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Event: 239
Key Event Title
Activation, Pregnane-X receptor, NR1l2
Short name
Biological Context
Level of Biological Organization |
---|
Molecular |
Cell term
Cell term |
---|
eukaryotic cell |
Organ term
Key Event Components
Process | Object | Action |
---|---|---|
signaling | nuclear receptor subfamily 1 group I member 2 | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
Nuclear receptor induced TH Catabolism and Developmental Hearing Loss | MolecularInitiatingEvent | Katie Paul Friedman (send email) | Open for adoption | Under Development |
PXR activation leads to liver steatosis | MolecularInitiatingEvent | John Frisch (send email) | Under development: Not open for comment. Do not cite | |
Activation, Pregnane-X receptor, NR1l2 leads to Increased, plasma LDL cholesterol | MolecularInitiatingEvent | John Frisch (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Life Stages
Life stage | Evidence |
---|---|
Adult | High |
Juvenile | Moderate |
Sex Applicability
Term | Evidence |
---|---|
Unspecific | High |
Key Event Description
Pregnane X receptor (PXR), also known as steroid NR subfamily 1, group I, member 2 (NR1I2), is a nuclear receptor that can be activated by pregnenolone and progesterone and many chemicals due to low specificity; once activated it binds to Retinoid X receptor (RXR) and increases upregulation of target genes (Mellor et al. 2016). PXR has an important role in lipid homeostasis by regulating the rate of lipid intake particularly through activation of cluster of differentiation 36, also known as platelet glycoprotein 4 [(CD36) (Zhou et al. 2006; Gwag et al. 2019)].
How It Is Measured or Detected
Effects of Pregnane X receptor (PXR) activation on expression of downstream genes can be investigating using metabolomics and RT-qPCR approaches. In addition, targeted ToxCast assays using SeqAPASS evaluations can evaluate gene expression changes from chemical exposure for model species (e.g. Lalone et al. 2018). Relevent ToxCast assays are ATG_PXRE_CIS; ATG_PXR_TRANS; TOX21_PXR_agonist; ATG_mPXR_XSP2; NVS_NR_hPXR (U.S. EPA 2024). An additional assay for human PXR is available (INDIGO Biosciences 2024).
Domain of Applicability
Life Stage: Older individuals are more likely to manifest this key event (adults > juveniles) due to increased opportunity to upregulate gene expression.
Sex: Applies to both males and females.
Taxonomic: Appears to be present broadly in vertebrates, with most representative studies in mammals (humans, lab mice, lab rats).
References
Gwag, T., Meng, Z., Sui, Y., Helsley, R.N., Park, S.-H., Wang, S., Greenberg, R.N., and Zhou, C. 2019. Non-nucleoside reverse transcriptase inhibitor efavirenz activates PXR to induce hypercholesterolemia and hepatic steatosis. Journal of Hepatology 70: 930–940.
INDIGO Biosciences. 2024. Retrieved from https://indigobiosciences.com/product/human-pxr-reporter-assay-kit/.
LaLone, C.A., Villeneuve, D.L., Doering, J.A., Blackwell, B.R., Transue, T.R., Simmons, C.W., Swintek, J., Degitz, S.J., Williams, A.J., and Ankley, G.T. 2018. Evidence for Cross Species Extrapolation of Mammalian-Based High-Throughput Screening Assay Results. Environmental Science and Technology 52: 13960−13971.
Mellor, C.L., Steinmetz, F.P., and Cronin, T.D. 2016. The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways. Critical Reviews in Toxicology 46(2): 138-152. DOI:10.3109/10408444.2015.1089471.
U.S. EPA. 2024. ToxCast & Tox21 Summary Files from invitrodb_v4. Retrieved from https://www.epa.gov/chemical-research/toxicity-forecaster-toxcasttm-data.
Zhou, J., Zhai, Y., Mu, Y., Gong, H., Uppal, H., Toma, D., Ren, S., Evans, R.M., and Xie, W. 2006. A Novel Pregnane X Receptor-mediated and Sterol Regulatory Element-binding Protein-independent lipogenic pathway. The Journal of Biological Chemistry 281(21): 15013–15020.
NOTE: Italics symbolize edits from John Frisch June 2024