The effect of licorice drink on cytochrome P3A6 and P-glycoprotein gene transcription in rabbits

Licorice is a widely used herb, and its components interact with a number of drugs. Rifampicin is an antibiotic known to induce some drug metabolizing enzymes and transporters and used in our study as a reference drug. The purpose of this research is to study the effect of licorice drink on the levels of cytochrome P3A6 (CYP3A6) and P-glycoprotein (P-gp) gene transcripts using rabbit as an animal model. Four groups of locally inbred male New Zealand rabbits were used, including two control groups, and two treated groups. One group was given a daily oral dose of licorice drink (4 ml/kg body weight) for one week, while the other group was given a daily oral dose of rifampicin (100 mg/kg body weight) for four days. Messenger RNAs were extracted from hepatic and the proximal (first 10-15 cm) intestinal tissues of the four groups and real-time polymerase chain reaction was conducted on them. The licorice treated group showed a significant induction of hepatic CYP3A6 expression (17.6-fold, p=0.004), and inhibition of intestinal CYP3A6 expression (7.6-fold, p=0.0006). Licorice administration did not affect P-gp expression neither in hepatic nor in intestinal tissues. Rifampicin administration significantly induced hepatic CYP3A6 expression with no significant changes in transcription of intestinal CYP3A6, hepatic and intestinal P-gp. It is concluded that licorice can affect the metabolism of drugs that are CYP3A6 substrates, but it might not affect the transport of drugs dependent on P-gp

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1. Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving human CYP3A4. Annu Rev Pharmacol Toxicol. 1998;38:389-430.

2. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994;270(1):414-23.

3. Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC. The human intestinal cytochrome P450 "pie". Drug Metab Dispos. 2006;34(5):880-6.

4. Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins PB. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest. 1992;90(5):1871-8.

5. Tsunoda SM, Velez RL, von Moltke LL, Greenblatt DJ. Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Clin Pharmacol Ther. 1999;66(5):461-71.

6. Lown KS, Kolars JC, Thummel KE, Barnett JL, Kunze KL, Wrighton SA, Watkins PB. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test. Drug Metab Dispos. 1994;22:947-55.

7. Damkier P, Hansen LL, Brøsen K. Effect of fluvoxamine on the pharmacokinetics of quinidine. Euro J Clin Pharmacol. 1999;55(6):451-6.

8. Hirota N, Ito K, Iwatsubo T, Green CE, Tyson CA, Shimada N, Suzuki H, Sugiyama Y. In vitro/in vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans. Biopharm Drug Dispos. 2001;22(2):53-71.

9. Watkins PB. The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv Drug Deliv Rev. 1997;27(2-3):161-70.

10. Thörn M, Finnström N, Lundgren S, Rane A, Lööf L. Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract. Br J Clin Pharmacol. 2005;60(1):54-60.

11. Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev. 2003;55(1):3-29.

12. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA. 1987;84(21):7735-8.

13. Fischer V, Einolf HJ, Cohen D. Efflux transporters and their clinical relevance. Mini Rev Med Chem. 2005;5(2):183-95.

14. Wessler JD, Grip LT, Mendell J, Giugliano RP. The P glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol. 2013;61(25):2495-502.

15. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog. 1995;13(3):129-34.

16. van Waterschoot RA, Schinkel AH. A critical analysis of the interplay between cytochrome P450 3A and P-glycoprotein: recent insights from knockout and transgenic mice. Pharmacol Rev. 2011;63(2):390-410.

17. Biondi DM, Rocco C, Ruberto G. Dihydrostilbene derivatives from Glycyrrhiza glabra leaves. J Nat Prod. 2005;68(7):1099-102.

18. Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res PTR. 2008;22(6):709-24.

19. Sharma V, Agrawal RC. Glycyrrhiza glabra- A plant for the future. Mintage J Pharm Med Sci. 2013;2:15-20.

20. Lakshmi T, Geetha RV. Glycyrrhiza glabra linn commonly known as licorice: A therapeutic review. Int J Pharm Pharm Sci. 2011;3:20-5.

21. Omar HR, Komarova I, El-Ghonemi M, Fathy A, Rashad R, Abdelmalak HD, Yerramadha MR, Ali Y, Helal E, Camporesi EM. Licoriceabuse: time to send a warning message. Ther Adv Endocrinol Metab. 2012;3(4):125-38.

22. Ferrari P. Licorice: a sweet alternative to prevent hyperkalemia in dialysis patients. Kidney Int. 2009;76(8):811-2.

23. Zhang YD, Lorenzo B, Reidenberg MM. Inhibition of 11 betahydroxysteroid dehydrogenase obtained from guinea pig kidney by furosemide, naringenin and some other compounds. J Steroid Biochem Mol Biol. 1994;49(1):81-5.

24. Al-Deeb ID, Arafat TA, Irshaid YM. The effect of licorice drink on the systemic exposure of verapamil in rabbits. Drug Metab Lett. 2010;4(3):173-9.

25. Weber A, Kaplan M, Chughtai SA, Cohn LA, Smith AL, Unadkat JD. CYP3A inductive potential of the rifamycins, rifabutin and rifampin, in the rabbit [Abstract]. Biopharm Drug Dispos. 2001;22(4):157-68.

26. Fang HM, Xu JM, Mei Q, Diao L, Chen ML, Jin J, Xu XH. Involvement of cytochrome P450 3A4 and P-glycoprotein in firstpass intestinal extraction of omeprazole in rabbits. Acta Pharmacol Sin. 2009;30(11):1566-72.

27. Irshaid YM, Zihlef MA, Zmeili SM, Al-Antary ET, Zmaily MG, AlEmbideen SN, Amireh AO. The effect of pomelo mix ethyl acetate extract on CYP3A6 and P-glycoprotein gene transcripts in rabbits. Drug Metab Lett. 2013;7(2):137-40.

28. Chen J, Raymond K. Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor. Ann Clin Microbiol Antimicrob. 2006;15:5:3.

29. Attar M, Ling KHJ, Tang-Liu DDS, Neamati, N, Lee VHL. Cytochrome P450 3A expression and activity in the rabbit lacrimal gland: Glucocorticoid modulation and the impact on androgen metabolism. Invest Ophthalmol Vis Sci. 2005;46(12):4697-706.

30. Bourguignon LY, Peyrollier K, Xia W, Gilad E. Hyaluronan-CD44 interaction activates stem cell marker nanog, Stat-3-mediated MDR1 Gene Expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J Biol Chem. 2008;283(25):17635–51.

31. Rosenblat M, Belinky P, Vaya J, Levy R, Hayek T, Coleman R, Merchav S, Aviram M. Macrophage enrichment with the isoflavan glabridin inhibits NADPH oxidase-induced cell-mediated oxidation of low density lipoprotein. A possible role for protein kinase C. J Biol Chem. 1999; 274(20):13790-9.

32. Fukai T, Satoh K, Nomura T, Sakagami H. Preliminary evaluation of antinephritis and radical scavenging activities of glabridin from Glycyrrhiza glabra. Fitote. 2003;74(7-8):624-9.

33. Bandyopadhyay D. Topical treatment of melasma. Indian J Dermatol. 2009;54(4):303-9.

34. Kahraman A, Erkasap N, Köken T, Serteser M, Aktepe F, Erkasap S. The antioxidative and antihistaminic properties of quercetin in ethanol-induced gastric lesions. Toxicology. 2003;183(1-3):133-42.

35. Omar H, Komarova I, El-Ghonemi M, Fathy A, Rashad R, Abdelmalak H, Yerramadha M, Ali Y, Helal E, and Enrico M. Camporesi E. Licorice abuse: time to send a warning message. Ther Adv Endocrinol Metab. 2012;3(4):125-38.

36. Chen M, Shimada F, Kato H, Yano S, Kanaoka M. Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone. Endocrinol Jpn. 1991;38(2):167-74.

37. Wang ZY, Nixon DW. Licorice and cancer. Nutr Cancer. 2001;39(1):1-11.

38. Yan M, Fang PF, Li HD, Xu P, Liu YP, Wang F, Cai HL, Tan QY. Lack of effect of continuous glycyrrhizin administration on the pharmacokinetics of the P-glycoprotein substrate talinolol in healthy volunteers. Eur J Clin Pharmacol. 2013;69(3):515-21

39. Nakamura T, Okada K, Nagata K, Yamazoe Y. Intestinal cytochrome P450 and response to rifampicin in rabbits. Jpn J Pharmacol. 2000;82(3):232-9.

40. Giessmann T, Modess C, Hecker U, Zschiesche M, Dazert P, KunertKeil C, Warzok R, Engel G, Weitschies W, Cascorbi I, Kroemer HK, Siegmund W. CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects. Clin Pharmacol Ther. 2004;75(3):213-22.