The Pregnane X Receptor

Potassium Competitive Acid Blockers The pregnane X receptor (PXR) is a promiscuous nuclear receptor, that has evolved to protect the body from toxic chemicals. It is activated by a wide variety of xenobiotics including several diugs like rifampicin, hyperforin ( the active ingredient of St. John s wort), clotrimazole and others. PXR heterodimerizes with the... 

Gene regulation by tocopherols has mainly been associated with PKC because of its deactivation by a-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, API). A direct participation of the pregnane X receptor (PXR)/ retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element appear in some cases to be implicated as well. The obser ved immunmodulatory function of a-tocopherol may also be attributed to the fact that the release of the proinflammatory cytokine interlukin-l 3 can be inhibited by a-tocopherol via... 

Ruhl, R. et al.. Carotenoids and their metabolites are naturally occurring activators of gene expression via the pregnane X receptor. Fur. J. Nutr, 43, 336, 2004. 

Yang D, Wang X, Chen Y, Deng R, Yan B (2009) Pyrethroid insecticides isoform-dependent hydrolysis, induction of cytochrome P450 3A4 and evidence on the involvement of the pregnane X receptor. Toxicol Appl Pharmacol 237 49-58... 

Moore, L.B., Goodwin, B., Jones, S.A., Wisely, G.B., Serabjit-Singh, C.J., Willson, T.M., Collins, J.L. and Kliewer, S. A. (2000) St. John s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proceedings of the National Academy of Sciences of the United States of America, 97, 7500-7502. 

H. Masuyama, N. Suwaki, Y. Tateishi, H. Nakatsukasa, T. Segawa, and Y. Hiramatsu. The pregnane X receptor regulates gene expression in a ligand- and promoter-selective fashion. Mol Endocrinol. 19 1170-1180 (2005). 

Moore LB, Goodwin B, Jones SA, et al. St. John s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 2000 97 7500-7502. 

Chen Y, Ferguson SS, Negishi M, Goldstein JA. Induction of human CYP2C9 by rifampicin, h5 perforin, and phenobarbital is mediated by the pregnane X receptor. J Pharmacol Exp Ther 2004 308(2) 495-501. 

Goodwin B, Redinbo, MR, Kliewer SA. Regulation of CYP3A gene transcription by the pregnane X receptor. Annu Rev Pharmacol Toxicol 2002 42 1-23. 

El-Sankary W, Bombail V, Gibson GG, Plant N (2002) Glucocorticoid-mediated induction of CYP3A4 is decreased by disruption of a protein DNA interaction distinct from the pregnane X receptor response element. Drug Metab Dispos 30, 1029-1034. 

Jones SA, Moore LB, Shenk JL, et al. The pregnane X receptor a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol 2000 14 27-39. 

Induction of CYP-mediated metabolism requires prior exposure of the hepatocyte s CYP-synthesis mechanism to a chemical inducer. The inducer signals the synthetic mechanisms to upregulate the production of one or more CYP isoforms, a process that takes time. Consequently, evidence of increased CYP activity is of slow onset following initiation of exposure to the inducer, and conversely slowly reverts to baseline after the inducer is removed (46,47). Enhancement of CYP expression/activity due to chemical induction therefore reflects prior, but not necessarily current, exposure to the inducer. Nuclear receptors, such as the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), have been identified as key elements in the process of transcriptional activation (48-56). 

Figure 2.26. Overview of the induction of cytochrome P450 3A4. A drug (D) binds to the pregnane X receptor (PXR) the complex moves to the nucleus, recruits additional proteins (otdy one of which is shown) and binds to specific regulatory sites on the DNA. This will induce transscription of CYP 3A4 ttiRNA, as well as other proteins such as conjugating enzymes and membrane transport proteins.

Guo GL, Moffit JS, Nicol CJ, Ward JM, Aleksunes LA, Slitt AL, Kliewer SA, Manautou JE, Gonzalez FJ. Enhanced acetaminophen toxicity by activation of the pregnane X receptor. Toxicol Sci 2004 82 374-80. 

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