The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux.

Abstract:

:Cytochrome P450 3A4 is an important mediator of drug catabolism that can be regulated by the steroid and xenobiotic receptor (SXR). We show here that SXR also regulates drug efflux by activating expression of the gene MDR1, which encodes the protein P-glycoprotein (ABCB1). Paclitaxel (Taxol), a commonly used chemotherapeutic agent, activated SXR and enhanced P-glycoprotein-mediated drug clearance. In contrast, docetaxel (Taxotere), a closely related antineoplastic agent, did not activate SXR and displayed superior pharmacokinetic properties. Docetaxel's silent properties reflect its inability to displace transcriptional corepressors from SXR. We also found that ET-743, a potent antineoplastic agent, suppressed MDR1 transcription by acting as an inhibitor of SXR. These findings demonstrate how the molecular activities of SXR can be manipulated to control drug clearance.

journal_name

Nat Med

journal_title

Nature medicine

authors

Synold TW,Dussault I,Forman BM

doi

10.1038/87912

keywords:

subject

Has Abstract

pub_date

2001-05-01 00:00:00

pages

584-90

issue

5

eissn

1078-8956

issn

1546-170X

pii

87912

journal_volume

7

pub_type

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