[Size=4]PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators.[/size]
Lamba V, Yasuda K, Lamba JK, Assem M, Davila J, Strom S, Schuetz EG.
Source
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
Abstract
To gain insight on the expression of pregnane X receptor (PXR), we analyzed PXR.1 and PXR alternatively spliced transcripts in a panel of 36 human tissues. PXR.1 was expressed in many more tissues than previously determined, including human bone marrow and select regions of the human brain. In each of these tissues, we observed alternative splicing of various exons of PXR that generated multiple distinct PXR isoforms. The most abundant PXR alternative mRNA transcripts lacked 111 nucleotides, deleting 37 amino acids from the PXR LBD (PXR.2), or lacked 123 nt, deleting 41 amino acids from the PXR LBD (PXR.3). CYP3A4, a gene transcriptionally regulated by PXR, showed incomplete overlap with PXR in its tissue distribution. Quantitation of PXR mRNAs in human liver demonstrated that PXR.2 and PXR.3 represented 6.7% and 0.32% of total PXR mRNA transcripts. Brain expression of PXR prompted analysis of whether some brain acting chemicals were PXR ligands. The neurosteroids allopregnanolone and pregnanolone activated PXR and induced transcription of a CYP3A4-luciferase reporter. Nicotine, the psychoactive and addictive chemical in cigarettes, and a known inducer of brain CYP2B6, was an efficacious activator of PXR and inducer of CYP3A4 transcription. Because nicotine activation of PXR will enhance metabolism of nicotine to the non-psychoactive cotinine, these results provide one molecular mechanism for the development of tolerance to nicotine. Moreover, the identification of PXR in many human tissues, such as brain, and activation by tissue specific ligands (such as neurosteroids) suggests additional biological roles for this receptor in these tissues.
PMID: 15364541 [PubMed - indexed for MEDLINE]
Tolerance is a hugemongous problem for me post finasteride.
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[Size=4]Stay tuned to PXR: an orphan actor that may not be D-structive only to bone.[/size]
Holick MF.
Source
Vitamin D, Skin, and Bone Research Laboratory, Section of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA. mfholick@bu.edu
Abstract
Pregnane X receptor (PXR) plays an important role in detoxifying xenobiotics and drugs. In this issue of the JCI, Pascussi et al. provide convincing evidence that PXR can also induce vitamin D deficiency and bone disease because of its ability to cross-talk with the vitamin D-responsive gene that catabolizes 25-hydroxy-vitamin D and 1,25-dihydroxyvitamin D. This cross-talk behavior has important health ramifications and can be mitigated through the identification and treatment of PXR-induced vitamin D deficiency.
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[Size=4]Cross-talk between androgen receptor and pregnane and xenobiotic receptor reveals existence of a novel modulatory action of anti-androgenic drugs.[/size]
Kumar S, Jaiswal B, Kumar S, Negi S, Tyagi RK.
Source
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
Abstract
The androgen receptor (AR) is a member of nuclear receptor superfamily (NRs) and plays a critical role in prostate cancer development and progression. Therefore, anti-androgens that repress AR activity remain a critical mainstay for prostate cancer therapy. However, molecular mechanisms by which anti-androgens exert their therapeutic effects are not clearly elucidated and hence are a major area of scientific pursuit. Here, we demonstrate that another member of NRs, pregnane and xenobiotic receptor (PXR), not only acts as a molecular sensor of anti-androgens but also influences the outcome of therapeutic regimen with anti-androgenic drugs via a novel AR-PXR cross-talk. Using ‘gain- and loss-of-function’ studies, we identified a distinct role of PXR as a potent repressor of AR-regulated transcription. Our study implicates PXR as a key determinant of anti-androgen action since down-regulation of PXR diminishes the potency of the anti-androgenic drugs and enhances transcriptional actions of androgens. In addition, our subcellular localization studies revealed that ligand-activated AR induces nuclear localization of PXR and the two receptors colocalize at discrete sites in nucleus and mitotic chromatin. Finally, we report a distinct antagonist-induced interaction between AR and PXR defining a hitherto unidentified mode of action of AR antagonist. In this perspective, the study may help in designing and development of novel AR antagonists offering improved avenues in prostate cancer therapy.
Wow this PXR thing does it all.
All studies from pubmed, google the title of study for link.
. Dunno if my other symptoms and this result are linked or not… my ureine is very yellow most of the time and my stools are hard, light-brown and odorless and usually at least one “piece” floats. I’m starting to think that I have some problems with digesting fat… my stools are also very infrequent, I can go like 2-3 days without unreleasing lol. Usually it’s like every other day.