Spaces:
Sleeping
Sleeping
| Convert this text to Markdown with correct reading order. Stay close to original content. | |
| ```` | |
| © 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``` | |
| ```` | |