User:Islom1/sandbox

During development, embryos utilize steroid signals to direct sexual differentiation of tissues necessary for reproduction. Disruption of these signals by exogenous substances (both natural and synthetic) frequently produce phenotypic effects that can persist into adulthood and influence reproduction. This paper reviews the evidence that during embryonic development, progesterone metabolites and xenobiotic-sensing nuclear receptors may interact to increase the expression of numerous enzymes responsible for steroid metabolism in oviparous and placental amniotes. In these groups, embryonic development is characterized by (1) elevated progesterone concentrations, (2) 5β reduction being the primary metabolic pathway of progesterone, (3) the presence of xenobiotic-sensing nuclear receptors that can bind 5β metabolites of progesterone, and (4) increased expression of a suite of enzymes responsible for the metabolism of multiple steroids. We propose that xenobiotic-sensing nuclear receptors initially evolved to buffer the developing embryo from the potentially adverse effects of various maternal steroids on sexual differentiation.

Xenobiotic receptors, are recognized for their roles in sensing foreign chemicals (xenobiotics) and triggering detoxification and metabolism pathways in different host tissues. However, these receptors can also act as important regulators of inflammation and immunity, especially in the intestine.27, 39-41 The PXR, a master regulator of the human drug metabolism enzyme CYP3A4 (CYP3A11 in mice), is expressed throughout the intestine and liver where it can “sense” endogenous and exogenous substances.

abstract
The xenobiotic receptors CAR and PXR constitute two important members of the NR1I nuclear receptor family.

They function as sensors of toxic byproducts derived from endogenous metabolism and of exogenous chemicals, in order to enhance their elimination. This unique function of CAR and PXR sets them apart from the steroid hormone receptors. In contrast, the steroid receptors, exemplified by the estrogen receptor (ER) and glucocorticoid receptor (GR), are the sensors that tightly monitor and respond to changes in circulating steroid hormone levels to maintain body homeostasis. This divergence of the chemical- and steroid-sensing functions has evolved to ensure the fidelity of the steroid hormone endocrine regulation while allowing development of metabolic elimination pathways for xenobiotics. The development of the xenobiotic receptors CAR and PXR also reflect the increasing complexity of metabolism in higher organisms, which necessitate novel mechanisms for handling and eliminating metabolic by-products and foreign compounds from the body. The purpose of this review is to discuss similarities and differences between the xenobiotic receptors CAR and PXR with the prototypical steroid hormone receptors ER and GR. Interesting differences in structure explain in part the divergence in function and activation mechanisms of CAR/PXR from ER/GR. In addition, the physiological roles of CAR and PXR will be reviewed, with discussion of interactions of CAR and PXR with endocrine signaling pathways.

they both play physiological roles in regulating metabolic pathways important for the elimination of cholesterol. Interestingly, no physiological ligands have been definitively identified

CAR and PXR are xenobiotic receptors and they both are members of NR1I nuclear receptor family. The regulate the metabolic pathway for the elimination of cholesterol. However, there is no physiological ligands was identified. Xenobiotic receptors recognize the foreign chemicals and trigger detoxification and metabolism pathways in different host tissues.

Functions
Several genes involved in cytochrome P450, phase I, and glucuronosyltransferases conjugation catalysis in phase II are regulated by phenobarbital(PB) as well the transport mediated pathways of drug elimination. Induction of PB in xenobiotic-metabolizes of cytochromes CYP2b undergoes a transcriptional process, thus raising mRNA levels. Expression of the CAR summarized in a UniGene database, mainly in the kidney, liver, sometimes in the heart, GI tissues, and the human brain tissues. PB in the past ten years has been shown as an enhancer that is responsive to human(PBREM), rat(CYP2B), and the mouse; Constitutive Activated Receptor(CAR) identified was depicted to bind DR-4 motifs. The circulating thyroid hormone levels can be regulated by CAR. TH pathways of conjugation can be induced in PB treatment in a way that can lead to reductions that are fast-induced in T4 levels and serum triiodothyronine and finished serum thyroxine(T4).

Phase II and I enzymes PXR carries out induction. Expression of PXR is mainly evident in the liver, testis, human embryonic tissues, GI tract, and liver of the mouse. Research carried out on macrolide antibiotics, and glucocorticoids induction of CYP3A were perceived to utilize glucocorticoid receptor. This was explained by the induction of the CYP3A relationships obtained from the steroid structure-activity evaluation results. Research conducted in 1998 said that PXR was responsible for the induction of CYP3A and differences in the species in the induction of CYP3A by RIF and PCN. Based on this and other investigations, PXR has been perceived as a xenobiotic regulation mediator of CYP3A.

CAR has been depicted to be linked with a cofactor transcriptional induced by homeostasis energy regulation and fasting. Hemostasis of BA also aids in keeping the correct cholesterol levels. CAR can also impact gluconeogenesis regulation mediated by a transcription factor; the transcription factor binding can be regulated to Insulin Response Sequence(IRS). PXR protects the body from bile acid toxicity. Regarding the cholesterol levels regulation by CAR, PXR-null mice pretreatment using TCPOBOP does not reduce danger to cholesterol; therefore, toxicity from cholesterol can be controlled using PXR.