Abstract
Pregnane X receptor (PXR) is a nuclear receptor considered to be a master xenobiotic receptor that coordinately regulates the expression of genes encoding drug-metabolizing enzymes and drug transporters to essentially detoxify and eliminate xenobiotics and endotoxins from the body. In the past several years, the function of PXR in the regulation of xenobiotic metabolism has been extensively studied, and the role of PXR as a xenobiotic sensor has been well established. It is now clear, however, that PXR plays many other roles in addition to its xenobiotic-sensing function. For instance, recent studies have discovered previously unidentified roles of PXR in inflammatory response, cell proliferation, and cell migration. PXR also contributes to the dysregulation of these processes in diseases states. These recent discoveries of the role of PXR in the physiologic and pathophysiologic conditions of other cellular processes provides the possibility of novel targets for drug discovery. This review highlights areas of PXR regulation that require further clarification and summarizes the recent progress in our understanding of the nonxenobiotic functions of PXR that can be explored for relevant therapeutic applications.
Highlights
Animals are constantly exposed to environmental chemicals and toxic endogenous compounds, and to sense and protect against such, mammals have evolved a defensive network regulated by xenobiotic receptors such as pregnane X receptor (PXR; known as steroid and xenobiotic receptor [SXR]; NR1I2) (Bertilsson et al, 1998; Blumberg et al, 1998; Kliewer et al, 1998), which is a well-established xenobiotic sensor
Pregnane X receptor (PXR) induces the expression of genes encoding drugmetabolizing enzymes, such as cytochrome P450 enzymes (e.g., CYP3A4), conjugation enzymes, and transporters (Rosenfeld et al, 2003; Zhou et al, 2009; Chai et al, 2013)
Previous studies have demonstrated that PXR, which is expressed in various cancers, such as colon, ovary, breast, endometrial, and prostate cancers, contributes to tumor progression and drug resistance by inducing enzymes such as CYP3A4, thereby enabling the metabolism of therapeutic agents and steroid hormones such as estrogens (Chen and Nie, 2009; Qiao et al, 2013)
Summary
Animals are constantly exposed to environmental chemicals and toxic endogenous compounds, and to sense and protect against such, mammals have evolved a defensive network regulated by xenobiotic receptors such as pregnane X receptor (PXR; known as steroid and xenobiotic receptor [SXR]; NR1I2) (Bertilsson et al, 1998; Blumberg et al, 1998; Kliewer et al, 1998), which is a well-established xenobiotic sensor. This review summarizes recent advances in the discovery of the new functions of PXR beyond its canonical role in detoxification of xenobiotics and focuses on less discussed topics, such as its involvement in inflammation, proliferation, migration, apoptosis, and DNA damage.
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