Details of Host Protein-DME Interaction (HOSPPI)

General Information of Drug-Metabolizing Enzyme (DME ID: DME0001)
DME Name Cytochrome P450 3A4 (CYP3A4), Homo sapiens DME Info
UniProt ID
CP3A4_HUMAN
EC Number    EC: 1.14.14.55     (Click to Show/Hide the Complete EC Tree)
Oxidoreductase
Oxygen paired donor oxidoreductase
Flavin/flavoprotein donor oxidoreductase
EC: 1.14.14.55
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:      10 HOSPPI
                     Oligomerization
                            Cytochrome b5 (CYB5A) Health Heterooligomer
Uniprot ID
CYB5_HUMAN
Interaction Name CYB5A, POR and CYP3A4 heterotrimerization [1]
Studied Cell Lines Whole-BTC cell line
Activity Km = 2.84 microM
Description Cytochrome b5 (CYB5A) and NADPH-CYP450 reductase (POR) are reported to heterooligomerize with the CYP3A4 gene, which is necessary for sustaining the enzyme activity of Cytochrome P450 3A4. As a result, the interaction among CYB5A, POR and CYP3A4 is necessary for sustaining the drug-metabolizing process of Cytochrome P450 3A4.
                            Cytochrome P450 1A1 (CYP1A1) Health Heterooligomer
Uniprot ID
CP1A1_HUMAN
Interaction Name CYP1A1-CYP3A4 heterooligomerization [2]
Studied Cell Lines Escherichia coli cell line
Affected Substrate(s): Testosterone (Metabolic product: Testosterone 6beta-hydroxylation)
Activity Increasing Vmax 4.5 nmol/min/nmol P450
Description Cytochrome P450 1A1 (CYP1A1) is reported to heterooligomerize with the CYP3A4 protein, which leads to an increased activity of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between CYP1A1 and CYP3A4 can facilitate the drug-metabolizing process of Cytochrome P450 3A4.
                            Cytochrome P450 1A2 (CYP1A2) Health Heterooligomer
Uniprot ID
CP1A2_HUMAN
Interaction Name CYP1A2-CYP3A4 heterooligomerization [2]
Studied Cell Lines Escherichia coli cell line
Affected Substrate(s): Testosterone (Metabolic product: Testosterone 6beta-hydroxylation)
Activity Increasing Vmax 2.9 nmol/min/nmol P450
Description Cytochrome P450 1A2 (CYP1A2) is reported to heterooligomerize with the CYP3A4 protein, which leads to an increased activity of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between CYP1A2 and CYP3A4 can facilitate the drug-metabolizing process of Cytochrome P450 3A4.
                            Cytochrome P450 2C9 (CYP2C9) Health Heterooligomer
Uniprot ID
CP2C9_HUMAN
Interaction Name CYP2C9-CYP3A4 heterooligomerization [3]
Studied Cell Lines pCW vector
Affected Substrate(s): Testosterone
Description Cytochrome P450 2C9 (CYP2C9) is reported to heterooligomerize with the CYP3A4 protein, which has no effect on the enzyme activity of Cytochrome P450 3A4. As a result, the interaction between CYP2C9 and CYP3A4 can have no effect on the drug-metabolizing process of Cytochrome P450 3A4.
                            Cytochrome P450 2D6 (CYP2D6) Health Heterooligomer
Uniprot ID
CP2D6_HUMAN
Interaction Name CYP2D6-CYP3A4 heterooligomerization [4]
Studied Cell Lines Living cells
Description Cytochrome P450 2D6 (CYP2D6) is reported to heterooligomerize with the CYP3A4 protein, which leads to a suppressed activity of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between CYP2D6 and CYP3A4 can inhibit the drug-metabolizing process of Cytochrome P450 3A4.
                            Cytochrome P450 2E1 (CYP2E1) Health Heterooligomer
Uniprot ID
CP2E1_HUMAN
Interaction Name CYP2E1-CYP3A4 heterooligomerization [5]
Studied Cell Lines Insect cell microsomes
Affected Substrate(s): 7-Benzyloxyquinoline (Metabolic product: 7-BQ O-debenzylation)
Description Cytochrome P450 2E1 (CYP2E1) is reported to heterooligomerize with the CYP3A4 protein, which leads to a slight effect on the activity of drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between CYP2E1 and CYP3A4 slightly affects the drug-metabolizing process of Cytochrome P450 3A4.
                            Cytochrome P450 3A5 (CYP3A5) Health Heterooligomer
Uniprot ID
CP3A5_HUMAN
Interaction Name CYP3A5-CYP3A4 heterooligomerization [5]
Studied Cell Lines Insect cell microsomes
Affected Substrate(s): 7-Benzyloxyquinoline (Metabolic product: 7-BQ O-debenzylation)
Description Cytochrome P450 3A5 (CYP3A5) is reported to heterooligomerize with the CYP3A4 protein, which leads to activation of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between CYP3A5 and CYP3A4 can activate the drug-metabolizing process of Cytochrome P450 3A4.
                            Mutated NADPH-CYP450 reductase (mPOR) Health Heterooligomer
Uniprot ID
NCPR_HUMAN
Interaction Name mPOR-CYP3A4 heterooligomerization [6]
Studied Cell Lines Escherichia coli BL21(DE3) cell line
Description Mutated NADPH-CYP450 reductase (mPOR) is reported to heterooligomerize with the CYP3A4 protein, which leads to a suppressed activity of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between mPOR and CYP3A4 can inhibit the drug-metabolizing process of Cytochrome P450 3A4.
                            NADPH-CYP450 reductase (POR) Health Heterooligomer
Uniprot ID
NCPR_HUMAN
Interaction Name POR, CYB5A and CYP3A4 heterotrimerization [1]
Studied Cell Lines Whole-BTC cell line
Activity Km = 2.84 microM
Description NADPH-CYP450 reductase (POR) and Cytochrome b5 (CYB5A) are reported to heterooligomerize with the CYP3A4 gene, which is necessary for sustaining the enzyme activity of Cytochrome P450 3A4. As a result, the interaction among POR, CYB5A and CYP3A4 is necessary for sustaining the drug-metabolizing process of Cytochrome P450 3A4.
                            Progesterone receptor 1 (PGRMC1) Health Heterooligomer
Uniprot ID
PGRC1_HUMAN
Interaction Name PGRMC1-CYP3A4 heterooligomerization [7]
Studied Cell Lines Primary human hepatocytes
Affected Substrate(s): Atorvastatin (Metabolic product: Atorvastatin 2-hydroxylase)
Description Progesterone receptor 1 (PGRMC1) is reported to heterooligomerize with the CYP3A4 protein, which leads to a suppressed activity of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between PGRMC1 and CYP3A4 can inhibit the drug-metabolizing process of Cytochrome P450 3A4.
      ICD Disease Classification 02 Neoplasms
               ICD-11: 2B90 Colorectal cancer Click to Show/Hide the Full List of HOSPPI:        3 HOSPPI
                     Transcription-factor regulation
                            Pregnane X receptor (PXR) Colorectal cancer Activation
Uniprot ID
NR1I2_HUMAN
Interaction Name PXR-CYP3A4 interaction [9]
Studied Cell Lines LS180, Caco-2, HT29, HCT116, DLD-1, LoVo, SW48 and SW620 cell lines
Ensembl ID
ENSG00000144852
Description Pregnane X receptor (PXR) is reported to activate the transcription of CYP3A4 gene, which leads to an increased expression of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between PXR and CYP3A4 can activate the drug-metabolizing process of Cytochrome P450 3A4.
                            Vitamin D3 receptor (VDR) Colorectal cancer Activation
Uniprot ID
VDR_HUMAN
Interaction Name VDR-CYP3A4 interaction [10]
Studied Cell Lines LS174T and CACO-2 cell lines
Ensembl ID
ENSG00000111424
Description Vitamin D3 receptor (VDR) is reported to activate the transcription of CYP3A4 gene, which leads to an increased expression of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between VDR and CYP3A4 can activate the drug-metabolizing process of Cytochrome P450 3A4.
                     Non-coding RNA regulation
                            hsa-miR-27b-3p Colorectal cancer Suppression
miRBase ID
MIMAT0000419
Interaction Name hsa-miR-27b-3p--CYP3A4 regulation [8]
Studied Cell Lines LS-180 cell line
Description hsa-miR-27b-3p is reported to suppress CYP3A4 mRNA translation by binding to the 3' untranslated region (3'UTR) of CYP3A4 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Cytochrome P450 3A4.
               ICD-11: 2C12 Liver cancer Click to Show/Hide the Full List of HOSPPI:      10 HOSPPI
                     Oligomerization
                            Progesterone receptor 1 (PGRMC1) Liver cancer Heterooligomer
Uniprot ID
PGRC1_HUMAN
Interaction Name PGRMC1-CYP3A4 heterooligomerization [18], [19]
Studied Cell Lines Human embryonic kidney cell line (HEK293) and Human liver cancer cell line (HepG2)
Affected Substrate(s): Luciferin (Metabolic product: Luciferin 6' pentafluorobenzyl ether depentafluorobenzylation)
Testosterone (Metabolic product: Testosterone 6-hydroxylase)
Midazolam (Metabolic product: Midazolam 1-hydroxylase)
Description Progesterone receptor 1 (PGRMC1) is reported to heterooligomerize with the CYP3A4 protein, which leads to a suppressed activity of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between PGRMC1 and CYP3A4 can inhibit the drug-metabolizing process of Cytochrome P450 3A4.
                     Transcription-factor regulation
                            Constitutive androstane receptor (CAR) Liver cancer Activation
Uniprot ID
CXAR_HUMAN
Interaction Name CAR-CYP3A4 interaction [11]
Studied Cell Lines HepG2 cell line
Ensembl ID
ENSG00000154639
Description Constitutive androstane receptor (CAR) is reported to activate the transcription of CYP3A4 gene, which leads to an increased expression of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between CAR and CYP3A4 can activate the drug-metabolizing process of Cytochrome P450 3A4.
                            D site-binding protein (DBP) Liver cancer Activation
Uniprot ID
DBP_HUMAN
Interaction Name DBP-CYP3A4 interaction [12]
Studied Cell Lines HepG2 cell line
Ensembl ID
ENSG00000105516
Description D site-binding protein (DBP) is reported to activate the transcription of CYP3A4 gene, which leads to an increased expression of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between DBP and CYP3A4 can activate the drug-metabolizing process of Cytochrome P450 3A4.
                            Farnesoid X receptor (FXR) Liver cancer Activation
Uniprot ID
NR1H4_HUMAN
Interaction Name FXR-CYP3A4 interaction [13]
Studied Cell Lines HepG2 cell line
Ensembl ID
ENSG00000012504
Description Farnesoid X receptor (FXR) is reported to activate the transcription of CYP3A4 gene, which leads to an increased expression of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between FXR and CYP3A4 can activate the drug-metabolizing process of Cytochrome P450 3A4.
                            Hepatocyte NF 4-alpha (HNF4A) Liver cancer Activation
Uniprot ID
HNF4A_HUMAN
Interaction Name HNF4A-CYP3A4 interaction [14]
Studied Cell Lines HepG2 cell line
Ensembl ID
ENSG00000101076
Description Hepatocyte NF 4-alpha (HNF4A) is reported to activate the transcription of CYP3A4 gene, which leads to an increased expression of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between HNF4A and CYP3A4 can activate the drug-metabolizing process of Cytochrome P450 3A4.
                            Pregnane X receptor (PXR) Liver cancer Activation
Uniprot ID
NR1I2_HUMAN
Interaction Name PXR-CYP3A4 interaction [17]
Studied Cell Lines HepG2 cell line
Ensembl ID
ENSG00000144852
Description Pregnane X receptor (PXR) is reported to activate the transcription of CYP3A4 gene, which leads to an increased expression of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between PXR and CYP3A4 can activate the drug-metabolizing process of Cytochrome P450 3A4.
                            Small heterodimer partner (SHP) Liver cancer Activation
Uniprot ID
NR0B2_HUMAN
Interaction Name SHP-CYP3A4 interaction [13]
Studied Cell Lines HepG2 cell line
Ensembl ID
ENSG00000131910
Description Small heterodimer partner (SHP) is reported to activate the transcription of CYP3A4 gene, which leads to an increased expression of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between SHP and CYP3A4 can activate the drug-metabolizing process of Cytochrome P450 3A4.
                            Vitamin D3 receptor (VDR) Liver cancer Activation
Uniprot ID
VDR_HUMAN
Interaction Name VDR-CYP3A4 interaction [10]
Studied Cell Lines HepG2 cell line
Ensembl ID
ENSG00000111424
Description Vitamin D3 receptor (VDR) is reported to activate the transcription of CYP3A4 gene, which leads to an increased expression of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between VDR and CYP3A4 can activate the drug-metabolizing process of Cytochrome P450 3A4.
                     Histone modification
                            Histone deacetylases (HDACs) Liver cancer Repression
Uniprot ID
HDAC1_HUMAN
Interaction Name HDACs-CYP3A4 interaction [15]
Studied Cell Lines HepG2 cell line
Description Histone deacetylases (HDACs) are reported to deacetylate the CYP3A4 gene and thereby repress the transcriptional activity of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between HDACs and CYP3A4 can inhibit the drug-metabolizing process of Cytochrome P450 3A4.
                            Histone methyltransferases (HMTs) Liver cancer Activation
Uniprot ID
EHMT1_HUMAN
Interaction Name HMTs-CYP3A4 interaction [16]
Studied Cell Lines HepG2 cell line
Description The Histone 3 lysine 4 dimethylation of CYP3A4 gene is reported to activate the transcriptional activity of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between Histone methyltransferases (HMTs) and CYP3A4 can enhance the drug-metabolizing process of Cytochrome P450 3A4.
               ICD-11: 2C77 Cervical cancer Click to Show/Hide the Full List of HOSPPI:        2 HOSPPI
                     Oligomerization
                            Neuferricin (CYB5D2) Cervical cancer Heterooligomer
Uniprot ID
NEUFC_HUMAN
Interaction Name CYB5D2-CYP3A4 heterooligomerization [20]
Studied Cell Lines HeLa cell line
Affected Substrate(s): Luciferin (Metabolic product: Luciferin 6' pentafluorobenzyl ether depentafluorobenzylation)
Paclitaxel
Cisplatin
Doxorubicin
Description Neuferricin (CYB5D2) is reported to heterooligomerize with the CYP3A4 protein, which leads to activation of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between CYB5D2 and CYP3A4 can activate the drug-metabolizing process of Cytochrome P450 3A4.
                            Progesterone receptor 1 (PGRMC1) Cervical cancer Heterodimer
Uniprot ID
PGRC1_HUMAN
Interaction Name PGRMC1-CYP3A4 heterodimerization [20]
Studied Cell Lines HeLa cell line
Affected Substrate(s): Paclitaxel
Cisplatin
Doxorubicin
Description Progesterone receptor 1 (PGRMC1) is reported to heterodimerize with the CYP3A4 protein, which leads to a suppressed activity of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between PGRMC1 and CYP3A4 can inhibit the drug-metabolizing process of Cytochrome P450 3A4.
      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-CYP3A4 interaction [21]
Studied Cell Lines Blood
Description DNA methyltransferase (DNMT) is reported to significantly hyper-methylate the CYP3A4 gene, which leads to a significantly decreased expression of the drug-metabolizing enzyme Cytochrome P450 3A4. As a result, the interaction between DNMT and CYP3A4 can significantly affect the drug-metabolizing process of Cytochrome P450 3A4.
References
1 Human cytochrome P450 expression in bacteria: whole-cell high-throughput activity assay for CYP1A2, 2A6 and 3A4. Biochem Pharmacol. 2018 Dec;158:134-140.
2 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.
3 CYP2C9-CYP3A4 protein-protein interactions: role of the hydrophobic N terminus. Drug Metab Dispos. 2010 Jun;38(6):1003-9.
4 Microsomal monooxygenase as a multienzyme system: the role of P450-P450 interactions. Expert Opin Drug Metab Toxicol. 2011 May;7(5):543-58.
5 Interactions among cytochromes P450 in microsomal membranes: oligomerization of cytochromes P450 3A4, 3A5, and 2E1 and its functional consequences. J Biol Chem. 2015 Feb 6;290(6):3850-64.
6 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.
7 PPARA: a novel genetic determinant of CYP3A4 in vitro and in vivo. Clin Pharmacol Ther. 2012 Jun;91(6):1044-52.
8 MicroRNAs regulate CYP3A4 expression via direct and indirect targeting. Drug Metab Dispos. 2009 Oct;37(10):2112-7.
9 Involvement of promoter methylation in the regulation of Pregnane X receptor in colon cancer cells. BMC Cancer. 2011 Feb 22;11:81.
10 Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene. Biochem Pharmacol. 2010 Jan 15;79(2):277-87.
11 A CAR-responsive enhancer element locating approximately 31 kb upstream in the 5'-flanking region of rat cytochrome P450 (CYP) 3A1 gene. Drug Metab Pharmacokinet. 2015 Apr;30(2):188-97.
12 Molecular basis for rhythmic expression of CYP3A4 in serum-shocked HepG2 cells. Pharmacogenet Genomics. 2007 Dec;17(12):1047-56.
13 GW4064, an agonist of farnesoid X receptor, represses CYP3A4 expression in human hepatocytes by inducing small heterodimer partner expression. Drug Metab Dispos. 2015 May;43(5):743-8.
14 Genetic polymorphism of hepatocyte nuclear factor-4alpha influences human cytochrome P450 2D6 activity. Hepatology. 2008 Aug;48(2):635-45.
15 Histone deacetylase inhibitor stimulate CYP3A4 proximal promoter activity in HepG2 cells. Arch Pharm Res. 2004 Apr;27(4):407-14.
16 Effects of pargyline on histone methylation in promoter and enhancer regions and transcription of CYP3A4/3A7. Yao Xue Xue Bao. 2017 Jan;52(1):91-8.
17 Human PXR-mediated transcriptional activation of CYP3A4 by 'Fuzi' extracts. Toxicol Mech Methods. 2019 Mar;29(3):155-164.
18 Progesterone receptor membrane component 1 inhibits the activity of drug-metabolizing cytochromes P450 and binds to cytochrome P450 reductase. Mol Pharmacol. 2011 Mar;79(3):340-50.
19 Progesterone receptor membrane component 1 modulates human cytochrome p450 activities in an isoform-dependent manner. Drug Metab Dispos. 2011 Nov;39(11):2057-65.
20 CYB5D2 requires heme-binding to regulate HeLa cell growth and confer survival from chemotherapeutic agents. PLoS One. 2014 Jan 22;9(1):e86435.
21 Blood DNA methylation pattern is altered in mesial temporal lobe epilepsy. Sci Rep. 2017 Mar 9;7:43810.

If you find any error in data or bug in web service, please kindly report it to Dr. Yin and Dr. Li.