resources/case_2/prompt_1.txt

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© 2001 Nature Publishing Group 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 clearance12. This indicates a
 mental chemicals, endogenous broad role for SXR in the coordinated in
 ERIN SCHUETZ1 & STEPHEN STROM2
 T he body responds to drugs, environ
 steroids and bile acids by inducing the co duction of multiple detoxification path
 ordinated expression of a battery of drug some antileukemic agents, and such ther ways.
 detoxification genes in tissues such as apy has been shown to exert negative ef Because concurrent administration of
 liver and intestine. These include the cy fects on survival while increasing cancer CYP3A4 and P-glycoprotein inducers
 tochromes P450 (CYPs), which are the relapse4 . Recent studies have shown that (such as rifampicin) with drugs that serve
 enzymes responsible for oxidative, perox SXR, a member of the nuclear hormone as substrates for these proteins is a major
 idative and reductive metabolism of toxic receptor superfamily, regulates expres basis of drug–drug interactions5 , pharma
 compounds. Expression of drug transport sion of CYP3A (ref. 5,6). SXR is activated ceutical companies are now using SXR
 proteins such as P-glycoprotein (encoded by a pharmacopia of drugs, including an binding and -activation assays to screen
 by MDR1 and also known as MDR1 and tibiotics, statin cholesterol-lowering and predict which compounds will in
 ABCB1) leads to the efficient efflux these drugs, antiseizure medications, steroids duce CYP3A expression and potentially
 drugs from the body. Activation of drug such as glucocorticoids5 , some bile acids7 , cause drug interactions. These types of as
 transport can be beneficial in instances environmental contaminants such as says may also identify compounds that
 where it is important to remove toxins organochlorine pesticides and polychlori induce CYP2C9 and MDR1 , and cause
 from the body, but detrimental in situa nated biphenyls8 , and herbal supple auto-induction of their own clearance. It
 tions where it is important for a patient ments such as St. John’s wort9 . might be possible to someday create
 to retain effective levels of a therapeutic Little is known about how certain drugs drugs that are ‘SXR transparent’ by mini
 drug. In this issue, Snyold et al. 1 demon induce CYP and MDR1 gene expression. mizing or eliminating binding activity. In
 strate that steroid xenobiotic receptor Synold et al. 1 demonstrate that SXR is ac this regard, the report of Synold et al . 1
 (SXR; also known as PXR), a transcription tivated by paclitaxel (Taxol) and is re shows that docetaxel, unlike the struc
 factor known to mediate drug, xenobiotic sponsible for inducing expression of not tural analog paclitaxel, does not induce
 and steroid induction of the major liver only CYP3A (previously shown to be in CYP3A4 or MDR1 expression because it
 drug metabolizing enzyme, can also regu duced by paclitaxel10) but also CYP2C9 does not activate SXR. This should result
 late the expression of a drug efflux path and MDR1 . Paclitaxel is metabolized by in superior pharmacokinetic properties
 ©
 way, indicating a novel strategy to both CYP3A4 and CYP2C9 (ref. 11) and relative to paclitaxel.
 control drug clearance. transported by P-glycoprotein, and in Synold et al . 1 demonstrate that
 CYP3A4, the most abundant drug-me duction of all of these proteins leads to its Ecteinascidin-743 (ET-743), an antineo
 tabolizing enzyme in the liver and plastic agent, can antagonize SXR
 intestine, is responsible for the activation and inhibit MDR1 ex
 metabolism of 50% of all drugs. pression. The authors suggest that
 Feed forward and feed back pathways
 Many drugs are substrates for both SXR antagonists that downregu
 CYP3A4 and P-glycoprotein, a late the P-glycoprotein pathway of
 Paclitaxel
 broad-specificity efflux pump pro drug elimination could be ex
 tein encoded by the gene MDR1 . It ploited to improve drug retention.
 was first demonstrated in 1996 This approach should be under
 that MDR1 expression is coordi taken cautiously, because clinical
 nated with expression of CYP3A4 , trials involving drugs that inhibit
 with both gene products being in P-glycoprotein activity, given in an
 SXR
 duced by the same spectrum of effort to reduce drug resistance,
 Regulates
 drugs2 . P-glycoprotein and have had limited success and led to
 the expression
 CYP3A4 are colocalized in liver undesired pharmacokinetic side
 of MDR1
 and intestine, and serve as a coor effects13. MDR1 expression ‘modu
 and CYP3A4
 dinated system for the absorption, lators’ should be carefully screened
 MDR1 CYP3A
 CYP2C9
 metabolism and disposition of for their potential to inhibit or
 many drugs. Many drug–drug in modulate metabolism of other
 teractions arise from concurrent medications taken by a patient.
 Fig. 1 Feedforward and feedback pathways of drug metabo
 administration of drugs which are Given the knowledge that SXR has
 lism. Paclitaxel is a ligand for SXR, causing this nuclear receptor
 both substrates and inducers of multiple detoxification genes as
 to activate transcription of the P-glycoprotein efflux pump pro
 CYP3A4 and MDR1 expression3 . targets, antagonism of SXR might
 tein encoded by MDR1 , and the drug metabolizing enzymes
 CYP3A and CYP2C9. These pathways, however, mediate drug
 Long-term therapy with drugs lead to increased drug toxicity.
 clearance and reduce paclitaxel activation of SXR in a feedback
 that induce CYP3A4 and MDR1 in Synold et al . 1 emphasize the feed
 mechanism. Manipulation of this pathway may be used to pro
 crease the systemic clearance of forward pathways of drug clear
 long or reduce drug retention.
 536 NATURE MEDICINE • VOLUME 7 • NUMBER 5 • MAY 2001```
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