The enzyme CYP3A4 is responsible for the metabolism of more than 50% of clinically used drugs and other chemicals not normally found within the human body (known as xenobiotics). CYP3A4 expression is regulated in part by the steroid and xenobiotic receptor (SXR). It has long been known that inflammation and infection inhibit the expression of CYP genes, and exposure to xenobiotic chemicals can impair immune function. However, the molecular bases for these 2 phenomena have remained unknown.

In a study appearing online on July 13 in advance of print publication in the August issue of the Journal of Clinical Investigation, Bruce Blumberg and colleagues from the University of California, Irvine, show that activation of SXR by drugs commonly used by humans inhibits the activity of NF-kappaB in mice, a key regulator of inflammation and the immune response. They go on to show that activation of the NF-kappaB pathway reciprocally inhibits SXR activity and SXR target genes. The crosstalk between SXR and NF-kappaB signaling pathways establishes an important relationship between drug/xenobiotic metabolism and the inflammatory and immune responses. The results of this study also suggest that there may be clinical consequences, particularly the observation of anti-inflammatory effects, in individuals undergoing exposure to the wide variety of drugs that are also SXR agonists.

TITLE: Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation

AUTHOR CONTACT:
Bruce Blumberg
University of California, Irvine, California, USA.
E-mail: blumberguci.edu.

View the PDF of this article at: https://www.the-jci/article.php?id=26283



JCI Table of Contents: July 13, 3006

Contact: Brooke Grindlinger
Journal of Clinical Investigation