Selenium and drug metabolism—II Independence of glutathione peroxidase and reversibility of hepatic enzyme modulations in deficient mice

Abstract

Male mice were fed a diet containing less than 0.01 ppm selenium (Se −) for 6 months. A control group received the same diet containing 0.5 ppm selenium (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-glycuronyltransferase: 200%; GSH-thioltransferase: 64%; sulphotransferase: 62%; NADPH-cytochrome-P-450-reductase: 65%; flavin-containing mono-oxygenase: 57%. No significant changes were observed for GSH-transferase activity assayed with ethacrynic acid or for microsomal H 2O 2 formation and aniline hydroxylase activity. In single-pulse repletion experiments by injection of 250 μg selenium/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 hr for the microsomal NADPH-cytochrome-P-450 reductase to over 29 hr for GSH-Px up to 44 hr for part of the GSH-transferase activity. 250 μg selenium/kg bodt 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 μg selenium/kg body wt for 50% restorage. The results demonstrate that processes other than those related to GSH-Px take place in a later phase of selenium deficiency in mouse liver with a chronologically common beginning. The different repletion and depletion kinetics as well as the different need of these processes for the trace element are discussed with respect to the existence of two separate selenium pools.