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Papers In Press, published online ahead of print June 18, 2002
J. Biol. Chem, 10.1074/jbc.M111245200
Submitted on November 26, 2001
Revised on June 3, 2002
Accepted on June 17, 2002
Division of Endocrinology and Metabolism, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Minato, Tokyo 105-8470
Corresponding Author: coactivator{at}mac.com
Cytochrome P450 monooxygenase 3A4 (CYP3A4) is responsible for the metabolism of endogenous steroids and drugs in liver. Many inducers of human CYP3A4 such as rifampicin, bind to the orphan nuclear receptor SXR (steroid and xenobiotic receptor) as ligands, and stimulate transcription on xenobiotic-response elements, located in the CYP3A4 promoter. Conversely, it is not known whether SXR mediates the transcriptional repression. We thus examined transcriptional repression of SXR and its interaction with corepressors (NCoR and SMRT) using reporter assays in the absence and presence of ligand. Cotransfection of SMRT, but not NCoR, inhibited not only basal, but also rifampicin-induced transcriptional activity of SXR on the CYP3A4 promoter through specific SMRT-SXR interaction in HepG2 cells. Interestingly, rifampicin also increased the interaction of SXR with SMRT, as well as with coactivator SRC-1. On the other hand, the anti-fungal agent, ketoconazole decreased SXR interaction with both SRC-1 and SMRT. Ketoconazole partially inhibited corticosterone-induced SXR-mediated transcription on the CYP3A4 promoter. Taken together, our results suggest that the differential interaction of coactivators and corepressors induced by various xenobiotics may alter SXR-mediated transcription. Further, the effects of ketoconazole on the CYP3A4 gene suppression may explain, in part, drug-induced inhibition of the CYP3A4 action at transcriptional level.
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