Endotoxin suppresses the oltipraz-mediated induction of major hepatic glutathione transferases and cytochromes P450 in the rat.
The effect of Escherichia coli lipopolysaccharide (LPS), a classic inducer of the acute-phase response, has been analyzed on both constitutive and oltipraz (a chemoprotective agent)-inducible messenger RNAs (mRNAs) and enzyme activities of major cytochromes P450 (CYPs) and glutathione transferases (rGSTs) in rat liver. At the dose administered (1 mg/kg) and the time studied (6 and 24 hours), endotoxin had no effect on the expression of either CYPs and GSTs with the exception of CYP1A2, which was reduced at both mRNA and activity levels. A strong increase of rGSTA1/2, rGSTM1, rGSTP1, CYP1A2, CYP2B1/2, and CYP2E1 was observed after 3 days of treatment with oltipraz (0.075%, wt/wt). Oltipraz induction of these enzymes (with the exception of CYP2E1) was found to be suppressed at both mRNA, protein, and activity levels during the acute-phase response to endotoxin. Moreover, it is shown that oltipraz induction of CYP1A2 and CYP2B1/2 and its suppression by E. coli LPS occurred at a transcriptional level. These data support the idea that the chemoprotective effect of oltipraz is altered in the course of inflammation and that adaptation in chemoprotective strategies should be considered in certain physiopathologic situations.
Mahéo
K
K
INSERM Unité 456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France.
Morel
F
F
Antras-Ferry
J
J
Langoüet
S
S
Desmots
F
F
Corcos
L
L
Guillouzo
A
A
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004731:Endotoxins / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013871:Thiones; D013876:Thiophenes
D016588:Anticarcinogenic Agents; D004731:Endotoxins; D008070:Lipopolysaccharides; D011719:Pyrazines; D012333:RNA, Messenger; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase