Decrease in hepatic CYP2C11 mRNA and increase in heme oxygenase activity after intracerebroventricular injection of bacterial endotoxin.
We previously reported (Arch. Toxcol. 1998, 72, 492-498) that the differential decrease in the levels of hepatic cytochrome P450 (CYP) isozymes in rats was observed 24 hr after intracerebroventricular (i.c.v.) injection of bacterial lipopolysaccharide (LPS) at the dose ineffective (0.1 microgram) when injected intraperitoneally (i.p.). Among CYP isozymes we examined, the male specific CYP isozyme, CYP2C11 was most severely affected by i.c.v. injection of LPS. In this study, we examined the gene expression of CYP2C11, the total P450 contents, the CYP2C11-dependent activity of imipramine N-demethylase (IMND) and protein of CYP2C11 10 hr after i.c.v. or i.p. injections of LPS. Intracerebroventricular injection of LPS significantly decreased the level of CYP2C11 mRNA (to 63% of saline i.c.v. control), the total P450 contents (to 70% of saline i.c.v. control), the IMND activity (to 74% of saline i.c.v. control), but not protein of CYP2C11 in rat liver. In contrast, i.p. injection of LPS at the same dose as i.c.v. did not significantly affect these parameters. Since CYP is a heme protein, we also measured the activity of heme oxygenase (HO) using the same rat liver microsomes. The HO activity was increased to 166% by i.c.v. injection of LPS and 135% by i.p. injection of LPS compared to corresponding saline control. It is suggested that i.c.v. injection of LPS down-regulates the expression of CYP2C11 at transcriptional level and that both the decrease in CYP2C11 mRNA and the increase in heme degradation may be involved in the decreased level of protein and activity of CYP2C11 by i.c.v. injection of LPS in rat liver.
Shimamoto
Y
Y
Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Tasaki
T
T
Kitamura
H
H
Hirose
K
K
Kazusaka
A
A
Fujita
S
S
D018759:Adrenergic Uptake Inhibitors / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015152:Blotting, Northern; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D015536:Down-Regulation / Q000187:drug effects; D004926:Escherichia coli; D015870:Gene Expression / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D007099:Imipramine / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*
D018759:Adrenergic Uptake Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D006419:Heme Oxygenase (Decyclizing); D007099:Imipramine