Details of Host Protein-DME Interaction (HOSPPI)

General Information of Drug-Metabolizing Enzyme (DME ID: DME0019)
DME Name Cytochrome P450 2C9 (CYP2C9), Homo sapiens DME Info
UniProt ID
CP2C9_HUMAN
EC Number    EC: 1.14.14.1     (Click to Show/Hide the Complete EC Tree)
Oxidoreductase
Oxygen paired donor oxidoreductase
Flavin/flavoprotein donor oxidoreductase
EC: 1.14.14.1
Lineage    Species: Homo sapiens     (Click to Show/Hide the Complete Species Lineage)
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Interactome
Disease Specific Interactions between Host Protein and DME (HOSPPI)
      ICD Disease Classification Healthy
               ICD-11: Healthy Click to Show/Hide the Full List of HOSPPI:        8 HOSPPI
                     Oligomerization
                            Cytochrome b5 (CYB5A) Health Heterooligomer
Uniprot ID
CYB5_HUMAN
Interaction Name CYB5A-CYP2C9 heterooligomerization [1], [2]
Studied Cell Lines Escherichia coli cell line
Affected Substrate(s): Tolbutamide (Metabolic product: Tolbutamide methyl hydroxylation)
Activity Increasing Vmax 3.7 nmol/min/nmol P450
Description Cytochrome b5 (CYB5A) is reported to heterooligomerize with the CYP2C9 protein, which leads to an increased activity of the drug-metabolizing enzyme Cytochrome P450 2C9. As a result, the interaction between CYB5A and CYP2C9 can facilitate the drug-metabolizing process of Cytochrome P450 2C9.
                            Cytochrome P450 2C19 (CYP2C19) Health Heterooligomer
Uniprot ID
CP2CJ_HUMAN
Interaction Name CYP2C19-CYP2C9 heterooligomerization [3]
Studied Cell Lines Living cells
Affected Substrate(s): Diclofenac (Metabolic product: Diclofenac 4-hydroxylase)
Description Cytochrome P450 2C19 (CYP2C19) is reported to heterooligomerize with the CYP2C9 protein, which leads to activation of the drug-metabolizing enzyme Cytochrome P450 2C9. As a result, the interaction between CYP2C19 and CYP2C9 can activate the drug-metabolizing process of Cytochrome P450 2C9.
                            Cytochrome P450 2D6 (CYP2D6) Health Heterooligomer
Uniprot ID
CP2D6_HUMAN
Interaction Name CYP2D6-CYP2C9 heterooligomerization [2]
Studied Cell Lines DLPC vesicles
Affected Substrate(s): (S)-flurbiprofen (Metabolic product: 4'-OH Flurbiprofen)
Activity Decreasing Vmax by up to 50%
Description Cytochrome P450 2D6 (CYP2D6) is reported to heterooligomerize with the CYP2C9 protein, which leads to a suppressed activity of the drug-metabolizing enzyme Cytochrome P450 2C9. As a result, the interaction between CYP2D6 and CYP2C9 can inhibit the drug-metabolizing process of Cytochrome P450 2C9.
                            Cytochrome P450 3A4 (CYP3A4) Health Heterooligomer
Uniprot ID
CP3A4_HUMAN
Interaction Name CYP3A4-CYP2C9 heterooligomerization [4], [5]
Studied Cell Lines pCW vector; Human hepatocyte culture model
Affected Substrate(s): S-naproxen
S-flurbiprofen
Diclofenac
Description Cytochrome P450 3A4 (CYP3A4) is reported to heterooligomerize with the CYP2C9 protein, which leads to a suppressed activity of the drug-metabolizing enzyme Cytochrome P450 2C9. As a result, the interaction between CYP3A4 and CYP2C9 can inhibit the drug-metabolizing process of Cytochrome P450 2C9.
                            Mutated NADPH-CYP450 reductase (mPOR) Health Heterooligomer
Uniprot ID
NCPR_HUMAN
Interaction Name mPOR-CYP2C9 heterooligomerization [7]
Studied Cell Lines Reconstituted liposomes
Affected Substrate(s): Warfarin
Diclofenac
Losartan
Description Mutated NADPH-CYP450 reductase (mPOR) is reported to heterooligomerize with the CYP2C9 protein, which leads to a suppressed activity of the drug-metabolizing enzyme Cytochrome P450 2C9. As a result, the interaction between mPOR and CYP2C9 can inhibit the drug-metabolizing process of Cytochrome P450 2C9.
                            NADPH-CYP450 reductase (POR) Health Heterooligomer
Uniprot ID
NCPR_HUMAN
Interaction Name POR-CYP2C9 heterooligomerization [8]
Studied Cell Lines Transformed E. coli C41 (DE3) cell line
Affected Substrate(s): Warfarin
Diclofenac
Losartan
Description NADPH-CYP450 reductase (POR) is reported to heterooligomerize with the CYP2C9 protein, which leads to activation of the drug-metabolizing enzyme Cytochrome P450 2C9. As a result, the interaction between POR and CYP2C9 can activate the drug-metabolizing process of Cytochrome P450 2C9.
                     Transcription-factor regulation
                            PPA receptor alpha (PPARA) Health Repression
Uniprot ID
PPARA_HUMAN
Interaction Name PPARA-CYP2C9 interaction [9]
Studied Cell Lines Endothelial cell line
Ensembl ID
ENSG00000186951
Description PPA receptor alpha (PPARA) is reported to repress the transcription of CYP2C9 gene, which leads to a decreased expression of the drug-metabolizing enzyme Cytochrome P450 2C9. As a result, the interaction between PPARA and CYP2C9 can repress the drug-metabolizing process of Cytochrome P450 2C9.
                     Histone modification
                            Histone deacetylases (HDACs) Health Repression
Uniprot ID
HDAC1_HUMAN
Interaction Name HDACs-CYP2C9 interaction [6]
Studied Cell Lines Mouse Model
Description Histone deacetylases (HDACs) are reported to deacetylate the CYP2C9 gene and thereby repress the transcriptional activity of the drug-metabolizing enzyme Cytochrome P450 2C9. As a result, the interaction between HDACs and CYP2C9 can inhibit the drug-metabolizing process of Cytochrome P450 2C9.
      ICD Disease Classification 02 Neoplasms
               ICD-11: 2C12 Liver cancer Click to Show/Hide the Full List of HOSPPI:        5 HOSPPI
                     Oligomerization
                            Progesterone receptor 1 (PGRMC1) Liver cancer Heterooligomer
Uniprot ID
PGRC1_HUMAN
Interaction Name PGRMC1-CYP2C9 heterooligomerization [15]
Studied Cell Lines Human liver cancer cell line (HepG2)
Affected Substrate(s): S-Warfarin (Metabolic product: S-warfarin 7-hydroxylase)
Diclofenac (Metabolic product: Diclofenac 4-hydroxylase)
Description Progesterone receptor 1 (PGRMC1) is reported to heterooligomerize with the CYP2C9 protein, which leads to a suppressed activity of the drug-metabolizing enzyme Cytochrome P450 2C9. As a result, the interaction between PGRMC1 and CYP2C9 can inhibit the drug-metabolizing process of Cytochrome P450 2C9.
                     Transcription-factor regulation
                            Hepatocyte NF 4-alpha (HNF4A) Liver cancer Activation
Uniprot ID
HNF4A_HUMAN
Interaction Name HNF4A-CYP2C9 interaction [10], [11], [12]
Studied Cell Lines HepG2 cell line
Ensembl ID
ENSG00000101076
Description Hepatocyte NF 4-alpha (HNF4A) is reported to activate the transcription of CYP2C9 gene, which leads to an increased expression of the drug-metabolizing enzyme Cytochrome P450 2C9. As a result, the interaction between HNF4A and CYP2C9 can activate the drug-metabolizing process of Cytochrome P450 2C9.
                     Non-coding RNA regulation
                            hsa-miR-128-3p Liver cancer Suppression
miRBase ID
MIMAT0000424
Interaction Name hsa-miR-128-3p--CYP2C9 regulation [13]
Studied Cell Lines HepG2 cell line
Description hsa-miR-128-3p is reported to suppress CYP2C9 mRNA translation by binding to the 3' untranslated region (3'UTR) of CYP2C9 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Cytochrome P450 2C9.
                            hsa-miR-130b-3p Liver cancer Suppression
miRBase ID
MIMAT0000691
Interaction Name hsa-miR-130b-3p--CYP2C9 regulation [14]
Studied Cell Lines HepaRG cell line
Description hsa-miR-130b-3p is reported to suppress CYP2C9 mRNA translation by binding to the 3' untranslated region (3'UTR) of CYP2C9 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Cytochrome P450 2C9.
                            hsa-miR-143-3p Liver cancer Suppression
miRBase ID
MIMAT0000435
Interaction Name hsa-miR-143-3p--CYP2C9 regulation [13]
Studied Cell Lines HepG2 cell line
Description hsa-miR-143-3p is reported to suppress CYP2C9 mRNA translation by binding to the 3' untranslated region (3'UTR) of CYP2C9 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Cytochrome P450 2C9.
      ICD Disease Classification 08 Nervous system diseases
               ICD-11: 8A60 Epilepsy Click to Show/Hide the Full List of HOSPPI:        1 HOSPPI
                     DNA methylation
                            DNA methyltransferase (DNMT) Epilepsy Significant hypermethylation
Uniprot ID
DNMT1_HUMAN
Interaction Name DNMT-CYP2C9 interaction [16]
Studied Cell Lines Blood
Description DNA methyltransferase (DNMT) is reported to significantly hyper-methylate the CYP2C9 gene, which leads to a significantly decreased expression of the drug-metabolizing enzyme Cytochrome P450 2C9. As a result, the interaction between DNMT and CYP2C9 can significantly affect the drug-metabolizing process of Cytochrome P450 2C9.
References
1 Reconstitution of recombinant cytochrome P450 2C10(2C9) and comparison with cytochrome P450 3A4 and other forms: effects of cytochrome P450-P450 and cytochrome P450-b5 interactions. Arch Biochem Biophys. 1997 Jun 15;342(2):329-37.
2 CYP2D6-CYP2C9 protein-protein interactions and isoform-selective effects on substrate binding and catalysis. Drug Metab Dispos. 2009 Aug;37(8):1682-9.
3 Microsomal monooxygenase as a multienzyme system: the role of P450-P450 interactions. Expert Opin Drug Metab Toxicol. 2011 May;7(5):543-58.
4 CYP2C9-CYP3A4 protein-protein interactions: role of the hydrophobic N terminus. Drug Metab Dispos. 2010 Jun;38(6):1003-9.
5 Altered CYP2C9 activity following modulation of CYP3A4 levels in human hepatocytes: an example of protein-protein interactions. Drug Metab Dispos. 2014 Nov;42(11):1940-6.
6 The effect of MS-275 on CYP450 isoforms activity in rats by cocktail method. Int J Clin Exp Pathol. 2015 Aug 1;8(8):9360-7.
7 Variability in human drug metabolizing cytochrome P450 CYP2C9, CYP2C19 and CYP3A5 activities caused by genetic variations in cytochrome P450 oxidoreductase. Biochem Biophys Res Commun. 2019 Jul 12;515(1):133-138.
8 Variability in loss of multiple enzyme activities due to the human genetic variation P284T located in the flexible hinge region of NADPH cytochrome P450 oxidoreductase. Front Pharmacol. 2019 Oct 15;10:1187.
9 The anti-tumorigenic properties of peroxisomal proliferator-activated receptor alpha are arachidonic acid epoxygenase-mediated. J Biol Chem. 2010 Apr 23;285(17):12840-50.
10 Hepatocyte nuclear factor 4{alpha} regulates rifampicin-mediated induction of CYP2C genes in primary cultures of human hepatocytes. Drug Metab Dispos. 2010 Apr;38(4):591-9.
11 Involvement of hepatocyte nuclear factor 4alpha in the different expression level between CYP2C9 and CYP2C19 in the human liver. Drug Metab Dispos. 2006 Jun;34(6):1012-8.
12 Nuclear receptor coactivator 6 mediates the synergistic activation of human cytochrome P-450 2C9 by the constitutive androstane receptor and hepatic nuclear factor-4alpha. Mol Pharmacol. 2008 Sep;74(3):913-23.
13 Suppression of CYP2C9 by microRNA hsa-miR-128-3p in human liver cells and association with hepatocellular carcinoma. Sci Rep. 2015 Feb 23;5:8534.
14 Inflammation-associated microRNA-130b down-regulates cytochrome P450 activities and directly targets CYP2C9. Drug Metab Dispos. 2015 Jun;43(6):884-8.
15 Progesterone receptor membrane component 1 modulates human cytochrome p450 activities in an isoform-dependent manner. Drug Metab Dispos. 2011 Nov;39(11):2057-65.
16 Blood DNA methylation pattern is altered in mesial temporal lobe epilepsy. Sci Rep. 2017 Mar 9;7:43810.

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