glutathione