Differential effects of oltipraz on CYP1A and CYP2B in rat lung.
Oltipraz (OPZ) is a potent chemopreventive agent against chemically-induced carcinogenesis in several animal models. It affects the expression and/or activity of xenobiotic-metabolizing enzymes and its effects are altered in the course of inflammation in liver. The present study was undertaken to analyse the effect of OPZ alone or in combination with Escherichia coli lipopolysaccharide (LPS) on the expression and activities of glutathione S-transferases (GSTs) and cytochrome P450 (CYPs) in rat lung and kidney. Male Wistar rats were fed a diet containing OPZ for 1-5 days. LPS was injected 24 h before the end of OPZ treatment (from 48 to 72 h). Total GST activity, measured using 1-chloro-2,4-dinitrobenzene as a substrate, increased slightly in both lung and kidney during OPZ treatment. As previously demonstrated in the liver, OPZ induced rat GSTP1 in both kidney and lung and this effect was totally (kidney) or partially (lung) inhibited by co-treatment with LPS. CYP1A expression and activity were strongly increased in both tissues 24 h after starting OPZ treatment and maintained for 5 days. This increase was suppressed during the acute-phase response to endotoxin. OPZ has no effect on CYP2B1 mRNA expression in the lung, but it dramatically decreased the amount and activity of the corresponding apoprotein. The OPZ-dependent decrease in the CYP2B1 apoprotein was abolished and its corresponding activity partially reversed during LPS treatment. In reconstitution experiments using cytosol from OPZ-treated or control rat lungs and microsomal fractions, CYP2B1 apoprotein was rapidly degraded in the presence of cytosol from treated rats. This effect was partially reversed in the presence of MG132, a proteasome inhibitor. These observations support the conclusion that the decrease of CYP2B1 by OPZ involves proteasome-dependent degradation and represents a new mechanism of regulation by this compound.
Le Ferrec
E
E
INSERM U456, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, 35043 Rennes, France.
Ilyin
G
G
Mahéo
K
K
Bardiau
C
C
Courtois
A
A
Guillouzo
A
A
Morel
F
F
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013871:Thiones; D013876:Thiophenes
D016588:Anticarcinogenic Agents; D007527:Isoenzymes; D008070:Lipopolysaccharides; D011719:Pyrazines; D012333:RNA, Messenger; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D005982:Glutathione Transferase; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease