resources/case_2/output_0.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). This indicates a broad role for SXR in the coordinated induction of multiple detoxification pathways.

**Erin Schuetz** & **Stephen Strom**  
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 MDR1 and ABCB1) leads to the efficient efflux of these 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, Synold et al. 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.

CYP3A4, the most abundant drug-metabolizing enzyme in the liver and intestine, is responsible for the metabolism of 50% of all drugs. Many drugs are substrates for both CYP3A4 and P-glycoprotein, a broad-specificity efflux pump protein encoded by the gene MDR1. It was first demonstrated in 1996 that MDR1 expression is coordinated with expression of CYP3A4, with both gene products being induced by the same spectrum of drugs. P-glycoprotein and CYP3A4 are colocalized in liver and intestine, and serve as a coordinated system for the absorption, metabolism and disposition of many drugs. Many drug–drug interactions arise from concurrent administration of drugs which are both substrates and inducers of CYP3A4 and MDR1 expression.

Long-term therapy with drugs that induce CYP3A4 and MDR1 increase the systemic clearance of some antileukemic agents, and such therapy has been shown to exert negative effects on survival while increasing cancer relapse. Recent studies have shown that SXR, a member of the nuclear hormone receptor superfamily, regulates expression of CYP3A (ref. 5,6). SXR is activated by a pharmacopia of drugs, including antibiotics, statin cholesterol-lowering drugs, antiseizure medications, steroids such as glucocorticoids, some bile acids, environmental contaminants such as organochlorine pesticides and polychlorinated biphenyls, and herbal supplements such as St. John’s wort. 

Little is known about how certain drugs induce CYP and MDR1 gene expression. Synold et al. demonstrate that SXR is activated by paclitaxel (Taxol) and is responsible for inducing expression of not only CYP3A (previously shown to be induced by paclitaxel) but also CYP2C9 and MDR1. Paclitaxel is metabolized by both CYP3A4 and CYP2C9 (ref. 11) and transported by P-glycoprotein, and induction of all of these proteins leads to its enhanced clearance. This indicates a broad role for SXR in the coordinated induction of multiple detoxification pathways.

Synold et al. show 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. also demonstrate that Ecteinascidin-743 (ET-743), an antineoplastic agent, can antagonize SXR activation 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. MDR1 expression modulators should be carefully screened for their potential to inhibit or modulate metabolism of other medications taken by a patient.

**Figure 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.

NATURE MEDICINE • VOLUME 7 • NUMBER 5 • MAY 2001