Decrease in Hepatic CYP2C11 mRNA and Increase in Heme Oxygenase Activity after Intracerebroventricular Injection of Bacterial Endotoxin.

Abstract

ABSTRACT. 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 (icv) injection of bacterial lipopolysaccharide (LPS) at the dose ineffective (0.1 µg) when injected intraperitoneally (ip). Among CYP isozymes we examined, the male specific CYP isozyme, CYP2C11 was most severely affected by icv 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 icv or ip injections of LPS. Intracerebroventricular injection of LPS significantly decreased the level of CYP2C11 mRNA (to 63% of saline icv control), the total P450 contents (to 70% of saline icv control), the IMND activity (to 74% of saline icv control), but not protein of CYP2C11 in rat liver. In contrast, ip injection of LPS at the same dose as icv 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 icv injection of LPS and 135% by ip injection of LPS compared to corresponding saline control. It is suggested that icv 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 icv injection of LPS in rat liver.-KEY WORDS: CYP2C11, cytochrome P450, intracerebroventricular, lipopolysaccharide, messenger RNA.J. Vet. Med. Sci. 61(6): 609-613, 1999 injection of LPS. In this study, to clarify the mechanism of the down-regulation of this isozyme by icv injection of LPS, we first examined the expression of CYP2C11 mRNA and the level of protein of CYP2C11 and its drug metabolizing activity in rat liver 10 hr after icv injection of LPS. Furthermore, to estimate the effect of icv injection of LPS on heme degradation, we also measured the activity of heme oxygenase using the same rat liver microsomes. MATERIALS AND METHODSChemicals: LPS (Escherichia coli 0111: B4), imipramine hydrochloride and desipramine were purchased from Sigma (St. Louis, Mo.). 2-Hydroxyimipramine was kindly donated by Geigy (Basel, Switzerland). Hemin and bilirubin were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). All other chemicals and solvents were of analytical grade.Treatment of animals and preparation of liver microsomes: Male Wistar rats (Nihon SLC, Hamamatsu, Japan) weighing 210-230 g were housed in plastic cages at 24 ± 1˚C with a 12-hr light-dark cycle (lights on at 7:00-19:00) and given laboratory chow and water ad lib. All rats were anesthetized with sodium pentobarbital at a dose of 40 mg/kg by intraperitoneal (ip) injection and implanted with a sterilized polyethylene cannula (0.6 mm o.d.) in the right lateral cerebral ventricle (at the bregma, 3.6 ...

Differential Effects of Sunitinib on the Expression Profiles of Xenobiotic‐Metabolizing Enzymes and Transporters in Rat Liver and Kidneys

“…Examples of these mechanisms include increased mRNA degradation and increased protein stability by phosphorylation or acetylation [34,35]. This result is consistent with the results of Shimamoto and coworkers who reported a decrease in hepatic CYP2C11 mRNA levels by inflammation with no significant change at its protein expression levels [36]. On the other hand, SUN significantly induced hepatic and renal CYP2E1 mRNA levels only at the highest dose (100 mg/kg) by approximately 4-and 8.5-fold, respectively ( fig.…”

Investigations of the posttranslational mechanism of arsenite‐mediated downregulation of human cytochrome P4501A1 levels: The role of heme oxygenase‐1

“…Other inducers of HO-1 also decreased expression levels of some CYP enzymes. Intracerebroventricular injection of bacterial endotoxin in rats resulted in significantly decreased levels of CYP2C11 mRNA and total CYP protein contents, while HO-1 activity was increased significantly in treated rats, relative to untreated controls [11]. SnCl 2 induced HO-1 protein in rat kidney inner and outer medulla cells, and decreased CYP4A protein expression levels in the inner medulla, but CYP2 protein levels of the outer medulla were not significantly affected [12].…”