Differential inductive and suppressive effects of endotoxin and particulate irritants on hepatic and renal cytochrome P-450 expression.
Inflammatory stimuli such as bacterial lipopolysaccharide (LPS) have been shown to down-regulate the mRNA and protein expression of hepatic cytochrome P-450 (P-450) isozymes 2C11, 2C12, 2E1 and 3A2 and to induce the mRNA expression of the P-450 4A subfamily. In this study, we examined the effects of irritants on the hepatic and renal expression of P-450 2C11, 2E1 and 3A2 and the 4A subfamily in the rat. Fischer 344 rats were administered doses of SiO2 (Celite), BaSO4, kaolin and LPS intraperitoneally and killed after different times for hepatic and renal RNA and microsome isolation. The administration of each irritant was found to suppress hepatic P-450 2C11 mRNA and protein and to induce P-450 4A1, 4A2 and 4A3 mRNA expression while having no significant effect on P-450 2E1 or 3A2. P-450 4A2, 4A3 and 2E1 mRNAs were all induced in the kidney cortices of the irritant- and LPS-treated rats. The effects of BaSO4 and SiO2 were found to be dose dependent. Chlorzoxazone-6-hydroxylase activity increased in the kidneys of irritant-treated rats, which is consistent with an increased expression of P-450 2E1. All irritants were found to induce the mRNA for the acute-phase protein fibrinogen; however, in contrast to LPS treatment, none of the irritants that were tested induced hepatic inducible nitric oxide synthase mRNA expression. These findings demonstrate the induction of renal P-450 isozymes after irritant and LPS administration. The findings of this study also suggest that different inflammatory stimuli affect the individual P-450 isozymes differentially.
Sewer
M B
MB
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322-3090, USA.
Koop
D R
DR
Morgan
E T
ET
D000818:Animals; D001466:Barium Sulfate / Q000494:pharmacology; D015152:Blotting, Northern; D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007509:Irritants / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012822:Silicon Dioxide / Q000494:pharmacology
D007509:Irritants; D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D001466:Barium Sulfate; D012822:Silicon Dioxide; D003577:Cytochrome P-450 Enzyme System