Endotoxemia in rats is associated with induction of the P4504A subfamily and suppression of several other forms of cytochrome P450.
Bacterial lipopolysaccharide (LPS) has been previously shown to down-regulate the mRNA and protein expression of the hepatic cytochrome P450 (P450) isozymes 2C11 and 2C12. In this study, we examined the effects of LPS on the constitutive expression of P4503A2, P4502E1, and the P4504A subfamily in the rat. Fischer 344 and Sprague-Dawley rats were each administered 1 mg/kg LPS intraperitoneally and killed for hepatic RNA and microsome isolation at different times. LPS treatment was found to suppress P4502C11, P4503A2, and P4502E1 protein and mRNA expression in both strains of rat. Total microsomal P450 levels decreased by 30%, which was smaller than the effects on the levels of individual isozymes. The magnitude of suppression exhibited in the Sprague-Dawley rats, however, seemed to be more variable than that in the F344 strain. The mRNAs of all three of the P4504A subfamily members were induced 2- to 6-fold in the F344 rat livers after LPS administration. P4504A3 protein expression increased 2-fold, whereas P4504A1/2 protein levels decreased by 30%. Lauric acid omega-hydroxylase activity increased 1.6-fold in LPS-treated Fischer 344 rats and omega-1-hydroxylase activity decreased by 38%. In the Sprague-Dawley strain, however, decreases were seen in both omega- and omega-1-hydroxylase activities after LPS treatment. Our data demonstrate that LPS administration induces P4504A subfamily mRNA and P4504A3 protein expression. Furthermore, our findings also suggest strain differences in both suppression and induction of P450s between the Sprague-Dawley and F344 rats.
Sewer
M B
MB
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322-3090, USA.
Koop
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DR
Morgan
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ET
D000818:Animals; D015153:Blotting, Western; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction; D004926:Escherichia coli; D007527:Isoenzymes / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D014115:Toxemia / Q000139:chemically induced / Q000201:enzymology*
D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A