SELENIUM AND DRUG-METABOLISM .2. INDEPENDENCE OF GLUTATHIONE-PEROXIDASE AND REVERSIBILITY OF HEPATIC ENZYME MODULATIONS IN DEFICIENT MICE

Male mice were fed a diet containing less than 0.01 ppm Se, (Se-) for 6 mo. A control group received the same diet containing 0.5 ppm Se (Se+). In the livers of the Se- animals a drastic decrease in glutathione peroxidase (GSH-Px) activity was observed. It reached undetectable levels after 17 days of the Se- diet. At that time, GSH-transferase activity began to increase significantly, followed by changes in many other enzyme activities. After the 60th day, these enzyme modulations had reached a plateau with the following percentage changes compared to controls: GSH-transferases: 320% (1,2-dichloro-4-nitrobenzene), 218% (1-chloro-2,4-dinitrobenzene); glutathione reductase: 160%; ethoxycoumarin deethylase: 330%; cytochrome P-450-hydroperoxidase: 230%; heme oxygenase: 240%; UDP-glucuronyltransferase: 200%; GSH-thioltransferase: 64%; sulfotransferase: 62%; NADPH-cytochrome-P-450-reductase: 65%; flavin-containing monooxygenase: 57%. No significant changes were observed for GSH-transferase activity assayed with ethacrynic acid or for microsomal H2O2 formation and aniline hydroxylase activity. In single-pulse repletion experiments by injection of 250 .mu.g Se/kg body wt, different individual time constants for the recovery process of the enzymatic perturbations were observed. The half-times for the recovery ranged from 5.7 h for the microsomal NADPH-cytochrome-P-450 reductase to over 29-h for GSH-Px up to 44 h for part of the GSH-transferase activity. Se 250 .mu.g/kg body wt were needed to restore 50% of GSH-Px activity in the long-term Se- mice compared to Se+ controls. All other enzymatic changes in the Se- mice needed a dose of 7 .mu.g Se/kg body wt for 50% restorage. Results demonstrate that processes other than those related to GSH-Px take place in a later phase of Se deficiency in mouse liver with a chronologically common beginning. The different repletion and depletion kinetics and the different need of these processes for the trace element are discussed with respect to the existence of 2 separate selenium pools.