PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators

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...

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Bibliographic Details
Published in:Toxicology and applied pharmacology 2004-09, Vol.199 (3), p.251-265
Main Authors: Lamba, Vishal, Yasuda, Kazuto, Lamba, Jatinder K., Assem, Mahfoud, Davila, Julio, Strom, Stephen, Schuetz, Erin G.
Format: Article
Language:English
Subjects:
Adult
Aged
Alternative Splicing - genetics
Amino Acid Sequence
Animals
Biological and medical sciences
Biological Evolution
Brain Chemistry - genetics
Conserved Sequence
CYP3A4
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - metabolism
DNA Primers
Dogs
Female
Fishes
Humans
Isomerism
Liver - metabolism
Macaca mulatta
Male
Medical sciences
Mice
Middle Aged
Molecular Sequence Data
Neurotransmitter Agents - pharmacology
Nicotine - pharmacology
Nicotinic Agonists - pharmacology
Plasmids - genetics
Pregnane X Receptor
PXR
Rabbits
Rats
Receptors, Cytoplasmic and Nuclear - agonists
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Steroid - agonists
Receptors, Steroid - genetics
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - biosynthesis
RNA, Messenger - genetics
Smoking - metabolism
Splice variants
Steroids - pharmacology
Swine
SXR
Tissue Distribution
Tobacco, tobacco smoking
Toxicology
Transfection
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Summary: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.
ISSN:0041-008X
1096-0333
DOI:10.1016/j.taap.2003.12.027