PubMed · 2664965
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J Y Reginster, M P Lecart, M Fontaine, R Deroisy, P Franchimont. 1989-05-15. [Corticosteroids and bone tissue].. https://pubmed.ncbi.nlm.nih.gov/2664965/
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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.
An oil tanker ran aground on the Galapagos island of San Cristóbal on 17 January 2001, spilling roughly three million litres of diesel and bunker oil. The slick started to spread westwards and was dispersed by strong currents, so only a few marine animals were killed immediately as a result. Here we draw on the long-term data sets gathered before the spill to show that a population of marine iguanas (Amblyrhychus cristatus) on Sante Fe island suffered a massive 62% mortality in the year after the accident, due to a small amount of residual oil contamination in the sea. Another population on the more remote island of Genovesa was unaffected.
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