CYP2 family: drug metabolising subset | Enzymes | IUPHAR/BPS Guide to IMMUNOPHARMACOLOGY

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CYP2 family: drug metabolising subset

CYP2 family: drug metabolising subset C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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CYP1, 2 and 3 family enzymes are involved in the biotransformation of xenobiotics, including clinically used drugs. Polymorphisms, particularly in the CYP2 family, impact upon an individual's response to drugs [31], including the risk of adverse drug reactions, drug efficacy and dose requirement.

Enzymes

1328

Targets of relevance to immunopharmacology are highlighted in blue

CYP2A6 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

1321

Nomenclature

CYP2A6

Previous and unofficial names

Genes

CYP2A6 (Hs)

Ensembl ID

ENSG00000255974 (Hs)

UniProtKB AC

P11509 (Hs)

EC number

1.14.14.1

Substrates

nicotine

tegafur

Inhibitors

esculetin pIC₅₀ 6.4 [21]

Comment

Metabolises coumarin [20].

CYP2A7 C Show summary »« Hide summary

Target Id

1322

Nomenclature

CYP2A7

Previous and unofficial names

Coumarin 7-hydroxylase | P450-IIA4 | cytochrome P450, subfamily IIA (phenobarbital-inducible), polypeptide 7 | cytochrome P450, family 2, subfamily A, polypeptide 7

Genes

CYP2A7 (Hs)

Ensembl ID

ENSG00000198077 (Hs)

UniProtKB AC

P20853 (Hs)

EC number

1.14.14.1

Comment

CYP2A7 is functionally inactive [11].

CYP2A13 C Show summary »« Hide summary

Target Id

1323

Nomenclature

CYP2A13

Previous and unofficial names

cytochrome P450, subfamily IIA (phenobarbital-inducible), polypeptide 13 | cytochrome P450, family 2, subfamily A, polypeptide 13

Genes

CYP2A13 (Hs)

Ensembl ID

ENSG00000197838 (Hs)

UniProtKB AC

Q16696 (Hs)

EC number

1.14.14.1

Inhibitors

kaempferol pK_i 6.9 [4]

Comment

Metabolises tobacco carcinogen, 4-methylnitrosoamino)-1-(3-pyridyl)-1-butanone [23]. Expressed specifically in the respiratory tract.

CYP2B6 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

1324

Nomenclature

CYP2B6

Previous and unofficial names

cytochrome P450, subfamily IIB (phenobarbital-inducible), polypeptide 6 | 1,4-cineole 2-exo-monooxygenase | cytochrome P450, family 2, subfamily B, polypeptide 6

Genes

CYP2B6 (Hs)

Ensembl ID

ENSG00000197408 (Hs)

UniProtKB AC

P20813 (Hs)

EC number

1.14.14.1

Inhibitors

thiotepa pK_i 5.3 [26]

ticlopidine pIC₅₀ 6.7 [9]

sibutramine pIC₅₀ 5.8 [2]

Comment

Drug substrates include efavirenz, bupropion, cyclophosphamide, ketamine, propofol [25].

CYP2C8 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

1325

Nomenclature

CYP2C8

Previous and unofficial names

cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 8 | cytochrome P450, family 2, subfamily C, polypeptide 8

Genes

CYP2C8 (Hs)

Ensembl ID

ENSG00000138115 (Hs)

UniProtKB AC

P10632 (Hs)

EC number

1.14.14.1

Inhibitors

phenelzine pK_i 5.1 [9]

Comment

Converts arachidonic acid to 11(R)-12(S)-epoxyeicosatrienoic acid or 14(R)-15(S)-epoxyeicosatrienoic acid [32]. Drug substrates include amodiaquine and paclitaxel [1].

CYP2C9 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

1326

Nomenclature

CYP2C9

Previous and unofficial names

Genes

CYP2C9 (Hs)

Ensembl ID

ENSG00000138109 (Hs)

UniProtKB AC

P11712 (Hs)

EC number

1.14.14.51
(S)-limonene + [reduced NADPH--hemoprotein reductase] + O(2) <=> (-)-trans-carveol + [oxidized NADPH--hemoprotein reductase] + H(2)O

Competitive inhibitor

sulphaphenazole [19]

Substrates

sulfaphenazole

Comment

Drug substrates include tolbutamide, losartan, phenytoin, warfarin [6,19,24].

CYP2C18 Show summary »« Hide summary

Target Id

1327

Nomenclature

CYP2C18

Previous and unofficial names

CYP2C17 | cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 18 | cytochrome P450, family 2, subfamily C, polypeptide 18

Genes

CYP2C18 (Hs)

Ensembl ID

ENSG00000108242 (Hs)

UniProtKB AC

P33260 (Hs)

EC number

1.14.14.1

Inhibitors

compound 9 [PMID: 11606127] pIC₅₀ 5.5 [12]

CYP2C19 C Show summary »« Hide summary

Target Id

1328

Nomenclature

CYP2C19

Previous and unofficial names

Genes

CYP2C19 (Hs)

Ensembl ID

ENSG00000165841 (Hs)

UniProtKB AC

P33261 (Hs)

EC number

1.14.14.51

Inhibitors

compound 30 [PMID: 22239545] pK_i 7.7 [10]

UE2343 pIC₅₀ 5.8 [27]

Comment

Drug substrates include omeprazole, proguanil, mephenytoin, diazepam [3,7,13]. Common genetic polymorphism for null function.

CYP2D6 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

1329

Nomenclature

CYP2D6

Previous and unofficial names

Debrisoquine 4-hydroxylase | cytochrome P450, subfamily IID (debrisoquine, sparteine, etc., -metabolising), polypeptide 8 pseudogene 2 | cytochrome P450, subfamily IID (debrisoquine, sparteine, etc., -metabolizing), polypeptide 6 | cytochrome P450, subfamily 2D, polypeptide 6 | cytochrome P450, subfamily II (debrisoquine, sparteine, etc., -metabolising), polypeptide 7 pseudogene 2 | cytochrome P450, family 2, subfamily D, polypeptide 6

Genes

CYP2D6 (Hs)

Ensembl ID

ENSG00000100197 (Hs)

UniProtKB AC

P10635 (Hs)

EC number

1.14.14.1

Inhibitors

berberine pIC₅₀ 5.4 [14]

Comment

Substrates include: debrisoquine, metoprolol, codeine [17]. Highly polymorphic enzyme.

CYP2E1 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

1330

Nomenclature

CYP2E1

Previous and unofficial names

Genes

CYP2E1 (Hs), Cyp2e1 (Mm), Cyp2e1 (Rn)

Ensembl ID

ENSG00000130649 (Hs), ENSMUSG00000025479 (Mm), ENSRNOG00000012458 (Rn)

UniProtKB AC

P05181 (Hs), Q05421 (Mm), P05182 (Rn)

EC number

1.14.14.1

Inhibitors

compound 23 [PMID: 17125252] pK_i 7.4 [30]

12-Imidazolyl-1-dodecanol pK_i 6.2 [8]

Comment

Substrates: Ethanol, p-nitrophenol [18].

CYP2F1 C Show summary »« Hide summary

Target Id

1331

Nomenclature

CYP2F1

Previous and unofficial names

cytochrome P450, subfamily 2F, polypeptide 1 | cytochrome P450, family 2, subfamily F, polypeptide 1

Genes

CYP2F1 (Hs)

Ensembl ID

ENSG00000197446 (Hs)

UniProtKB AC

P24903 (Hs)

EC number

1.14.14.1

Comment

Substrate: naphthalene [16].

CYP2J2 C Show summary »« Hide summary

Target Id

1332

Nomenclature

CYP2J2

Previous and unofficial names

cytochrome P450, subfamily IIJ (arachidonic acid epoxygenase) polypeptide 2 | Arachidonic acid epoxygenase | cytochrome P450, family 2, subfamily J, polypeptide 2

Genes

CYP2J2 (Hs)

Ensembl ID

ENSG00000134716 (Hs)

UniProtKB AC

P51589 (Hs)

EC number

1.14.14.1

Inhibitors

compound 4 [PMID: 16495056] pIC₅₀ 6.8 [15]

terfenadine pIC₅₀ 5.1 [15]

Comment

Converts arachidonic acid to 14(R)-15(S)-epoxyeicosatrienoic acid [28]. Hydroxylates albendazole[29]. Expressed in cardiomyocytes [22].

References

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1. Backman JT, Filppula AM, Niemi M, Neuvonen PJ. (2016) Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev, 68 (1): 168-241. [PMID:26721703]

2. Bae SH, Kwon MJ, Choi EJ, Zheng YF, Yoon KD, Liu KH, Bae SK. (2013) Potent inhibition of cytochrome P450 2B6 by sibutramine in human liver microsomes. Chem Biol Interact, 205 (1): 11-9. [PMID:23777987]

3. Bertilsson L, Henthorn TK, Sanz E, Tybring G, Säwe J, Villén T. (1989) Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype. Clin Pharmacol Ther, 45 (4): 348-55. [PMID:2495208]

4. Boonruang S, Prakobsri K, Pouyfung P, Prasopthum A, Rongnoparut P, Sarapusit S. (2020) Structure-activity relationship and in vitro inhibition of human cytochrome CYP2A6 and CYP2A13 by flavonoids. Xenobiotica, 50 (6): 630-639. [PMID:31578905]

5. Crosignani S, Jorand-Lebrun C, Campbell G, Prêtre A, Grippi-Vallotton T, Quattropani A, Bouscary-Desforges G, Bombrun A, Missotten M, Humbert Y et al.. (2011) Discovery of a Novel Series of CRTH2 (DP2) Receptor Antagonists Devoid of Carboxylic Acids. ACS Med Chem Lett, 2 (12): 938-42. [PMID:24900284]

6. Daly AK, Rettie AE, Fowler DM, Miners JO. (2017) Pharmacogenomics of CYP2C9: Functional and Clinical Considerations. J Pers Med, 8 (1). [PMID:29283396]

7. Desta Z, Zhao X, Shin JG, Flockhart DA. (2002) Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet, 41 (12): 913-58. [PMID:12222994]

8. Diesinger T, Buko V, Lautwein A, Dvorsky R, Belonovskaya E, Lukivskaya O, Naruta E, Kirko S, Andreev V, Buckert D et al.. (2020) Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis. PLoS One, 15 (7): e0235990. [PMID:32701948]

9. Fontana E, Dansette PM, Poli SM. (2005) Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity. Curr Drug Metab, 6 (5): 413-54. [PMID:16248836]

10. Foti RS, Rock DA, Han X, Flowers RA, Wienkers LC, Wahlstrom JL. (2012) Ligand-based design of a potent and selective inhibitor of cytochrome P450 2C19. J Med Chem, 55 (3): 1205-14. [PMID:22239545]

11. Fukami T, Nakajima M, Sakai H, McLeod HL, Yokoi T. (2006) CYP2A7 polymorphic alleles confound the genotyping of CYP2A6*4A allele. Pharmacogenomics J, 6 (6): 401-12. [PMID:16636685]

12. Ha-Duong NT, Dijols S, Marques-Soares C, Minoletti C, Dansette PM, Mansuy D. (2001) Synthesis of sulfaphenazole derivatives and their use as inhibitors and tools for comparing the active sites of human liver cytochromes P450 of the 2C subfamily. J Med Chem, 44 (22): 3622-31. [PMID:11606127]

13. Helsby NA, Ward SA, Edwards G, Howells RE, Breckenridge AM. (1990) The pharmacokinetics and activation of proguanil in man: consequences of variability in drug metabolism. Br J Clin Pharmacol, 30 (4): 593-8. [PMID:2291871]

14. Kim HG, Lee HS, Jeon JS, Choi YJ, Choi YJ, Yoo SY, Kim EY, Lee K, Park I, Na M et al.. (2020) Quasi-Irreversible Inhibition of CYP2D6 by Berberine. Pharmaceutics, 12 (10). DOI: 10.3390/pharmaceutics12100916 [PMID:32987920]

15. Lafite P, Dijols S, Buisson D, Macherey AC, Zeldin DC, Dansette PM, Mansuy D. (2006) Design and synthesis of selective, high-affinity inhibitors of human cytochrome P450 2J2. Bioorg Med Chem Lett, 16 (10): 2777-80. [PMID:16495056]

16. Lewis DF, Ito Y, Lake BG. (2009) Molecular modelling of CYP2F substrates: comparison of naphthalene metabolism by human, rat and mouse CYP2F subfamily enzymes. Drug Metabol Drug Interact, 24 (2-4): 229-57. [PMID:20408502]

17. Llerena A, Dorado P, Peñas-Lledó EM. (2009) Pharmacogenetics of debrisoquine and its use as a marker for CYP2D6 hydroxylation capacity. Pharmacogenomics, 10 (1): 17-28. [PMID:19102711]

18. Mahli A, Erwin Thasler W, Hellerbrand C. (2019) Establishment of a p-nitrophenol oxidation-based assay for the analysis of CYP2E1 activity in intact hepatocytes in vitro. Toxicol Mech Methods, 29 (3): 219-223. [PMID:30380359]

19. Miners JO, Smith KJ, Robson RA, McManus ME, Veronese ME, Birkett DJ. (1988) Tolbutamide hydroxylation by human liver microsomes. Kinetic characterisation and relationship to other cytochrome P-450 dependent xenobiotic oxidations. Biochem Pharmacol, 37 (6): 1137-44. [PMID:3355588]

20. Pelkonen O, Rautio A, Raunio H, Pasanen M. (2000) CYP2A6: a human coumarin 7-hydroxylase. Toxicology, 144 (1-3): 139-47. [PMID:10781881]

21. Qi X, Dou T, Wang Z, Wu J, Yang L, Zeng S, Deng M, Lü M, Liang S. (2019) Inhibition of human cytochrome P450 2A6 by 7-hydroxycoumarin analogues: Analysis of the structure-activity relationship and isoform selectivity. Eur J Pharm Sci, 136: 104944. [PMID:31163215]

22. Solanki M, Pointon A, Jones B, Herbert K. (2018) Cytochrome P450 2J2: Potential Role in Drug Metabolism and Cardiotoxicity. Drug Metab Dispos, 46 (8): 1053-1065. [PMID:29695613]

23. Su T, Bao Z, Zhang QY, Smith TJ, Hong JY, Ding X. (2000) Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cancer Res, 60 (18): 5074-9. [PMID:11016631]

24. Sykes MJ, McKinnon RA, Miners JO. (2008) Prediction of metabolism by cytochrome P450 2C9: alignment and docking studies of a validated database of substrates. J Med Chem, 51 (4): 780-91. [PMID:18237107]

25. Turpeinen M, Zanger UM. (2012) Cytochrome P450 2B6: function, genetics, and clinical relevance. Drug Metabol Drug Interact, 27 (4): 185-97. [PMID:23152403]

26. Walsky RL, Obach RS. (2007) A comparison of 2-phenyl-2-(1-piperidinyl)propane (ppp), 1,1',1''-phosphinothioylidynetrisaziridine (thioTEPA), clopidogrel, and ticlopidine as selective inactivators of human cytochrome P450 2B6. Drug Metab Dispos, 35 (11): 2053-9. [PMID:17682072]

27. Webster SP, McBride A, Binnie M, Sooy K, Seckl JR, Andrew R, Pallin TD, Hunt HJ, Perrior TR, Ruffles VS et al.. (2017) Selection and early clinical evaluation of the brain-penetrant 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor UE2343 (Xanamem™). Br J Pharmacol, 174 (5): 396-408. [PMID:28012176]

28. Wu S, Moomaw CR, Tomer KB, Falck JR, Zeldin DC. (1996) Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart. J Biol Chem, 271 (7): 3460-8. [PMID:8631948]

29. Wu Z, Lee D, Joo J, Shin JH, Kang W, Oh S, Lee DY, Lee SJ, Yea SS, Lee HS et al.. (2013) CYP2J2 and CYP2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole in human liver microsomes and recombinant P450 assay systems. Antimicrob Agents Chemother, 57 (11): 5448-56. [PMID:23959307]

30. Yano JK, Denton TT, Cerny MA, Zhang X, Johnson EF, Cashman JR. (2006) Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallization. J Med Chem, 49 (24): 6987-7001. [PMID:17125252]

31. Zanger UM, Schwab M. (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther, 138 (1): 103-41. [PMID:23333322]

32. Zeldin DC, DuBois RN, Falck JR, Capdevila JH. (1995) Molecular cloning, expression and characterization of an endogenous human cytochrome P450 arachidonic acid epoxygenase isoform. Arch Biochem Biophys, 322 (1): 76-86. [PMID:7574697]

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