4-HYDROXYPYRAZOLE: EFFECT ON GLUTATHIONE LEVELS AND ON THE INCORPORATION OF L-U-14CVALINE INTO PROTEIN IN ISOLATED RAT HEPATOCYTES

摘要

Isolated rat hepatocyles (8-12×106cells/ml) were incubated in Waymouth's medium in the presence of L-U-14Cvaline(0.01μCi/ml). Valine incorporation into protein as well as the total amount of glutathione (reduced and oxidized) in the cell suspension were determined after 1, 2 and 3 hr of incubation. When incubated for 3 hr, 4-hydroxypyrazole (0.5 and 1 mM) decreased (by about 20and 40respectively) valine incorporation into cellular as well as into secreted protein. The increment in glutathione level during incubation (3 hr) of hepatocytes was decreased by 35when 4-hydroxypyrazole (1 mM) was present in the incubation medium. Such a change was found to be neither ATP-dependent nor associated with malonaldehyde production or cellular leakage. Pyrazole at a high concentration (10 mM) decreased the rate of valine incorporation into protein by 20only, while the level of glutathione remained unchanged. These results suggest that the inhibition of protein biosynthesis after administration of the alcohol dehydrogenase inhibitor pyrazole to rats may be mediated by 4-hydroxypyrazole and that the decrease in glutathione level caused by 4-hydroxypyrazole could contribute to the hepatotoxicity of this latter compoun