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Papers In Press, published online ahead of print July 20, 2001
J. Biol. Chem, 10.1074/jbc.C100375200
Submitted on July 3, 2001
Revised on July 19, 2001
Accepted on July 20, 2001

Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR

Isabelle Dussault, Min Lin, Kevin Hollister, Eric H. Wang, Timothy W. Synold, and Barry Marc Forman

Molecular Medicine, The City of Hope National Medical Center, Duarte, CA 91010-3012

Corresponding Author: bmforman{at}earthlink.net

The orphan nuclear receptor SXR coordinately regulates drug clearance in response to a wide variety of xenobiotic compounds. This signaling system protects the body from exposure to toxic compounds, however, it can also pose a severe barrier to drug therapy. We now demonstrate that the HIV protease inhibitor ritonavir binds SXR and activates its target genes. This represents an example of a commonly used therapeutic agent that effectively activates SXR. We also show that other protease inhibitors are weaker (saquinavir) or unable to activate SXR (nelfinavir, indinavir) thus defining analogs which fail to induce SXR-regulated clearance pathways. Interestingly, HIV protease inhibitors are distinct from previously known SXR ligands in that they are peptide mimetic compounds. This expands the ligand specificity of SXR to include this unique chemical class whose pharmaceutical significance is expanding. Finally, we show that SXR ligands activate expression of MRP2, a critical regulator of bile flow and biliary drug excretion. These findings have important implications for the role of SXR in regulating drug clearance and hepatic disorders associated with impaired bile flow.


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