The potential role of transcription factor aryl hydrocarbon receptor in downregulation of hepatic cytochrome P-450 during sepsis
| Autor: | Subir R. Maitra, Mian Zhou, Ping Wang |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Interleukin-1beta Active Transport Cell Nucleus Down-Regulation Article Cell Line Proinflammatory cytokine Rats Sprague-Dawley Sepsis Downregulation and upregulation Cytochrome P-450 CYP1A2 Internal medicine Gene expression Genetics medicine Animals Transcription factor DNA Primers Polymyxin B Base Sequence Oncogene biology Tumor Necrosis Factor-alpha General Medicine respiratory system Aryl hydrocarbon receptor medicine.disease Immunohistochemistry Rats respiratory tract diseases Endotoxins Endocrinology Liver Receptors Aryl Hydrocarbon biology.protein Cytochromes Tumor necrosis factor alpha |
| Zdroj: | International Journal of Molecular Medicine. |
| ISSN: | 1791-244X 1107-3756 |
| DOI: | 10.3892/ijmm.21.4.423 |
| Popis: | 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-alpha and interleukin-1beta 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. |
| Databáze: | OpenAIRE |
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