Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics.
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 (nuclear receptor corepressor) and SMRT (silencing mediator for retinoid and thyroid receptors) 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 the transcriptional level.
Takeshita
Akira
A
Division of Endocrinology and Metabolism, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo 105-8470, Japan. coactivator@mac.com
Taguchi
Manabu
M
Koibuchi
Noriyuki
N
Ozawa
Yasunori
Y
D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017930:Genes, Reporter; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008957:Models, Genetic; D010957:Plasmids / Q000378:metabolism; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011987:Receptors, Steroid / Q000378:metabolism / Q000502:physiology*; D012293:Rifampin / Q000494:pharmacology; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques; D015262:Xenobiotics / Q000494:pharmacology*
D000305:Adrenal Cortex Hormones; D000904:Antibiotics, Antitubercular; D000935:Antifungal Agents; D008024:Ligands; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D008156:Luciferases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D012293:Rifampin