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FLASH GENE
Symbol CYP3A4 contributors: mct - updated : 05-04-2021
HGNC name cytochrome P450, family 3, subfamily A, polypeptide 4
HGNC id 2637
DNA
TYPE functioning gene
SPECIAL FEATURE component of a cluster
STRUCTURE 27.23 kb     13 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
Binding site   HRE
text structure
  • variant CYP3A4V in the 5' of promoter, high frequence in African-American people
  • NR1I2 responsive elements in the 5' upstream regulatory region of gene
  • dynamic DNA methylation elements are likely associated with key regulatory CYP3A4 promoter regions and may potentially contribute to the commonly observed interindividual expression of CYP3A4 as well as the hepatic developmental shift in its expression (pMID: 22906825)
    • MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    13 - 2768 57.3 503 - 1986 3460094
    13 - 2789 58 502 - 1986 3460094
    also called CYP3A3 variant
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   predominantly Homo sapiensAdult
     liver   predominantly Homo sapiensFetal
    Reproductivemale systemprostate   
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal 33-AAs domain embedded in the ER membrane with the bulk of its structure in the cytosol
    • conjugated HemoP
    mono polymer monomer
    HOMOLOGY
    interspecies homolog to C.elegans t10b9.10
    Homologene
    FAMILY
  • cytochrome P450 family
  • subfamily IIIA
  • multigenic cytochrome P450 superfamily of mixed-function monooxygenases
    • CATEGORY enzyme , transport
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,inner
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic,microsome
    basic FUNCTION
  • heme-thiolate monooxygenases, involved in an NADPH-dependent electron transport pathway
  • vitamin D 25-hydroxylase for vitamin D2 in hepatic microsomes and hydroxylates both 1alpha(OH)D2 and 1alpha(OH)D3
  • involved in the metabolism of more than 50 p100 of drugs and other xenobiotics
  • its induction represents an important detoxification mechanism
  • endoplasmic reticulum (ER)-anchored hemoprotein engaged in the oxidative biotransformation of various endo- and xenobiotics
  • encoding the major drug metabolizing enzyme, exhibits a high interindividual variation in hepatic expression that can lead to interindividual differences in drug metabolism and associated adverse drug effects
  • is a novel tumor suppressor gene related to a poor prognosis in Hepatocellular Carcinoma
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS electron transport
    PATHWAY
    metabolism drug , lipid/lipoprotein
    signaling
  • drug including acetaminophen, codeine, cyclosporin A, diazepam, erythromycin
  • an FGF21-NR1I2 signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in Nonalcoholic fatty liver disease (NAFLD)
    • a component
    INTERACTION
    DNA
    RNA
    small molecule cofactor, nucleotide,
  • NADPH, heme
    • protein
  • flavoprotein P450 oxidoreductase (POR)
  • transcriptional target of SMARCA4
  • NR1I2 promoter methylation is involved in the regulation of intestinal NR1I2 and CYP3A4 mRNA expression and might be associated with the inter-individual variability of the drug responses of colon cancer cells
  • PPARA is a direct transcriptional regulator of hepatic CYP3A4
  • RXRA mediates the sex-dependent influence of GH on CYP3A expression as an important signalling molecule
  • CYP3A4 activates, rather than inactivates, 20(OH)D3
  • steroid hormones are likely able to regulate CYP3A4 mRNA expression, although the circulating levels of these hormones can only regulate control endometrium and not endometriosis tissues
  • cross-talk between NR1I2 and AHR plays a role in the regulation of CYP3A4 gene expression
  • NR1I2 plays a central role in cortisol-mediated induction of CYP3A4 activity during pregnancy
    • cell & other
    REGULATION
    induced by induced to high levels in liver and other tissues by various foreign compounds, including drugs,
    pesticides, and carcinogens.
    glucocorticoids and some pharmacological agents
    VDR, transactivating CYP3A4 in the intestine by secondary bile acids
    NR1I2
    inhibited by by cholesterol
    Ketamine (Ketamine may inhibit CYP3A4 expression possibly through reducing calcium mobilization and mitochondrial ATP synthesis and consequently disturbing cytoskeleton remodeling)
    repressed by binding of nuclear receptors (NR2F1, NR2F2, THRA, THRB) competing for response element in the promoter
    Other phosphorylation of CYP3A4 Ser478, Thr264, and Ser420 AAs by cytosolic kinases is important both for its ubiquitination and proteasomal degradation
    ASSOCIATED DISORDERS
    corresponding disease(s)
    related resource Human Cytochrome P450 (CYP) Allele Nomenclature Committee
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in lung cancer
    constitutional       loss of function
    marked reduction of CYP3A4 activity among individuals with Crohn disease
    Susceptibility
  • to prostate cancer
  • to treatment-related leukemia
    • Variant & Polymorphism other
  • polymorphism CYP3A4V potentially increased susceptibility to prostate cancer
  • CYP3A4-W genotype may be at increased risk for treatment-related leukemia
  • CYP3A4-W genotype may increase production of potentially DNA-damaging reactive intermediates and may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone
  • CYP3A4 and CYP3A5 polymorphisms were significantly associated with an increased risk of prostate cancer
    • Candidate gene
    Marker
  • combination of CYP3A4 and CYP3A5 may serve as a novel prognostic biomarker in lung adenocarcinoma, which contribute to the precision of predicting the survival in lung adenocarcinoma
    • Therapy target
    ANIMAL & CELL MODELS