CYP3A4 | CYP3 family | IUPHAR/BPS Guide to PHARMACOLOGY

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CYP3A4

Target not currently curated in GtoImmuPdb

Target id: 1337

Nomenclature: CYP3A4

Family: CYP3 family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 503 7q21.1 CYP3A4 cytochrome P450 family 3 subfamily A member 4
Previous and Unofficial Names
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
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
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:  16
Enzyme Reaction
EC Number: 1.14.14.55 Quinine + NADPH + O2 = 3-hydroxyquinine + NADP+ + H2O2
EC Number: 1.14.13.97 Taurochenodeoxycholate + NADPH + O2 = taurohyocholate + NADP+ + H2O
Lithocholate + NADPH + O2 = hyodeoxycholate + NADP+ + H2O
EC Number: 1.14.14.56 1,8-cineole + NADPH + O2 = 2-exo-hydroxy-1,8-cineole + NADP+ + H2O
Substrates and Reaction Kinetics
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 - - 15
diazepam Hs - - 5
erlotinib Hs - - 5
saquinavir Hs Km 4x10-7 M pKm 6.4 Assessed in human small-intestinal microsomal preparations. 4
Products
Product Species Reference
4-hydroxy-tamoxifen Human 12
4-hydroxy-tamoxifen quinone methide Human 12
Cofactors
Cofactor Species Comments Reference
NADPH Human

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
troleandomycin Hs Inhibition 7.8 pKi 11
pKi 7.8 (Ki 1.58x10-8 M) [11]
ketoconazole Hs Inhibition 7.0 pKi 6
pKi 7.0 (Ki 1x10-7 M) [6]
ritonavir Hs Inhibition >7.0 pKi 9
pKi >7.0 (Ki <1x10-7 M) [9]
verapamil Hs Inhibition 6.2 pKi 18
pKi 6.2 (Ki 6x10-7 M) [18]
Description: Inhibition of testosterone 6β-hydroxylation.
nefazodone Hs Inhibition 6.0 pKi 10,13
pKi 6.0 (Ki 1x10-6 M) [10,13]
BMS-536924 Hs Inhibition 6.3 pIC50 17
pIC50 6.3 (IC50 5x10-7 M) [17]
compound 1a [PMID: 18573659] Hs Inhibition 5.7 pIC50 8
pIC50 5.7 (IC50 1.9x10-6 M) [8]
AMG-337 Hs Inhibition 4.3 pIC50 2
pIC50 4.3 (IC50 5x10-5 M) [2]
noscapine 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 N/A - 7.6 pKi 14
pKi 7.6 (Ki 2.8x10-8 M) [14]
Tissue Distribution
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. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

How to cite this page

CYP3 family: CYP3A4. Last modified on 04/02/2019. Accessed on 16/06/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1337.