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Title: The Nuclear Factor-kB Pathway Regulates Cytochrome P450 3A4 Protein Stability

Abstract

We have previously observed that CYP3A4 protein levels are suppressed by inhibition of the proteasome in primary cultured hepatocytes. Because this result is opposite of what would be expected if CYP3A4 is degraded by the proteasome, it seems likely that there is another protein that is susceptible to proteasomal degradation that regulates CYP3A4 expression. In this study, we evaluate whether the nuclear factor kappa B (NF-kB) pathway is involved in that process. Our model system uses an adenovirus system to express CYP3A4 protein in HepG2 cells, which are derived from human cancer cells. Similar to results in primary hepatocytes, we found that inhibition of the proteasome with MG132 suppresses CYP3A4. Consistent with reports that proteasome inhibition suppresses the NF-kB pathway, we also observe a suppression of inhibitory kB kinase protein levels after treatment with MG132. Treatment of the HepG2 cells with NK-kB Activation Inhibitor also suppresses CYP3A4 proteins levels. In contrast, inhibition of either the proteasome or NF-kB pathways increases CYP3A4 mRNA levels. When the HepG2 cells are treated with cycloheximide, a general inhibitor of translation, the loss of CYP3A4 protein is accelerated by co-treatment with an NF-kB Activation Inhibitor. These results indicate that NF-kB activity regulates CYP3A4 protein stabilitymore » and suggest that the NF-kB pathway is responsible for the decrease in CYP3A4 protein levels that results from the inhibition of proteasomal activity.« less

Authors:
; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
937044
Report Number(s):
PNNL-SA-54653
Journal ID: ISSN 0026-895X; MOPMA3; 400412000; TRN: US200820%%402
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Molecular Pharmacology, 73(6):1652-1658
Additional Journal Information:
Journal Volume: 73; Journal Issue: 6; Journal ID: ISSN 0026-895X
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ADENOVIRUS; CYCLOHEXIMIDE; CYTOCHROMES; LIVER CELLS; NEOPLASMS; PHOSPHOTRANSFERASES; PROTEINS; STABILITY

Citation Formats

Zangar, Richard C, Bollinger, Nikki, Verma, Seema, Karin, Norm J, and Lu, Yi. The Nuclear Factor-kB Pathway Regulates Cytochrome P450 3A4 Protein Stability. United States: N. p., 2008. Web. doi:10.1124/mol.107.043976.
Zangar, Richard C, Bollinger, Nikki, Verma, Seema, Karin, Norm J, & Lu, Yi. The Nuclear Factor-kB Pathway Regulates Cytochrome P450 3A4 Protein Stability. United States. https://doi.org/10.1124/mol.107.043976
Zangar, Richard C, Bollinger, Nikki, Verma, Seema, Karin, Norm J, and Lu, Yi. 2008. "The Nuclear Factor-kB Pathway Regulates Cytochrome P450 3A4 Protein Stability". United States. https://doi.org/10.1124/mol.107.043976.
@article{osti_937044,
title = {The Nuclear Factor-kB Pathway Regulates Cytochrome P450 3A4 Protein Stability},
author = {Zangar, Richard C and Bollinger, Nikki and Verma, Seema and Karin, Norm J and Lu, Yi},
abstractNote = {We have previously observed that CYP3A4 protein levels are suppressed by inhibition of the proteasome in primary cultured hepatocytes. Because this result is opposite of what would be expected if CYP3A4 is degraded by the proteasome, it seems likely that there is another protein that is susceptible to proteasomal degradation that regulates CYP3A4 expression. In this study, we evaluate whether the nuclear factor kappa B (NF-kB) pathway is involved in that process. Our model system uses an adenovirus system to express CYP3A4 protein in HepG2 cells, which are derived from human cancer cells. Similar to results in primary hepatocytes, we found that inhibition of the proteasome with MG132 suppresses CYP3A4. Consistent with reports that proteasome inhibition suppresses the NF-kB pathway, we also observe a suppression of inhibitory kB kinase protein levels after treatment with MG132. Treatment of the HepG2 cells with NK-kB Activation Inhibitor also suppresses CYP3A4 proteins levels. In contrast, inhibition of either the proteasome or NF-kB pathways increases CYP3A4 mRNA levels. When the HepG2 cells are treated with cycloheximide, a general inhibitor of translation, the loss of CYP3A4 protein is accelerated by co-treatment with an NF-kB Activation Inhibitor. These results indicate that NF-kB activity regulates CYP3A4 protein stability and suggest that the NF-kB pathway is responsible for the decrease in CYP3A4 protein levels that results from the inhibition of proteasomal activity.},
doi = {10.1124/mol.107.043976},
url = {https://www.osti.gov/biblio/937044}, journal = {Molecular Pharmacology, 73(6):1652-1658},
issn = {0026-895X},
number = 6,
volume = 73,
place = {United States},
year = {Sun Jun 01 00:00:00 EDT 2008},
month = {Sun Jun 01 00:00:00 EDT 2008}
}