The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism

Abstract

The steroid and xenobiotic receptor (SXR) (also known as pregnane X receptor or PXR) is a nuclear hormone receptor activated by a diverse array of endogenous hormones, dietary steroids, pharmaceutical agents, and xenobiotic compounds. SXR has an enlarged, flexible, hydrophobic ligand binding domain (LBD) which is remarkably divergent across mammalian species and SXR exhibits considerable differences in its pharmacology among mammals.The broad response profile of SXR has led to the development of "the steroid and xenobiotic sensor hypothesis". SXR has been established as a xenobiotic sensor that coordinately regulates xenobiotic clearance in the liver and intestine via induction of genes involved in drug and xenobiotic metabolism. In the past few years, research has revealed new and mostly unsuspected roles for SXR in modulating inflammation, bone homeostasis, vitamin D metabolism, lipid homeostasis, energy homeostasis and cancer.The identification of SXR as a xenobiotic sensor has provided an important tool for studying new mechanisms through which diet, chemical exposure, and environment ultimately impact health and disease. The discovery and pharmacological development of new PXR modulators might represent an interesting and innovative therapeutic approach to combat various diseases. SXR, a steroid and xenobiotic sensorThe mammalian xenobiotic response is mediated primarily through the activity of four families of cytochrome P450 (CYP) monooxygenases (CYP1, CYP2, CYP3, and CYP4) [Nelson et al., 1996]. CYP enzymes are the main enzymatic system for metabolism of lipophilic substrates of diverse structures and are important in the oxidative, peroxidative, and reductive metabolism of numerous endogenous compounds including steroids, bile acids, fatty acids, prostaglandins, leukotrienes, biogenic amines and retinoids [Nebert and Russell, 2002;Waxman, 1999]. Among four families of CYP enzymes, the CYP3A family is one of the most important since it is responsible for the metabolism of more than 50% of clinically used drugs and many xenobiotic chemicals [Guengerich, 1999]. The CYP2B family is responsible for another 25-30% of drug and xenobiotic metabolism [Xie and Evans, 2001]. The ability of organisms to induce P450 enzymes in response to elevated xenobiotic levels is crucial for their survival and normal homeostasis.CYP3A genes are responsible for the initial metabolism of numerous xenobiotic chemicals, making them a first line of defense against toxic substances in the diet and environment. It is notable that a large number of CYP3A substrates are also capable of inducing or up-regulating expression of the mRNAs encoding the enzymes themselves [Denison and Whitlock, 1995;Guengerich, 1999;Wrighton et al., 2000]. Because the CYP3A family genes produce key enzymes for the metabolism of more than 50% of prescription drugs, there has been a strong interest in understanding the mechanistic basis of CYP3A gene regulation. It is well known that drugs capable of inducing expression of CYP3A genes are likely to lead to int...

Deficiency of PXR decreases atherosclerosis in apoE-deficient mice

“…We and other groups have shown that activation of PXR also affects the expression of other hepatic genes involved in lipid homeostasis, including apoA-IV, oxysterol 7 ␣ -hydroxylase (CYP39A1), and 7-dehydrocholesterol reductase (DHCR7) in several animal models including WT, apoE ( 9,19,20 ). These studies indicate that PXR can mediate cholesterol and lipid homeostasis at multiple levels.…”

Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells

“…Novel physiological functions of PXR have been discovered including regulation of NF-kB-mediated inflammatory pathway, vitamin D metabolism, cholesterol and lipid homoeostasis, energy homoeostasis, apoptosis as well as cell proliferation (reviewed in Zhou et al, 2009). These new results suggest multitudes of PXR functions and potential use of PXR as a therapeutic target for treating certain diseases such as inflammatory bowl disease (IBD), cholestasis and hyperlipidemia in which PXR may influence the disease development.…”

Vitamin K, SXR, and GGCX

“…In 1998, SXR/PXR was cloned as a novel nuclear receptor that is mainly expressed in the liver and intestine [6]. At first, its functions were characterized as a ligand-dependent transcription factor which is activated by various pharmaceutical agents and xenobiotic compounds [7]. It was originally classified as an orphan receptor since the endogenous ligand was not known when it was cloned.…”