Down-regulation of multiple cytochrome P450 gene products by inflammatory mediators in vivo. Independence from the hypothalamo-pituitary axis.
Inflammatory stimuli suppress constitutive hepatic expression of the CYP2C11 and CYP2C12 genes in male and female rat livers, respectively. Because growth hormone (GH) is an important regulator of P450 gene expression in the rat, the effects of bacterial endotoxin injection in hypophysectomized rats were compared to those in normal animals. In intact females, 0.2 mg/kg endotoxin suppressed total P450 and hepatic expression of CYP2C6, CYP2C7, CYP2C12, and CYP2E1 mRNAs, as well as CYP2C12 and CYP2E1 proteins, measured 16 hr later. CYP2C7 and CYP2E1 mRNAs were most affected (17 and 13% of untreated levels, respectively). Endotoxin treatment also induced the mRNA for the hepatic acute phase protein, haptoglobin, to 260% of control female levels. In hypophysectomized females supplemented with GH infusion, endotoxin caused the same or greater effects on expression of the P450 and haptoglobin gene products than were observed in the intact animals. It is concluded that the P450 suppression observed after endotoxin administration can occur independently of an effect on pituitary hormone secretion.
Morgan
E T
ET
Department of Pharmacology, Emory University Medical School, Atlanta, GA 30322.
D000210:Acute-Phase Reaction / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D013006:Growth Hormone / Q000008:administration & dosage / Q000097:blood; D006242:Haptoglobins / Q000235:genetics; D007016:Hypophysectomy; D007249:Inflammation / Q000378:metabolism*; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D016207:Cytokines; D006242:Haptoglobins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System