Down-regulation of hepatic CYP1A2 plays an important role in inflammatory responses in sepsis

Crawford, Jack H.; Yang, Shaolong; Zhou, Mian; Simms, Henry S.; Wang, Haichao

doi:10.1097/01.ccm.0000109453.57709.e2

Cited by 45 publications

(32 citation statements)

References 37 publications

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“…A large number of reports have shown that CYP isoforms and their activities are, for the most part, suppressed in animal models of endotoxemia as well as in cultured hepatocytes stimulated by endotoxin (7)(8)(9)(10)(11). In this regard, a recent study from our laboratory showed that hepatic CYP1A2, the most predominant CYP isoform in the rat liver (12), is downregulated during the progression of polymicrobial sepsis induced by CLP (13).…”

Section: Introductionmentioning

confidence: 92%

“…Within the nucleus, the AhR-Arnt complex recognizes and binds to the specific regulatory sequences known as the dioxin responsive element (DRE) at the promoter region, and initiates the transcription of the CYP1A2 gene (31)(32)(33)(34). Using a polymicrobial sepsis model, we recently showed that CYP1A2 gene expression and its protein decreased significantly only at 10-20 h after CLP (13). In the present study, we further extended the observation and found that AhR gene expression and protein were decreased earlier.…”

Section: Discussionmentioning

confidence: 99%

“…We focused on the changes of the isoform CYP1A2 after the onset of sepsis in the present as well as the previous study (13). CYP1A2 was chosen because it is the most predominant isoform of the P-450 enzyme system in the rat liver.…”

Section: Discussionmentioning

confidence: 99%

“…The finding that the AhR gene and protein expression decreased significantly as early as 5 h after the onset of sepsis suggests that the downregulation may have occurred even earlier than 5 h post CLP. Our previous studies showed that hepatic CYP1A2 expression decreased at 10-20 h after CLP (13). The fact that AhR downregulation occurs earlier than that of CYP1A2 may suggest a cause and effect relationship.…”

Section: Alterations In Hepatic Ahr Expression In Septic Animalsmentioning

confidence: 99%

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The potential role of transcription factor aryl hydrocarbon receptor in downregulation of hepatic cytochrome P-450 during sepsis

Zhou

Maitra²,

Wang³

2008

Int J Mol Med

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We recently demonstrated that the hepatic cytochrome P-450 (CYP) isoform 1A2 is downregulated in sepsis, which appears to play an important role in the inflammatory response and liver injury. However, the mechanism responsible for the decreased CYP1A2 remains unknown. Since the transcription factor aryl hydrocarbon receptor (AhR) regulates the expression of CYP1A2 and the disruption of the AhR gene causes liver injuries, we hypothesized that downregulation of AhR plays an important role in the reduced hepatic CYP1A2 during sepsis. Adult male rats were subjected to sepsis by cecal ligation and puncture (CLP). Hepatic tissues were collected at 5, 10, and 20 h after CLP or sham-operation. The gene expression of AhR was assessed by RT-PCR technique. Its protein was determined by Western blot analysis. In addition, subcellular localization of AhR was examined by immunohistochemical staining. The results indicate that hepatic AhR gene expression decreased at 5 h and remained downregulated at 10-20 h after CLP. AhR protein levels were significantly reduced at 10-20 h after CLP. Immunohistochemical examination showed that AhR was mainly located in hepatocyte cytoplasm in sham animals. The translocation of AhR from the cytoplasm to the nucleus was observed in septic animals. The downregulation of hepatic AhR and CYP1A2 observed in septic animals does not appear to be due to the elevated endotoxin levels since administration of polymyxin B (an endotoxin-binding agent) did not affect AhR and CYP1A2 gene expression. However, proinflammatory cytokines tumor necrosis factor-α and interleukin-1ß decreased AhR and CYP1A2 expression. As AhR activates the specific gene expression by binding to the target genes, the translocation of AhR to the nucleus in sepsis would suggest that alterations at AhR binding sites may also contribute to the downregulated CYP1A2 expression in sepsis. Since AhR gene expression decreased earlier than the occurrence of depression of CYP1A2 (CYP1A2 decreased at 10-20 h post CLP), the decreased AhR may play an important role in downregulating hepatic CYP1A2 during the progression of sepsis.

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Section: Introductionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Alterations In Hepatic Ahr Expression In Septic Animalsmentioning

confidence: 99%

See 2 more Smart Citations

The potential role of transcription factor aryl hydrocarbon receptor in downregulation of hepatic cytochrome P-450 during sepsis

Zhou

Maitra²,

Wang³

2008

Int J Mol Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our recent studies have shown that one of the major hepatic P-450 isoforms in the rat, CYP1A2, is downregulated in sepsis (2). CYP1A2 is involved in the metabolism of various exogenous agents such as theophylline, imipramine, and naproxen and can be inhibited by chemicals such as cimetidine and fluoroquinolones (3).…”

Section: Introductionmentioning

confidence: 99%

Suppression of hepatocyte CYP1A2 expression by Kupffer cells via AhR pathway: The central role of proinflammatory cytokines

Cui²,

Dong³

et al. 2006

Int J Mol Med

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Abstract. The hepatic cytochrome P-450 (CYP) enzyme system provides a major aspect of liver function, yet alterations of CYP in sepsis remain largely unknown. Although we have recently shown that CYP1A2, one of the major isoforms of CYP in rats, is downregulated in sepsis, the underlying mechanism and possible therapeutic approaches warrant further investigation. The aim of this study was to determine whether Kupffer cells (KCs) play any role in suppressing CYP1A2 in the hepatocytes (HCs) and if so, how to modulate CYP1A2 expression in sepsis. To study this, primary KCs and HCs were cultured separately or together with or without transwells. Cells and supernatant samples were collected after various stimulations. Additionally, polymicrobial sepsis was induced in rats by cecal ligation and puncture (CLP) with or without curcumin pre-treatment. Liver samples were harvested 20 h post-CLP. The results show that lipopolysaccharide (LPS) did not suppress CYP1A2 in HC or HC/KC coculture with transwells. However, LPS downregulated CYP1A2, aryl hydrocarbon receptor (AhR, a nuclear receptor) and AhR nuclear translocator (Arnt) in coculture without transwells. Anti-TNF-· and anti-IL-1ß antibodies attenuated this downregulation. Moreover, elevated hepatic levels of TNF-· and IL-1ß post-CLP were decreased by curcumin pretreatment. This reduction was associated with increased expression of AhR and CYP1A2. These results indicate that KCs-derived proinflammatory cytokines may play an important role in downregulating CYP1A2 in sepsis. The reduction of AhR/Arnt may be the underlying mechanism for such downregulation. Inhibition of proinflammatory cytokines by curcumin may provide a novel approach to modulate the hepatic CYP function in sepsis.

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Clopidogrel in Critically Ill Patients

Schoergenhofer

Hobl

Schellongowski³

et al. 2017

Clin Pharma and Therapeutics

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Only limited data are available regarding the treatment of critically ill patients with clopidogrel. This trial investigated the effects and the drug concentrations of the cytochrome P450 (CYP450) activated prodrug clopidogrel (n = 43) and the half‐life of the similarly metabolized pantoprazole (n = 16) in critically ill patients. ADP‐induced aggregometry in whole blood classified 74% (95% confidence intervals 59–87%) of critically ill patients as poor responders (n = 43), and 65% (49–79%) responded poorly according to the vasodilator‐stimulated phosphoprotein phosphorylation (VASP‐P) assay. Although the plasma levels of clopidogrel active metabolite normally exceed the inactive prodrug ∼30‐fold, the parent drug levels even exceeded those of the metabolite 2‐fold in critically ill patients. The half‐life of pantoprazole was several‐fold longer in these patients compared with reference populations. The inverse ratio of prodrug/active metabolite indicates insufficient metabolization of clopidogrel, which is independently confirmed by the ∼5‐fold increase in half‐life of pantoprazole. Thus, high‐risk patients may benefit from treatment with alternative platelet inhibitors.

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Down-regulation of hepatic CYP1A2 plays an important role in inflammatory responses in sepsis

Cited by 45 publications

References 37 publications

The potential role of transcription factor aryl hydrocarbon receptor in downregulation of hepatic cytochrome P-450 during sepsis

The potential role of transcription factor aryl hydrocarbon receptor in downregulation of hepatic cytochrome P-450 during sepsis

Suppression of hepatocyte CYP1A2 expression by Kupffer cells via AhR pathway: The central role of proinflammatory cytokines

Clopidogrel in Critically Ill Patients

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