Kupffer cells and reactive oxygen species partially mediate lipopolysaccharide-induced downregulation of nuclear receptor pregnane x receptor and its target gene CYP3a in mouse liver

doi:10.1016/j.freeradbiomed.2004.03.021

Free Radical Biology and Medicine

Volume 37, Issue 1, 1 July 2004, Pages 10-22

https://doi.org/10.1016/j.freeradbiomed.2004.03.021 Get rights and content

Abstract

Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that regulates target gene transcription in a ligand-dependent manner. The in vivo effects of lipopolysaccharide (LPS) on expression of PXR and its target gene cytochrome P450 3A (CYP3A) in mouse liver were investigated in this study. Mice were injected intraperitoneally with different doses of LPS (0.1–5.0 mg/kg). PXR and CYP3A11 mRNA levels were measured using reverse transcription polymerase chain reaction. Results indicate that LPS significantly inhibits the expression of PXR mRNA in a dose-dependent manner, followed by suppression of CYP3A11 mRNA in mouse liver. LPS also represses the upregulation of CYP3A11 mRNA levels and erythromycin N-demethylase (ERND) catalytic activity in mice pretreated with PXR ligands dexamethasone, rifampicin, mifepristone, and phenobarbital. LPS-induced downregulation of PXR and CYP3A11 mRNA in liver was significantly attenuated in mice pretreated with gadolinium chloride, a selective Kupffer cell toxicant. Pretreatment with a single dose of gadolinium chloride (10 mg/kg) also significantly attenuated LPS-induced downregulation of dexamethasone-, rifampicim-, mifepristone-, and phenobarbital-inducible, CYP3A11 mRNA expression and ERND activity in mouse liver. Furthermore, LPS-induced downregulation of PXR and CYP3A11 mRNA was significantly attenuated in mice pretreated with allopurinol, an inhibitor of xanthine oxidase, and diphenyleneiodonium chloride, an inhibitor of NADPH oxidase. Allopurinol and diphenyleneiodonium chloride pretreatment also attenuated the repressive effects of LPS on dexamethasone-, rifampicin-, mifepristone-, and phenobarbital-inducible CYP3A11 mRNA expression and ERND catalytic activity in mouse liver. However, aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, has no effect on LPS-induced downregulation of PXR and CYP3A11 mRNA. Finally, LPS-induced downregulation of PXR and CYP3A11 mRNA was prevented in mice pretreated with either N-acetylcysteine or ascorbic acid. These antioxidants also prevented the repressive effects of LPS on dexamethasone-, rifampicin-, mifepristone-, and phenobarbital-inducible CYP3A11 mRNA expression and ERND catalytic activity in mouse liver. These results indicate that Kupffer cells contribute to LPS-induced downregulation of PXR and CYP3A in mouse liver. Reactive oxygen species, produced possibly by NADPH oxidase and perhaps by xanthine oxidase, are involved in LPS-induced downregulation of nuclear receptor PXR and its target gene CYP3A in mouse liver.

Introduction

Cytochrome P450 3A (CYP3A) is a member of the cytochrome P450 monooxygenase superfamily, which is responsible for the oxidative metabolism of numerous clinically used drugs [1]. CYP3A expression in liver is highly regulated by development, tissue-specific factors, hormonal influences, xenobiotics, and pathophysiological mechanisms [2], [3]. Recent studies have reported that pregnane X receptor (PXR), a member of the nuclear receptor superfamily, regulates CYP3A gene transcription in a ligand-dependent manner [4], [5], [6]. CYP3A inducers, such as dexamethasone, rifampicin, mifepristone, and phenobarbital, activate PXR and upregulate expressions of the CYP3A gene [7], [8].

On the other hand, numerous studies have indicated that inflammation and infection reduce cytochrome P450 levels in various species including human, rat, and mouse [9], [10]. Lipopolysaccharide (LPS)-induced downregulation of CYP3A has also been demonstrated in a mouse model [11], [12]. Furthermore, recent studies have shown that LPS-induced downregulation of CYP3A is associated with a marked reduction in PXR mRNA and protein levels [13], [14].

In vivo and in vitro studies have shown that pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α, as well as IFN, can mimic the downregulation of P450 gene products seen during infection or inflammation [15], [16], [17], so pro-inflammatory cytokines might be responsible for LPS-induced downregulation of cytochrome P450 gene expression. Moreover, Kupffer cells are the resident macrophages of the liver. When activated by LPS, Kupffer cells produce and release numerous mediators, including reactive oxygen species (ROS) and pro-inflammatory cytokines [18]. Therefore, Kupffer cells may play an important role in LPS-induced downregulation of PXR and CYP3A.

On the other hand, Warren et al. [19] tested the role of TNF-α in P450 downregulation by LPS in mice, using animals deficient in both the p55 and p75 receptors for this cytokine. The results indicated that LPS caused similar decreases in hepatic microsomal CYP1A, -2B, -3A, and -4A proteins and activities in both wild-type and TNF-α receptor-deficient animals. Siewert et al. [20] also observed a similar lack of effect of IL-6 gene deletion on suppression of CYP1A2, -2A5, -2E1, and -3A11 mRNAs after LPS administration to mice. These results suggest that multiple cytokines released during LPS-induced inflammation are involved in downregulation of cytochrome P450. Moreover, ROS are known to influence the expression of a number of genes, including pro-inflammatory cytokines. Therefore, we hypothesized that ROS may be involved in LPS-induced downregulation of nuclear receptor PXR and its target gene CYP3A in mouse liver.

In present study, we investigated the in vivo effects of LPS on PXR and CYP3A expression in mouse liver. Our results found that Kupffer cells and ROS mediate, at least partly, the LPS-induced downregulation of PXR and CYP3A in mouse liver.

Section snippets

Chemicals

Lipopolysaccharide (Escherichia coli LPS, serotype 0127:B8), dexamethasone (Dex), rifampicin (RIF), mifepristone (RU486), phenobarbital (PB), gadolinium chloride (GdCl₃·6H₂O₂), allopurinol (ALL), diphenyleneiodonium chloride (DPI), aminoguanidine (AG), ascorbic acid (AA), and N-acetylcysteine (NAC) were purchased from Sigma Chemical Company (St. Louis, MO, USA).

Animals and treatments

Female 8- to 10-week-old ICR mice, weighing 20–22 g, were purchased from Beijing Vital River, whose foundation colonies were all

Effects of LPS on constitutive expressions of PXR and CYP3A11 mRNAs

The effects of LPS on the constitutive expression of PXR and CYP3A11 mRNA are shown in Fig. 1. As expected, LPS significantly inhibited the constitutive expression of PXR mRNA. LPS downregulated PXR mRNA levels 6 h after LPS treatment, followed by suppression of CYP3A11 mRNA in mouse liver. LPS-induced downregulation of PXR and CYP3A11 mRNA levels lasted at least 24 h (Figs. 1A and 1B).

To explore whether a dose–response relationship existed, mice were injected with different doses of LPS

Discussion

Pregnane X receptor is a member of the nuclear receptor superfamily that regulates target gene transcription in a ligand-dependent manner. The in vivo effects of LPS on expressions of PXR and its target gene CYP3A in mouse liver were investigated in this study. Results indicate that LPS significantly inhibits the constitutive expression of PXR mRNA in a dose-respondent manner, followed by suppression of CYP3A11 mRNA and ERND catalytic activity in mouse liver. LPS also reverses the upregulation

Acknowledgements

The project (30371667) was supported by the National Natural Science Foundation of China. We gratefully acknowledge Professor Yuan Wang and Dr. Qing-Lin Fan for advice on molecular biology and techniques.

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Original ContributionKupffer cells and reactive oxygen species partially mediate lipopolysaccharide-induced downregulation of nuclear receptor pregnane x receptor and its target gene CYP3a in mouse liver

Abstract

Introduction

Section snippets

Chemicals

Animals and treatments

Effects of LPS on constitutive expressions of PXR and CYP3A11 mRNAs

Discussion

Acknowledgements

Cell

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Gastroenterology

Hepatology

Hepatology

Methods Enzymol.

J. Biol. Chem.

J. Biol. Chem.

Methods Enzymol.

Biochem. Pharmacol.

Biochem. Pharmacol.

Eur. J. Pharmacol.

J. Surg. Res.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

J. Hepatol.

In vitro and in vivo drug interactions involving human CYP3A

Annu. Rev. Pharmacol. Toxicol.

CYP3A regulation: from pharmacology to nuclear receptors

Drug Metab. Dispos.

Regulation of cyp3a gene transcription by the pregnane x receptor

Annu. Rev. Pharmacol. Toxicol.

The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions

J. Clin. Invest.

Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction

Proc. Natl. Acad. Sci. USA

Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR

Genes Dev.

Regulation of cytochrome p450 by inflammatory mediators: why and how?

Drug Metab. Dispos.

Regulation of cytochromes P450 during inflammation and infection

Drug Metab. Rev.

Downregulation of cytochrome P450 mRNAs and proteins in mice lacking a functional NOS2 gene

Mol. Pharmacol.

Effects of bacterial lipopolysaccharide on phenobarbital-induced CYP2B expression in mice

Drug Metab. Dispos.

Original Contribution
Kupffer cells and reactive oxygen species partially mediate lipopolysaccharide-induced downregulation of nuclear receptor pregnane x receptor and its target gene CYP3a in mouse liver