Phenobarbital prevents the inhibitory effects of tumor necrosis factor on glutathione-S-transferase mu in primary culture rat hepatocytes.
During inflammation and infection, overexpression of the tumor necrosis factor (TNF) is associated with changes in cytochromes P-450 levels in rat and human hepatocytes. The aim of this study was to investigate the effect of TNF on the expression of the glutathione-S-transferases (GSTs) in rat hepatocytes. TNF was added in vitro alone or simultaneously with phenobarbital (PB) into hepatocytes in primary culture or in vivo, before TNF, injected directly to rats. GST activity was assayed by spectrophotometry; protein GSTs alpha, mu and pi were evaluated by immunoblotting. When TNF was added alone to rat hepatocytes in vitro, total GST activity and GST alpha levels were not affected, while GST mu protein levels significantly decreased by 35%. GST pi protein was undetectable in hepatocytes whether treated or not with TNF. When PB was administered in vitro simultaneously to rat hepatocytes with TNF, the decrease observed for GST mu subunit was suppressed while total GST activity and GST alpha content were not affected. When hepatocytes were treated with TNF after PB given in vivo directly to the rat by i.p. injection, GST activity and GSTs subunits were induced by PB, while TNF did not exert any effect. These results indicate that TNF has an inhibitory effect on GST mu and PB abrogates this effect in primary cultured rat hepatocytes. Then, PB could prevent some TNF toxic effects.
Département de Pharmacotoxicologie et de Pharmacogénétique, CNRS URA, Institut Gustave-Roussy, Villejuif, France. liliane.massade@biomediale.univ.fr
L
L
Massaad-Massade
S
S
Chouaib
A
A
Gouyette
D000818:Animals; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D046911:Macromolecular Substances; D008297:Male; D010634:Phenobarbital / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D007527:Isoenzymes; D046911:Macromolecular Substances; D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D010634:Phenobarbital