Pregnane X receptor
Encyclopedia
In the field of molecular biology
, the pregnane X receptor (PXR), also known as the steroid and xenobiotic sensing nuclear receptor (SXR) or nuclear receptor subfamily 1, group I, member 2 (NR1I2) is a protein
that in humans is encoded by the NR1I2 gene.
PXR is a nuclear receptor whose primary function is to sense the presence of foreign toxic substances and in response up regulate
the expression of proteins involved in the detoxification and clearance of these substances from the body. PXR belongs to the nuclear receptor superfamily, members of which are transcription factors characterized by a ligand-binding domain and a DNA-binding domain
. The encoded protein is a transcriptional regulator of the cytochrome P450 gene CYP3A4
, binding to the response element of the CYP3A4 promoter as a heterodimer with the 9-cis retinoic acid receptor RXR
. It is activated by a range of compounds that induce CYP3A4, including dexamethasone
and rifampicin
. Several alternatively spliced
transcripts encoding different isoforms, some of which use non-AUG (CUG) translation initiation codon, have been described for this gene. Additional transcript variants exist, however, they have not been fully characterized.
and exogenous
chemicals including steroid
s, antibiotic
s, antimycotics, bile acid
s, hyperforin
, a constituent of the herbal antidepressant St. John's Wort, and many other herbal compounds.
with the retinoid X receptor
, and binds to hormone response element
s on DNA which elicits expression of gene
products.
One of the primary targets of PXR activation is the induction of CYP3A4
, an important phase I oxidative enzyme
that is responsible for the metabolism
of many drugs
. In addition, PXR up regulates the expression of phase II conjugating enzymes such as glutathione S-transferase
and phase III transport uptake and efflux proteins such as OATP2 and MDR1
.
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
, the pregnane X receptor (PXR), also known as the steroid and xenobiotic sensing nuclear receptor (SXR) or nuclear receptor subfamily 1, group I, member 2 (NR1I2) is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the NR1I2 gene.
PXR is a nuclear receptor whose primary function is to sense the presence of foreign toxic substances and in response up regulate
Downregulation and upregulation
Downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external variable...
the expression of proteins involved in the detoxification and clearance of these substances from the body. PXR belongs to the nuclear receptor superfamily, members of which are transcription factors characterized by a ligand-binding domain and a DNA-binding domain
DNA-binding domain
A DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...
. The encoded protein is a transcriptional regulator of the cytochrome P450 gene CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
, binding to the response element of the CYP3A4 promoter as a heterodimer with the 9-cis retinoic acid receptor RXR
Retinoid X receptor
The retinoid X receptor is a type of nuclear receptor that is activated by 9-cis retinoic acid. There are three retinoic X receptors : RXR-alpha, RXR-beta, and RXR-gamma, encoded by the , , genes, respectively....
. It is activated by a range of compounds that induce CYP3A4, including dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
and rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
. Several alternatively spliced
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
transcripts encoding different isoforms, some of which use non-AUG (CUG) translation initiation codon, have been described for this gene. Additional transcript variants exist, however, they have not been fully characterized.
Activation
PXR is activated by a large number of endogenousEndogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
and exogenous
Exogenous
Exogenous refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system....
chemicals including steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
s, antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s, antimycotics, bile acid
Bile acid
Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids compounded with a cation, usually sodium. In humans, the salts of taurocholic acid and glycocholic acid represent approximately eighty percent of all bile salts. The two major bile acids are cholic...
s, hyperforin
Hyperforin
Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum .- Occurrence :...
, a constituent of the herbal antidepressant St. John's Wort, and many other herbal compounds.
Function
Like other type II nuclear receptors, when activated, it forms a heterodimerProtein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
with the retinoid X receptor
Retinoid X receptor
The retinoid X receptor is a type of nuclear receptor that is activated by 9-cis retinoic acid. There are three retinoic X receptors : RXR-alpha, RXR-beta, and RXR-gamma, encoded by the , , genes, respectively....
, and binds to hormone response element
Hormone response element
A hormone response element is a response element for hormones, a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription...
s on DNA which elicits expression of gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
products.
One of the primary targets of PXR activation is the induction of CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
, an important phase I oxidative enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that is responsible for the metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of many drugs
DRUGS
Destroy Rebuild Until God Shows are an American post-hardcore band formed in 2010. They released their debut self-titled album on February 22, 2011.- Formation :...
. In addition, PXR up regulates the expression of phase II conjugating enzymes such as glutathione S-transferase
Glutathione S-transferase
Enzymes of the glutathione S-transferase family are composed of many cytosolic, mitochondrial, and microsomal proteins. GSTs are present in eukaryotes and in prokaryotes, where they catalyze a variety of reactions and accept endogenous and xenobiotic substrates.GSTs can constitute up to 10% of...
and phase III transport uptake and efflux proteins such as OATP2 and MDR1
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...
.