Pharmacology

Evading Search and Destroy

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Science  18 May 2001:
Vol. 292, Issue 5520, pp. 1263-1265
DOI: 10.1126/science.292.5520.1263e

Anticancer agents such as taxol often encounter two barriers to their effectiveness: metabolism by the cytochrome P450 family of enzymes (CYPs) and clearance from cells by the P-glycoprotein efflux pump (MDR1). Synold et al. demonstrate that taxol elicits both mechanisms in human hepatocytes and intestinal epithelial cells by activating the steroid and xenobiotic nuclear receptor (SXR), which detects a broad spectrum of drugs. Taxol reversed SXR interaction with nuclear corepressors, thereby allowing the expression of genes such as CYPs and MDR1. The inability of the taxol analog docetaxel to displace SXR corepressors may explain why it is a relatively effective antineoplastic agent, and the development of more “SXR-transparent” compounds such as docetaxel could improve the retention and duration of anticancer drugs. — LDC

Nature Med.7, 584 (2001).

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