CYP2C9

Cytochrome P450 2C9, abbreviated as CYP2C9, is a member of the cytochrome P450 mixed-function oxidase system.

CYP2C9 is found in the liver, kidney, testes, adrenal gland, prostate, ovary, and duodenum.

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O-Demethylation Reactions

CYP2C9 was shown to O-demethylate indomethacin to demethylindomethacin in human liver microsomes in vitro.[11] CYP2C9 and CYP1A2 were shown to O-demethylate S-naproxen to O-desmethylnaproxen in human liver microsomes in vitro.[12]

Indomethacin	CYP2C9	Demethylindomethacin
	->
Naproxen	CYP2C9	O-Desmethylnaproxen
	->

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Dehydrogenation Reactions

CYP2C9 was able to dehydrogenate estradiol at the 17beta-hydroxy position creating estrone, an action also carried out by CYP2C19 and CYP2C8.[8]

The enzyme Estradiol 17beta-dehydrogenase can also perform this action on estradiol.

Estradiol	CYP2C9	Estrone
	—->

CYP2C9 Inhibitors

Potent Inhibitors
Compound	Strength	Dosage	Verified in Humans
5-hydroxyeugenol	?	?	?
Apigenin	?	?	?
Black pepper (contains piperine)	?	5 grams (unverified)	?
Capsaicin (found in cayenne pepper, habanero peppers, etc.)	?	?	?
Cayenne pepper	?	500-800 mg (unverified)	?
Cinnamon (but not cinnamon oil)	?	?	?
Eicosapentaenoic acid (EPA)[13] (often found in fish oil)	?	?	?
Kava	?	?	?
linoleic acid[13] (found in many vegetable oils)	?	?	?
Pummelo	?	?	?
Quercetin	?	250 mg	?
Resveratrol	A 171% increase in substrates	1 gram daily for 4 weeks	Yes[14]
Saint John’s Wort (High doses)	?	?	?
Turmeric	?	?	?
Moderate Inhibitors
Compound	Strength	Dosage	Verified in Humans
Berberine	inhibition (200% increase in substrates)[19]	300 mg for 2 weeks[19]	Yes[19]
Eugenol	?	?	?
Glabridin (in licorice)1[6]	50%[9]	100 μM	?
Licorice (contains Glabridin) [6]	?	?	?
Star fruit juice	?	?	?
Inhibitors (unknown potency)
Compound	Strength	Dosage	Verified in Humans
Bergamottin [6]	?	?	?
Garlic [6]	?	?	?
Luteolin (inhibits then induces CYP2C9)	?	?	?
Milk Thistle (contains Silymarin)	?	?	?
Silymarin	?	?	?
In Vitro Inhibitors Ineffective in Humans
Compound	Strength	Dosage	Verified in Humans
Curcumin (as curcuminoids)	No Effect[4]	4  grams	Yes
Echinacea	No Effect[16] [17]	400 mg 4 times a day for 8 days[16]	Yes
Ginger	No Effect[18]	?	Yes
Ginkgo biloba	No Effect[15] [18]	?	Yes
Piperine	No Effect[4]	24 mg	Yes
Pomegranate juice	No Effect[5]	?	Yes
White Grapefruit juice	No Effect[7]	3 cups	Yes

CYP2C9 Inducers

Inducers
Compound	Strength	Dosage	Verified in Humans
DHEA (dehydroepiandrosterone)	?	?	?
Folic acid (Vitamin B9) [10]	"significantly increased"	?	Yes
Glycyrrhizin	?	?	?
Hyperforin	?	?	?
Licorice	?	?	?
Limonene	?	?	?
Orange EO	?	?	?
Retinoic acid	?	?	?
Rifampin	?	?	?
Saint John’s Wort [2][1]	Potent	Low doses	Yes
Valerian root	?	?	?
Valerian root EO	?	2-5 drops (unverified)	?

Possible CYP2C9 Inducers

These activate PXR and probably induce CYP2C9

Artemisia scoparia
Artemisinin
Atractylodes macrocephala
Berberine hydrochloride
Cafestol
Chinese angelica
Coptis chinensis
Curcumin
Epimedium brevicornum
Eugenol (inhibits strongly before induction)
Gardenia fruit
Ginkgo biloba
Guggulsterone
Ligusticum chuanxiong
Ligustilide
Luteolin
Lycium chinense
Milk Thistle
Ophiopogon japonicus
Paeonia lactiflora
Polygonum multiflorum
Rehmannia root
Resveratrol
Schisandra chinensis
Schisantherin A
Trichosanthes kirilowii
Turmeric

Bibliography

1. Shu-Feng Zhou, Zhi-Wei Zhou, Chun-Guang Li, Xiao Chen, Xiyong Yu, Charlie

Changli Xue, and Adrian Herington Identification of drugs that interact with herbs in drug development; Drug Discovery Today 12(15-16):pp. 664-673; Adrian (2007) (Download Attached PDF Document)

2. Komoroski BJ, Zhang S, Cai H, Hutzler JM, Frye R, Tracy TS, Strom SC, Lehmann T, Ang CY, Cui YY, Venkataramanan R;

Induction and inhibition of cytochromes P450 by the St. John's wort constituent hyperforin in human hepatocyte cultures; Drug Metab Dispos. 2004 May;32(5):512-8; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; PubMed PMID: 15100173

3. The role of dietary supplements in cytochrome P450-mediated drug interactions

Jan L Wahlstrom, Robert S Foti Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas 01/2008; ISSN: 0717-7917; (Download Attached PDF Document)

4. Br J Clin Pharmacol. 2013 Feb;75(2):450-62. doi: 10.1111/j.1365-2125.2012.04364.x;

Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers; Volak LP, Hanley MJ, Masse G, Hazarika S, Harmatz JS, Badmaev V, Majeed M, Greenblatt DJ, Court MH; Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston; PubMed PMID: 22725836

5. Clin Pharmacol Ther. 2012 Nov;92(5):651-7. doi: 10.1038/clpt.2012.170. Epub 2012 Oct 10.

Pomegranate juice and pomegranate extract do not impair oral clearance of flurbiprofen in human volunteers: divergence from in vitro results; Hanley MJ, Masse G, Harmatz JS, Court MH, Greenblatt DJ; Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA; PubMed PMID: 23047652;

6. Shufeng Zhou, Hwee-Ling Koh, Yihuai Gao,

Zhi-yuan Gong, Edmund Jon Deoon Lee; Herbal bioactivation: The good, the bad and the ugly; Life Sciences 74 (2004) 935 – 968; April 2003; DOI:10.1016/j.lfs.2003.09.035 (Download Attached PDF Document)

7. Effects of clarithromycin and grapefruit juice on the pharmacokinetics of glibenclamide.

Lilja JJ, Niemi M, Fredrikson H, Neuvonen PJ. PubMed PMID: 17223855

8. Role of cytochrome P450 in estradiol metabolism in vitro.

Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH. PubMed PMID: 11741520 (Download Attached PDF Document)

9. The licorice root derived isoflavan glabridin inhibits the activities of human cytochrome P450S 3A4, 2B6, and 2C9.

Kent UM, Aviram M, Rosenblat M, Hollenberg PF. PubMed: PMID: 12019199

10. Effects of folic acid supplementation on the pharmacokinetics and anticoagulant effect of warfarin: an open-label, prospective study of long-term administration in adults.

Muszkat M, Bialer O, Blotnick S, Adar L, Xie HG, Ufer M, Cascorbi I, Caraco Y.; Clin Ther. 2010 Feb;32(2):347-56. doi: 10.1016/j.clinthera.2010.02.008.; PMID: 20206792

11. Cytochrome P450 2C9 catalyzes indomethacin O-demethylation in human liver microsomes.

Nakajima M, Inoue T, Shimada N, Tokudome S, Yamamoto T, Kuroiwa Y.; Drug Metab Dispos. 1998 Mar;26(3):261-6.; PMID: 9492390

12. Cytochromes P450, 1A2, and 2C9 are responsible for the human hepatic O-demethylation of R- and S-naproxen.

Miners JO, Coulter S, Tukey RH, Veronese ME, Birkett DJ.; Biochem Pharmacol. 1996 Apr 26;51(8):1003-8.; PMID: 8866821

13. The inhibitory effect of polyunsaturated fatty acids on human CYP enzymes.

Yao HT, Chang YW, Lan SJ, Chen CT, Hsu JT, Yeh TK.; Life Sci. 2006 Nov 25;79(26):2432-40. Epub 2006 Aug 23. PMID: 16978661; DOI: 10.1016/j.lfs.2006.08.016

14.

Resveratrol Modulates Drug- and Carcinogen-Metabolizing Enzymes in a Healthy Volunteer Study H-H. Sherry Chow, Linda L. Garland, Chiu-Hsieh Hsu, Donna R. Vining, Wade M. Chew, Jessica A. Miller, Marjorie Perloff, James A. Crowell and David S. Alberts; DOI: 10.1158/1940-6207.CAPR-09-0155 Published September 2010; PubMed PMCID: PMC2933312; NIHMSID: NIHMS207754

15. Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro and in vivo.

Mohutsky MA, Anderson GD, Miller JW, Elmer GW.; Am J Ther. 2006 Jan-Feb;13(1):24-31.; PMID: 16428919;

16. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo.

Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, Desai M, Miller M, Hall SD.; Clin Pharmacol Ther. 2004 Jan;75(1):89-100.; PMID: 14749695; DOI: 10.1016/j.clpt.2003.09.013

17. Pharmacokinetic and pharmacodynamic interactions of echinacea and policosanol with warfarin in healthy subjects

Mohi Iqbal Mohammed Abdul, Xuemin Jiang, Kenneth M Williams, Richard O Day, Basil D Roufogalis, Winston S Liauw, Hongmei Xu, Anita Matthias, Reginald P Lehmann, and Andrew J McLachlan; Br J Clin Pharmacol. 2010 May; 69(5): 508–515.; PMCID: PMC2856051; doi: 10.1111/j.1365-2125.2010.03620.x

18. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.

Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO, McLachlan AJ.; Br J Clin Pharmacol. 2005 Apr;59(4):425-32.; PMID: 15801937; PMCID: PMC1884814; DOI: 10.1111/j.1365-2125.2005.02322.x [[bibliography]]

19. Repeated administration of berberine inhibits cytochromes P450 in humans

Ying Guo, Yao Chen, Zhi-rong Tan, Curtis D. Klaassen, Hong-hao Zhou; Published online 2011 Aug 26.; Eur J Clin Pharmacol. 2012 Feb; 68(2): 213–217.; doi: 10.1007/s00228-011-1108-2; NIHMSID: NIHMS583946; PMCID: PMC4898966

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If an inducer or inhibitor is present on this page and reliable human in vivo studies are available but not shown on this page please leave a comment about it using the Discuss link at the bottom of this page so we can update the inhibitor's data.

Footnotes

1. Glabridin shows competitive inhibition of CYP2C9.