resources/case_2/output_1.txt

© 2001 Nature Publishing Group [http://medicine.nature.com](http://medicine.nature.com)

## NEWS & VIEWS

### Promiscuous regulator of xenobiotic removal

The transcription factor SXR mediates drug, xenobiotic, and steroid induction of a major drug-metabolizing enzyme. Drugs such as paclitaxel (Taxol) can bind and activate this transcription factor and therefore regulate their own metabolism and efflux from cells. Manipulation of this pathway might lead to new ways to improve therapeutic efficacy and to minimize toxicity (584-590).

Enhanced clearance<sup>12</sup>. This indicates a broad role for SXR in the coordinated induction of multiple detoxification pathways.

**ERIN SCHUETZ<sup>1</sup> & STEPHEN STROM<sup>2</sup>**

The body responds to drugs, environmental chemicals, endogenous steroids, and bile acids by inducing the coordinated expression of a battery of drug detoxification genes in tissues such as liver and intestine. These include the cytochromes P450 (CYPs), which are the enzymes responsible for oxidative, peroxidative, and reductive metabolism of toxic compounds. Expression of drug transport proteins such as P-glycoprotein (encoded by MDR1 and also known as ABCB1) leads to the efficient efflux of drugs from the body. Activation of drug transport can be beneficial in instances where it is important to remove toxins from the body, but detrimental in situations where it is important for a patient to retain effective levels of a therapeutic drug.

In this issue, Snyold et al.<sup>1</sup> demonstrate that steroid xenobiotic receptor (SXR; also known as PXR), a transcription factor known to mediate drug, xenobiotic, and steroid induction of the major liver drug-metabolizing enzyme, can also regulate the expression of a drug efflux pathway, indicating a novel strategy to control drug clearance.

Because concurrent administration of CYP3A4 and P-glycoprotein inducers (such as rifampicin) with drugs that serve as substrates for these proteins is a major basis of drug-drug interactions<sup>5</sup>, pharmaceutical companies are now using SXR-binding and -activation assays to screen and predict which compounds will induce CYP3A expression and potentially cause drug interactions. These types of assays may also identify compounds that induce CYP2C9 and MDR1, causing auto-induction of their own clearance. It might be possible to someday create drugs that are ‘SXR transparent’ by minimizing or eliminating binding activity.

In this regard, the report of Synold et al.<sup>1</sup> shows that docetaxel, unlike the structural analog paclitaxel, does not induce CYP3A4 or MDR1 expression because it does not activate SXR. This should result in superior pharmacokinetic properties relative to paclitaxel.

Synold et al.<sup>1</sup> demonstrate that Ecteinascidin-743 (ET-743), an antineoplastic agent, can antagonize SXR and inhibit MDR1 expression. The authors suggest that SXR antagonists that downregulate the P-glycoprotein pathway of drug elimination could be exploited to improve drug retention. This approach should be undertaken cautiously, because clinical trials involving drugs that inhibit P-glycoprotein activity, given in an effort to reduce drug resistance, have had limited success and led to undesired pharmacokinetic side effects<sup>13</sup>. MDR1 expression ‘modulators’ should be carefully screened for their potential to inhibit or modulate metabolism of other medications taken by a patient.

### Fig. 1: Feedforward and feedback pathways of drug metabolism

Paclitaxel is a ligand for SXR, causing this nuclear receptor to activate transcription of the P-glycoprotein efflux pump protein encoded by MDR1, and the drug-metabolizing enzymes CYP3A and CYP2C9. These pathways, however, mediate drug clearance and reduce paclitaxel activation of SXR in a feedback mechanism. Manipulation of this pathway may be used to prolong or reduce drug retention.

536 NATURE MEDICINE • VOLUME 7 • NUMBER 5 • MAY 2001