Lipopolysaccharide-Mediated Modulation of Cytochromes P450 in Stat1 Null Mice

Pan, Jingshun; Xiang, Qian; Ball, S.; Scatina, JoAnn; Kao, John Y.; Hong, Jun-Yan

doi:10.1124/dmd.31.4.392

Cited by 14 publications

(10 citation statements)

References 32 publications

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“…For example, an initial study suggested that LPS-mediated alteration of hepatic and renal P450 expression was mediated by peroxisome proliferator-activated receptor-␣ (Barclay et al, 1999). However, subsequent experiments have demonstrated that LPS-mediated downregulation of hepatic P450 expression is independent of peroxisome proliferator-activated receptor-␣, pregnane X receptor, and signal transducer and activator of transcription-1 (Pan et al, 2003;Richardson and Morgan, 2005). Although we did not directly investigate the mechanism by which LPS alters P450 expression and metabolic activity, the observed isoform-and tissue-specific response suggests that the mechanism is complex and most likely involves multiple transcription factors that vary across isoforms and tissues.…”

Section: Downloaded Frommentioning

confidence: 77%

Activation of the Acute Inflammatory Response Alters Cytochrome P450 Expression and Eicosanoid Metabolism

et al. 2010

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ABSTRACT:Cytochrome P450 (P450)-mediated metabolism of arachidonic acid regulates inflammation in hepatic and extrahepatic tissue. CYP2C/ CYP2J-derived epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EET؉DHET) elicit anti-inflammatory effects, whereas CYP4A/ CYP4F-derived 20-hydroxyeicosatetraenoic acid (20-HETE) is proinflammatory. Because the impact of inflammation on P450-mediated formation of endogenous eicosanoids is unclear, we evaluated P450 mRNA levels and P450 epoxygenase (EET؉DHET) and -hydroxylase (20-HETE) metabolic activity in liver, kidney, lung, and heart in mice 3, 6, 24, and 48 h after intraperitoneal lipopolysaccharide (LPS) (1 mg/kg) or saline administration. Hepatic Cyp2c29, Cyp2c44, and Cyp2j5 mRNA levels and EET؉DHET formation were significantly lower 24 and 48 h after LPS administration. Hepatic Cyp4a12a, Cyp4a12b, and Cyp4f13 mRNA levels and 20-HETE formation were also significantly lower at 24 h, but recovered to baseline at 48 h, resulting in a significantly higher 20-HETE/EET؉DHET formation rate ratio compared with that for saline-treated mice. Renal P450 mRNA levels and P450-mediated eicosanoid metabolism were similarly suppressed 24 h after LPS treatment. Pulmonary EET؉DHET formation was lower at all time points after LPS administration, whereas 20-HETE formation was suppressed in a time-dependent manner, with the lowest formation rate observed at 24 h. No differences in EET؉DHET or 20-HETE formation were observed in heart. Collectively, these data demonstrate that acute activation of the innate immune response alters P450 expression and eicosanoid metabolism in mice in an isoform-, tissue-, and time-dependent manner. Further study is necessary to determine whether therapeutic restoration of the functional balance between the P450 epoxygenase and -hydroxylase pathways is an effective anti-inflammatory strategy.

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Section: Downloaded Frommentioning

confidence: 77%

Activation of the Acute Inflammatory Response Alters Cytochrome P450 Expression and Eicosanoid Metabolism

et al. 2010

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“…On the other hand, numerous studies indicated that inflammation and infection reduce hepatic CYP levels in various species including human, rat and mouse (Morgan, 1997(Morgan, , 2001. The effect of LPS on P450 expression is very well documented in a variety of systems and tissues (Renton and Nicholson, 2000;Li-Masters and Morgan, 2001;Morgan et al, 2002;Pan et al, 2003;Kalitsky-Szirtes et al, 2004). LPS-induced downregulation of cyp3a in liver has also been demonstrated in mouse model (Sewer et al, 1998).…”

Section: Introductionmentioning

confidence: 92%

Lipopolysaccharide treatment downregulates the expression of the pregnane X receptor, cyp3a11 and mdr1a genes in mouse placenta

Chen

Wang

et al. 2005

Toxicology

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“…As was expected, BCG lost its ability to phosphorylate both STAT1 and STAT3 in IL-6 KO mouse livers. Pan et al (2003) reported that CYP3A11 and 2C29 mRNAs are markedly down-regulated by LPS in STAT1 KO mice and in wild-type mice. Thus, STAT1 is unlikely to be involved in LPS-induced CYP3A11 and 2C29 mRNA down-regulation.…”

Section: Figurementioning

confidence: 99%

Involvement of Interleukin-6 and Tumor Necrosis Factor Α in Cyp3a11 and 2c29 Down-Regulation by Bacillus Calmette-Guérin and Lipopolysaccharide in Mouse Liver

Ashino¹,

Oguro

Shioda

et al. 2004

Drug Metab Dispos

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ABSTRACT:Bacillus Calmette-Gué rin (BCG) and lipopolysaccharide (LPS) are well known potent activators of the cell-mediated immune system and thus lead to the decreases in cytochrome P450 (P450). In this study we used interleukin (IL)-1␣/␤, IL-6, or tumor necrosis factor ␣ (TNF␣) knockout (KO) mice to investigate how each cytokine is involved in P450 down-regulation, especially CYP3A11 and 2C29. BCG (40 mg/kg) was found to reduce both CYP3A11 and 2C29 mRNAs at 24 h after treatment in IL-1␣/␤ ⌲⌷ mice in a manner similar to that seen in wild-type mice. CYP3A11 mRNA, but not CYP2C29 mRNA, was significantly decreased by BCG treatment in the TNF␣ KO mice, although the decrease was less than that of wild-type or IL-1␣/␤ KO mice. In contrast, BCG showed no significant effect on CYP3A11 and 2C29 mRNAs in IL-6 KO mice. On the other hand, LPS was able to decrease CYP3A11 and 2C29 mRNA levels in all of the cytokine KO mice and markedly increased systemic levels of TNF␣; BCG (40 mg/kg) lacked such activity. The present study has shown that IL-6 and TNF␣ are likely to be major factors involved in the down-regulation of CYP3A11 and 2C29 mRNAs in mice. In addition, there exist differences in the amount and/or kind of cytokines released by BCG or LPS, the latter being more potent than the former. This will be a possible reason for differential capability of P450 down-regulation between BCG and LPS.

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Lipopolysaccharide-Mediated Modulation of Cytochromes P450 in Stat1 Null Mice

Cited by 14 publications

References 32 publications

Activation of the Acute Inflammatory Response Alters Cytochrome P450 Expression and Eicosanoid Metabolism

Activation of the Acute Inflammatory Response Alters Cytochrome P450 Expression and Eicosanoid Metabolism

Lipopolysaccharide treatment downregulates the expression of the pregnane X receptor, cyp3a11 and mdr1a genes in mouse placenta

Involvement of Interleukin-6 and Tumor Necrosis Factor Α in Cyp3a11 and 2c29 Down-Regulation by Bacillus Calmette-Guérin and Lipopolysaccharide in Mouse Liver

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