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CYP3A4

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Target not currently curated in GtoImmuPdb

Target id: 1337

Nomenclature: CYP3A4

Family: CYP3 family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 503 7q22.1 CYP3A4 cytochrome P450 family 3 subfamily A member 4
Previous and Unofficial Names Click here for help
albendazole monooxygenase | Nifedipine oxidase | Quinine 3-monooxygenase | taurochenodeoxycholate 6-α-hydroxylase | cytochrome P450, subfamily IIIA (niphedipine oxidase), polypeptide 4 | albendazole sulfoxidase | cytochrome P450, family 3, subfamily A, polypeptide 4
Database Links Click here for help
Alphafold P08684 (Hs)
BRENDA 1.14.14.55, 1.14.14.56
ChEMBL Target CHEMBL340 (Hs)
Ensembl Gene ENSG00000160868 (Hs)
Entrez Gene 1576 (Hs)
Human Protein Atlas ENSG00000160868 (Hs)
KEGG Enzyme 1.14.14.55, 1.14.14.56
KEGG Gene hsa:1576 (Hs)
OMIM 124010 (Hs)
Pharos P08684 (Hs)
SynPHARM 82822 (in complex with ritonavir)
UniProtKB P08684 (Hs)
Wikipedia CYP3A4 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structures of human cytochrome P450 3A4 bound to progesterone
PDB Id:  1W0F
Ligand:  progesterone   This ligand is endogenous
Resolution:  2.65Å
Species:  Human
References:  19
Enzyme Reaction Click here for help
EC Number: 1.14.14.55
EC Number: 1.14.14.56
Substrates and Reaction Kinetics Click here for help
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
tamoxifen Hs - - 5
codeine Hs - - 5
nifedipine N/A - - 7
atorvastatin Hs - - 5
midazolam N/A - - 18
diazepam Hs - - 5
erlotinib Hs - - 5
saquinavir Hs Km 4x10-7 M pKm 6.4 Assessed in human small-intestinal microsomal preparations. 4
CYP3A4 fluorogenic substrate F8 Hs Km 3.6x10-7 M - 8
Products Click here for help
Product Species Reference
4-hydroxy-tamoxifen Human 14
4-hydroxy-tamoxifen quinone methide Human 14
Cofactors Click here for help
Cofactor Species Comments Reference
NADPH Human

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
troleandomycin Small molecule or natural product Approved drug Hs Inhibition 7.8 pKi 13
⤷ pKi 7.8 (Ki 1.58x10-8 M) [13]
ketoconazole Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 7.0 pKi 6
⤷ pKi 7.0 (Ki 1x10-7 M) [6]
ritonavir Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition >7.0 pKi 10
⤷ pKi >7.0 (Ki <1x10-7 M) [10]
verapamil Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 6.2 pKi 21
⤷ pKi 6.2 (Ki 6x10-7 M) [21]
Description: Inhibition of testosterone 6β-hydroxylation.
nefazodone Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 6.0 pKi 12,16
⤷ pKi 6.0 (Ki 1x10-6 M) [12,16]
BMS-536924 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.3 pIC50 20
⤷ pIC50 6.3 (IC50 5x10-7 M) [20]
compound 1a [PMID: 18573659] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.7 pIC50 9
⤷ pIC50 5.7 (IC50 1.9x10-6 M) [9]
voxelotor Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 4.9 pIC50 11
⤷ pIC50 4.9 (IC50 1.25x10-5 M) [11]
Description: Measuring inhibition of CYP3A4 activity using testosterone as substrate.
efavirenz Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibition 4.8 pIC50 15
⤷ pIC50 4.8 (IC50 1.75x10-5 M) [15]
Description: Inhibition of CYP3A-mediated conversion of triazolam to 4-OH-triazolam in human liver microsomes.
AMG-337 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 4.3 pIC50 2
⤷ pIC50 4.3 (IC50 5x10-5 M) [2]
noscapine Small molecule or natural product Ligand has a PDB structure N/A Inhibition - -
⤷
View species-specific inhibitor tables
Inhibitor Comments
Indiana University, Department of Medicine provides a useful webpage tabulating CYP substrates, inhibitors and inducers [5].
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
azalanstat Small molecule or natural product N/A - 7.6 pKi 17
⤷ pKi 7.6 (Ki 2.8x10-8 M) [17]
Tissue Distribution Click here for help
Liver
Expression level:  High
Species:  Human
Technique: 
References: 
Weak levels of expression are measured in some brain locations
Expression level:  Low
Species:  Human
Technique:  In situ hybridisation, RT-PCR and immunohistochemistry.
References:  1,3

References

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1. Agarwal V, Kommaddi RP, Valli K, Ryder D, Hyde TM, Kleinman JE, Strobel HW, Ravindranath V. (2008) Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite. PLoS ONE, 3 (6): e2337. [PMID:18545703]

2. Boezio AA, Berry L, Albrecht BK, Bauer D, Bellon SF, Bode C, Chen A, Choquette D, Dussault I, Fang M et al.. (2009) Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors. Bioorg Med Chem Lett, 19 (22): 6307-12. [PMID:19819693]

3. Dutheil F, Dauchy S, Diry M, Sazdovitch V, Cloarec O, Mellottée L, Bièche I, Ingelman-Sundberg M, Flinois JP, de Waziers I et al.. (2009) Xenobiotic-metabolizing enzymes and transporters in the normal human brain: regional and cellular mapping as a basis for putative roles in cerebral function. Drug Metab Dispos, 37 (7): 1528-38. [PMID:19359404]

4. Fitzsimmons ME, Collins JM. (1997) Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4: potential contribution to high first-pass metabolism. Drug Metab Dispos, 25 (2): 256-66. [PMID:9029057]

5. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed on 18/11/2014. Modified on 18/11/2014. http://medicine.iupui.edu/clinpharm/ddis/clinical-table/

6. Greenblatt DJ, Harmatz JS. (2015) Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies. Br J Clin Pharmacol, 80 (3): 342-50. [PMID:25923589]

7. Guengerich FP, Martin MV, Beaune PH, Kremers P, Wolff T, Waxman DJ. (1986) Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J Biol Chem, 261 (11): 5051-60. [PMID:3514607]

8. He RJ, Tian ZH, Huang J, Sun MR, Wei F, Li CY, Zeng HR, Zhang F, Guan XQ, Feng Y et al.. (2023) Rationally Engineered CYP3A4 Fluorogenic Substrates for Functional Imaging Analysis and Drug-Drug Interaction Studies. J Med Chem, 66 (10): 6743-6755. [PMID:37145039]

9. Jin J, An M, Sapienza A, Aiyar N, Naselsky D, Sarau HM, Foley JJ, Salyers KL, Knight SD, Keenan RM et al.. (2008) Urotensin-II receptor antagonists: synthesis and SAR of N-cyclic azaalkyl benzamides. Bioorg Med Chem Lett, 18 (14): 3950-4. [PMID:18573659]

10. Kharasch ED, Mitchell D, Coles R, Blanco R. (2008) Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob Agents Chemother, 52 (5): 1663-9. [PMID:18285471]

11. Metcalf B, Chuang C, Dufu K, Patel MP, Silva-Garcia A, Johnson C, Lu Q, Partridge JR, Patskovska L, Patskovsky Y et al.. (2017) Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Med Chem Lett, 8 (3): 321-326. [PMID:28337324]

12. Orr ST, Ripp SL, Ballard TE, Henderson JL, Scott DO, Obach RS, Sun H, Kalgutkar AS. (2012) Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure-activity relationships and discovery strategies to mitigate drug-drug interaction risks. J Med Chem, 55 (11): 4896-933. [PMID:22409598]

13. Sevrioukova IF, Poulos TL. (2015) Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions. Adv Exp Med Biol, 851: 83-105. [PMID:26002732]

14. Shahrokh K, Cheatham 3rd TE, Yost GS. (2012) Conformational dynamics of CYP3A4 demonstrate the important role of Arg212 coupled with the opening of ingress, egress and solvent channels to dehydrogenation of 4-hydroxy-tamoxifen. Biochim Biophys Acta, 1820 (10): 1605-17. [PMID:22677141]

15. von Moltke LL, Greenblatt DJ, Granda BW, Giancarlo GM, Duan SX, Daily JP, Harmatz JS, Shader RI. (2001) Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. J Clin Pharmacol, 41 (1): 85-91. [PMID:11225565]

16. von Moltke LL, Greenblatt DJ, Granda BW, Grassi JM, Schmider J, Harmatz JS, Shader RI. (1999) Nefazodone, meta-chlorophenylpiperazine, and their metabolites in vitro: cytochromes mediating transformation, and P450-3A4 inhibitory actions. Psychopharmacology (Berl.), 145 (1): 113-22. [PMID:10445380]

17. Walker KA, Kertesz DJ, Rotstein DM, Swinney DC, Berry PW, So OY, Webb AS, Watson DM, Mak AY, Burton PM et al.. (1993) Selective inhibition of mammalian lanosterol 14 alpha-demethylase: a possible strategy for cholesterol lowering. J Med Chem, 36 (15): 2235-7. [PMID:8340925]

18. Williams JA, Ring BJ, Cantrell VE, Jones DR, Eckstein J, Ruterbories K, Hamman MA, Hall SD, Wrighton SA. (2002) Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos, 30 (8): 883-91. [PMID:12124305]

19. Williams PA, Cosme J, Vinkovic DM, Ward A, Angove HC, Day PJ, Vonrhein C, Tickle IJ, Jhoti H. (2004) Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science, 305 (5684): 683-6. [PMID:15256616]

20. Wittman M, Carboni J, Attar R, Balasubramanian B, Balimane P, Brassil P, Beaulieu F, Chang C, Clarke W, Dell J et al.. (2005) Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity. J Med Chem, 48 (18): 5639-43. [PMID:16134929]

21. Yeo KR, Yeo WW. (2001) Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes. Br J Clin Pharmacol, 51 (5): 461-70. [PMID:11422004]

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