Bioactive Candy: Effects of Licorice on the Cardiovascular System

Mikkel R Deutch, Daniela Grimm, Markus Wehland, Manfred Infanger, Marcus Krüger, Mikkel R Deutch, Daniela Grimm, Markus Wehland, Manfred Infanger, Marcus Krüger

Abstract

Licorice, today chiefly utilized as a flavoring additive in tea, tobacco and candy, is one of the oldest used herbs for medicinal purposes and consists of up to 300 active compounds. The main active constituent of licorice is the prodrug glycyrrhizin, which is successively converted to 3β-monoglucuronyl-18β-glycyrrhetinic acid (3MGA) and 18β-glycyrrhetinic acid (GA) in the intestines. Despite many reported health benefits, 3MGA and GA inhibit the 11-β-hydrogenase type II enzyme (11β-HSD2) oxidizing cortisol to cortisone. Through activation of mineralocorticoid receptors, high cortisol levels induce a mild form of apparent mineralocorticoid excess in the kidney and increase systemic vascular resistance. Continuous inhibition of 11β-HSD2 related to excess licorice consumption will create a state of hypernatremia, hypokalemia and increased fluid volume, which can cause serious life-threatening complications especially in patients already suffering from cardiovascular diseases. Two recent meta-analyses of 18 and 26 studies investigating the correlation between licorice intake and blood pressure revealed statistically significant increases both in systolic (5.45 mmHg) and in diastolic blood pressure (3.19/1.74 mmHg). This review summarizes and evaluates current literature about the acute and chronic effects of licorice ingestion on the cardiovascular system with special focus on blood pressure. Starting from the molecular actions of licorice (metabolites) inside the cells, it describes how licorice intake is affecting the human body and shows the boundaries between the health benefits of licorice and possible harmful effects.

Keywords: 11-β-dehydrogenase isozyme 2; glabridin; glycyrrhetinic acid; glycyrrhizin; hyperaldosteronism; hypertension; hypokalemia; licorice.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Inflorescence of Glycyrrhiza glabra L.; (b) licorice-containing candies; (c) chemical structure of the prodrug glycyrrhizin (C42H62O16), the main active compound of licorice. The molecule consists of two molecules of glucuronic acid (left) that are linked to 18β-glycyrrhetinic acid; (d) chemical structure of glabridin (C20H20O4), a further bioactive licorice compound. Colors indicate molecule structures used in following schematics.
Figure 2
Figure 2
Suggested glycyrrhizin metabolism. Dependent on the gut microbiome glycyrrhizin is stepwise hydrolyzed to 3β-monoglucuronyl-18β-glycyrrhetinic acid (3MGA) and 18β-glycyrrhetinic acid (GA; blue structure) in the intestines. Both 3MGA and GA were absorbed from the gut and transported systemically in the bloodstream. In the liver, they undergo hepatic biotransformation before products were excreted via bile. The flavonoid glabridin (yellow structure) is also absorbed from the gut and circulates in the blood in its aglycone form. The hepatic metabolization of glabridin is not shown here. Green hexagons: glucuronic acid. Parts of the figure were drawn by using pictures from Servier Medical Art (http://smart.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0).
Figure 3
Figure 3
(a) Correlation between licorice intake, the renin-angiotensin-aldosterone-system and licorice-induced adverse effects on the cardiovascular system. (b) Detailed pharmacodynamics of 3β-monoglucuronyl-18β-glycyrrhetinic acid (3MGA) and 18β-glycyrrhetinic acid (GA; blue structure) in the kidney. In addition to a possible direct binding to the mineralocorticoid receptor (MR), 3MGA and GA have inhibiting effects on 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and 5β-reductase. 11β-HSD2 converts cortisol to cortisone; 5β-reductase is involved in the degradation of aldosterone in the liver. Inhibition of both enzymes contributes to apparent mineralocorticoid excess. The insert shows the localization of the processes within the Henle loop. ACE: angiotensin converting enzyme, ENaC: epithelial sodium channel, ET-1: endothelin 1, HRE: hormone response element, NAD(H): nicotinamide adenine dinucleotide, NO: nitric oxide, ROMK: renal outer medullary potassium channel. Parts of the figure were drawn by using pictures from Servier Medical Art (http://smart.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0).

References

    1. Foster C.A., Church K.S., Poddar M., Van Uum S.H., Spaic T. Licorice-induced hypertension: A case of pseudohyperaldosteronism due to jelly bean ingestion. Postgrad. Med. 2017;129:3293–3331. doi: 10.1080/00325481.2017.1291062.
    1. Fenwick G.R., Lutomski J., Nieman C. Liquorice, Glycyrrhiza glabra L.—Composition, uses and analysis. Food Chem. 1990;38:1191–1243. doi: 10.1016/0308-8146(90)90159-2.
    1. Kao T.C., Wu C.H., Yen G.C. Bioactivity and potential health benefits of licorice. J. Agric. Food Chem. 2014;62:542–553. doi: 10.1021/jf404939f.
    1. Fiore C., Eisenhut M., Ragazzi E., Zanchin G., Armanini D. A history of the therapeutic use of liquorice in europe. J. Ethnopharmacol. 2005;99:317–324. doi: 10.1016/j.jep.2005.04.015.
    1. Allcock E., Cowdery J. Hypertension induced by liquorice tea. BMJ Case Rep. 2015 doi: 10.1136/bcr-2015-209926.
    1. Isbrucker R.A., Burdock G.A. Risk and safety assessment on the consumption of licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin. Regul. Toxicol. Pharmacol. 2006;46:167–192. doi: 10.1016/j.yrtph.2006.06.002.
    1. NCCIH Licorice Root. [(accessed on 24 September 2019)]; Available online: .
    1. Sabbadin C., Bordin L., Donà G., Manso J., Avruscio G., Armanini D. Licorice: From pseudohyperaldosteronism to therapeutic uses. Front. Endocrinol. 2019 doi: 10.3389/fendo.2019.00484.
    1. Volqvartz T., Vestergaard A.L., Aagaard S.K., Andreasen M.F., Lesnikova I., Uldbjerg N., Larsen A., Bor P. Use of alternative medicine, ginger and licorice among Danish pregnant women—A prospective cohort study. BMC Complement. Altern. Med. 2019;19:5. doi: 10.1186/s12906-018-2419-y.
    1. Yang R., Wang L.Q., Yuan B.C., Liu Y. The pharmacological activities of licorice. Planta Med. 2015;81:1654–1669. doi: 10.1055/s-0035-1557893.
    1. Aly A.M., Al-Alousi L., Salem H.A. Licorice: A possible anti-inflammatory and anti-ulcer drug. AAPS PharmSciTech. 2005;6:E74–E82. doi: 10.1208/pt060113.
    1. Jalilzadeh-Amin G., Najarnezhad V., Anassori E., Mostafavi M., Keshipour H. Antiulcer properties of Glycyrrhiza glabra L. Extract on experimental models of gastric ulcer in mice. Iranian J. Pharm. Res. 2015;14:1163–1170.
    1. Yang R., Yuan B.C., Ma Y.S., Zhou S., Liu Y. The anti-inflammatory activity of licorice, a widely used chinese herb. Pharm. Biol. 2017;55:5–18. doi: 10.1080/13880209.2016.1225775.
    1. Wang L., Yang R., Yuan B., Liu Y., Liu C. The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta Pharm. Sin. B. 2015;5:310–315. doi: 10.1016/j.apsb.2015.05.005.
    1. Fukuchi K., Okudaira N., Adachi K., Odai-Ide R., Watanabe S., Ohno H., Yamamoto M., Kanamoto T., Terakubo S., Nakashima H., et al. Antiviral and antitumor activity of licorice root extracts. In Vivo. 2016;30:777–785. doi: 10.21873/invivo.10994.
    1. Huo H.Z., Wang B., Liang Y.K., Bao Y.Y., Gu Y. Hepatoprotective and antioxidant effects of licorice extract against CCl4-induced oxidative damage in rats. Int. J. Mol. Sci. 2011;12:6529–6543. doi: 10.3390/ijms12106529.
    1. Jung J.-C., Lee Y.-H., Kim S.H., Kim K.-J., Kim K.-M., Oh S., Jung Y.-S. Hepatoprotective effect of licorice, the root of Glycyrrhiza uralensis Fischer, in alcohol-induced fatty liver disease. BMC Complement. Altern. Med. 2016;16:19. doi: 10.1186/s12906-016-0997-0.
    1. Wang Z.Y., Nixon D.W. Licorice and cancer. Nutr. Cancer. 2001;39:1–11. doi: 10.1207/S15327914nc391_1.
    1. Rahnama M., Mehrabani D., Japoni S., Edjtehadi M., Saberi Firoozi M. The healing effect of licorice (Glycyrrhiza glabra) on Helicobacter pylori infected peptic ulcers. J. Res. Med. Sci. 2013;18:532–533.
    1. Momeni A., Rahimian G., Kiasi A., Amiri M., Kheiri S. Effect of licorice versus bismuth on eradication of Helicobacter pylori in patients with peptic ulcer disease. Pharmacogn. Res. 2014;6:341–344. doi: 10.4103/0974-8490.138289.
    1. Wu F., Jin Z., Jin J. Hypoglycemic effects of glabridin, a polyphenolic flavonoid from licorice, in an animal model of diabetes mellitus. Mol. Med. Rep. 2013;7:1278–1282. doi: 10.3892/mmr.2013.1330.
    1. Simmler C., Pauli G.F., Chen S.N. Phytochemistry and biological properties of glabridin. Fitoterapia. 2013;90:160–184. doi: 10.1016/j.fitote.2013.07.003.
    1. Stepien M., Kujawska-Luczak M., Szulinska M., Kregielska-Narozna M., Skrypnik D., Suliburska J., Skrypnik K., Regula J., Bogdanski P. Beneficial dose-independent influence of Camellia sinensis supplementation on lipid profile, glycemia, and insulin resistance in an NaCl-induced hypertensive rat model. J. Physiol. Pharmacol. 2018 doi: 10.26402/jpp.2018.2.13.
    1. Sontia B., Mooney J., Gaudet L., Touyz R.M. Pseudohyperaldosteronism, liquorice, and hypertension. J. Clin. Hypertens. 2008;10:153–157. doi: 10.1111/j.1751-7176.2008.07470.x.
    1. Varma R., Ross C.N. Liquorice: A root cause of secondary hypertension. JRSM Open. 2017;8:2054270416685208. doi: 10.1177/2054270416685208.
    1. Morris D.J. Liquorice: New insights into mineralocorticoid and glucocorticoid hypertension. R. I. Med. 1993;76:251–254.
    1. Sigurjónsdóttir H.Á., Franzson L., Manhem K., Ragnarsson J., Sigurdsson G., Wallerstedt S. Liquorice-induced rise in blood pressure: A linear dose-response relationship. J. Hum. Hypertens. 2001;15:549–552. doi: 10.1038/sj.jhh.1001215.
    1. Leskinen M.H., Hautaniemi E.J., Tahvanainen A.M., Koskela J.K., Päällysaho M., Tikkakoski A.J., Kähönen M., Kööbi T., Niemelä O., Mustonen J., et al. Daily liquorice consumption for two weeks increases augmentation index and central systolic and diastolic blood pressure. PLoS ONE. 2014;9:e105607. doi: 10.1371/journal.pone.0105607.
    1. Falet J.P., Elkrief A., Green L. Hypertensive emergency induced by licorice tea. CMAJ. 2019;191:E581–E583. doi: 10.1503/cmaj.180550.
    1. Omar H.R. The cardiovascular complications of licorice. Cardiovasc. Endocrinol. 2013;2:46–49. doi: 10.1097/XCE.0b013e328362e3dd.
    1. Forouzanfar M.H., Liu P., Roth G.A., Ng M., Biryukov S., Marczak L., Alexander L., Estep K., Hassen Abate K., Akinyemiju T.F., et al. Global burden of hypertension and systolic blood pressure of at least 110 to 115 mm hg, 1990–2015. JAMA. 2017;317:165–182. doi: 10.1001/jama.2016.19043.
    1. Williams B., Mancia G., Spiering W., Agabiti Rosei E., Azizi M., Burnier M., Clement D.L., Coca A., de Simone G., Dominiczak A., et al. 2018 esc/esh guidelines for the management of arterial hypertension. Eur. Heart J. 2018;39:3021–3104. doi: 10.1093/eurheartj/ehy339.
    1. Charles L., Triscott J., Dobbs B. Secondary hypertension: Discovering the underlying cause. Am. Fam. Phys. 2017;96:453–461.
    1. Wang Q., Qian Y., Wang Q., Yang Y.F., Ji S., Song W., Qiao X., Guo D.A., Liang H., Ye M. Metabolites identification of bioactive licorice compounds in rats. J. Pharm. Biomed. Anal. 2015;115:515–522. doi: 10.1016/j.jpba.2015.08.013.
    1. Nieman C. Licorice. Adv. Food Res. 1957;7:339–381.
    1. Kim D.-H., Lee S.-W., Han M.J. Biotransformation of glycyrrhizin to 18β-glycyrrhetinic acid-3-o-β-d-glucuronide by streptococcus lj-22, a human intestinal bacterium. Biol. Pharm. Bull. 1999;22:320–322. doi: 10.1248/bpb.22.320.
    1. Hattori M., Sakamoto T., Yamagishi T., Sakamoto K., Konishi K., Kobashi K., Namba T. Metabolism of glycyrrhizin by human intestinal flora. Ii. Isolation and characterization of human intestinal bacteria capable of metabolizing glycyrrhizin and related compounds. Chem. Pharm Bull. 1985;33:210–217. doi: 10.1248/cpb.33.210.
    1. Armanini D., Nacamulli D., Francini-Pesenti F., Battagin G., Ragazzi E., Fiore C. Glycyrrhetinic acid, the active principle of licorice, can reduce the thickness of subcutaneous thigh fat through topical application. Steroids. 2005;70:538–542. doi: 10.1016/j.steroids.2005.01.007.
    1. Feng X., Ding L., Qiu F. Potential drug interactions associated with glycyrrhizin and glycyrrhetinic acid. Drug Metab. Rev. 2015;47:229–238. doi: 10.3109/03602532.2015.1029634.
    1. Omar H.R., Komarova I., El-Ghonemi M., Fathy A., Rashad R., Abdelmalak H.D., Yerramadha M.R., Ali Y., Helal E., Camporesi E.M. Licorice abuse: Time to send a warning message. Ther. Adv. Endocrinol. 2012;3:125–138. doi: 10.1177/2042018812454322.
    1. Ploeger B., Mensinga T., Sips A., Meulenbelt J., DeJongh J. A human physiologically-based model for glycyrrhzic acid, a compound subject to presystemic metabolism and enterohepatic cycling. Pharm. Res. 2000;17:1516–1525. doi: 10.1023/A:1007661209921.
    1. Cao J., Chen X., Liang J., Yu X.Q., Xu A.L., Chan E., Wei D., Huang M., Wen J.Y., Yu X.Y., et al. Role of p-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of glycyrrhiza glabra. Drug Metab. Dispos. 2007;35:539–553. doi: 10.1124/dmd.106.010801.
    1. Ito C., Oi N., Hashimoto T., Nakabayashi H., Aoki F., Tominaga Y., Yokota S., Hosoe K., Kanazawa K. Absorption of dietary licorice isoflavan glabridin to blood circulation in rats. J. Nutr. Sci. Vitaminol. 2007;53:358–365. doi: 10.3177/jnsv.53.358.
    1. Aoki F., Nakagawa K., Tanaka A., Matsuzaki K., Arai N., Mae T. Determination of glabridin in human plasma by solid-phase extraction and lc-ms/ms. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2005;828:70–74. doi: 10.1016/j.jchromb.2005.09.012.
    1. Raggi M.A., Maffei F., Bugamelli F., Cantelli Forti G. Bioavailability of glycyrrhizin and licorice extract in rat and human plasma as detected by a hplc method. Pharmazie. 1994;49:269–272.
    1. Cantelli-Forti G., Maffei F., Hrelia P., Bugamelli F., Bernardi M., D’Intino P., Maranesi M., Raggi M.A. Interaction of licorice on glycyrrhizin pharmacokinetics. Environ. Health Perspect. 1994;102(Suppl. 9):65–68. doi: 10.1289/ehp.94102s965.
    1. Ishiuchi K., Morinaga O., Ohkita T., Tian C., Hirasawa A., Mitamura M., Maki Y., Kondo T., Yasujima T., Yuasa H., et al. 18beta-glycyrrhetyl-3-o-sulfate would be a causative agent of licorice-induced pseudoaldosteronism. Sci. Rep. 2019;9:1587. doi: 10.1038/s41598-018-38182-2.
    1. Morinaga O., Ishiuchi K., Ohkita T., Tian C., Hirasawa A., Mitamura M., Maki Y., Yasujima T., Yuasa H., Makino T. Isolation of a novel glycyrrhizin metabolite as a causal candidate compound for pseudoaldosteronism. Sci. Rep. 2018;8:15568. doi: 10.1038/s41598-018-33834-9.
    1. Armanini D., Karbowiak I., Funder J.W. Affinity of liquorice derivatives for mineralocorticoid and glucocorticoid receptors. Clin. Endocrinol. 1983;19:609–612. doi: 10.1111/j.1365-2265.1983.tb00038.x.
    1. Calo L.A., Zaghetto F., Pagnin E., Davis P.A., De Mozzi P., Sartorato P., Martire G., Fiore C., Armanini D. Effect of aldosterone and glycyrrhetinic acid on the protein expression of pai-1 and p22(phox) in human mononuclear leukocytes. J. Clin. Endocrinol. Metab. 2004;89:1973–1976. doi: 10.1210/jc.2003-031545.
    1. Størmer F.C., Reistad R., Alexander J. Glycyrrhizic acid in liquorice—Evaluation of health hazard. Food Chem. Toxicol. 1993;31:303–312. doi: 10.1016/0278-6915(93)90080-I.
    1. Stewart P.M., Wallace A.M., Valentino R., Burt D., Shackleton C.H., Edwards C.R. Mineralocorticoid activity of liquorice: 11-beta-hydroxysteroid dehydrogenase deficiency comes of age. Lancet. 1987;2:821–824. doi: 10.1016/S0140-6736(87)91014-2.
    1. Ferrari P. The role of 11beta-hydroxysteroid dehydrogenase type 2 in human hypertension. Biochim. Biophys. Acta. 2010;1802:1178–1187. doi: 10.1016/j.bbadis.2009.10.017.
    1. Atanasov A.G., Ignatova I.D., Nashev L.G., Dick B., Ferrari P., Frey F.J., Odermatt A. Impaired protein stability of 11beta-hydroxysteroid dehydrogenase type 2: A novel mechanism of apparent mineralocorticoid excess. J. Am. Soc. Nephrol. 2007;18:1262–1270. doi: 10.1681/ASN.2006111235.
    1. Christy C., Hadoke P.W., Paterson J.M., Mullins J.J., Seckl J.R., Walker B.R. 11beta-hydroxysteroid dehydrogenase type 2 in mouse aorta: Localization and influence on response to glucocorticoids. Hypertension. 2003;42:580–587. doi: 10.1161/01.HYP.0000088855.06598.5B.
    1. Lombes M., Alfaidy N., Eugene E., Lessana A., Farman N., Bonvalet J.P. Prerequisite for cardiac aldosterone action. Mineralocorticoid receptor and 11 beta-hydroxysteroid dehydrogenase in the human heart. Circulation. 1995;92:175–182. doi: 10.1161/01.CIR.92.2.175.
    1. Hadoke P.W., Christy C., Kotelevtsev Y.V., Williams B.C., Kenyon C.J., Seckl J.R., Mullins J.J., Walker B.R. Endothelial cell dysfunction in mice after transgenic knockout of type 2, but not type 1, 11beta-hydroxysteroid dehydrogenase. Circulation. 2001;104:2832–2837. doi: 10.1161/hc4801.100077.
    1. Van Uum S.H. Liquorice and hypertension. Neth. J. Med. 2005;63:119–120.
    1. Monder C., Stewart P.M., Lakshmi V., Valentino R., Burt D., Edwards C.R. Licorice inhibits corticosteroid 11 beta-dehydrogenase of rat kidney and liver: In vivo and in vitro studies. Endocrinology. 1989;125:1046–1053. doi: 10.1210/endo-125-2-1046.
    1. Tanahashi T., Mune T., Morita H., Tanahashi H., Isomura Y., Suwa T., Daido H., Gomez-Sanchez C.E., Yasuda K. Glycyrrhizic acid suppresses type 2 11 beta-hydroxysteroid dehydrogenase expression in vivo. J. Steroid Biochem. Mol. Biol. 2002;80:441–447. doi: 10.1016/S0960-0760(02)00033-X.
    1. Kato H., Kanaoka M., Yano S., Kobayashi M. 3-monoglucuronyl-glycyrrhetinic acid is a major metabolite that causes licorice-induced pseudoaldosteronism. J. Clin. Endocrinol. Metab. 1995;80:1929–1933. doi: 10.1210/jcem.80.6.7775643.
    1. Hammer F., Stewart P.M. Cortisol metabolism in hypertension. Best Pract. Res. Clin. Endocrinol. Metab. 2006;20:337–353. doi: 10.1016/j.beem.2006.07.001.
    1. Souness G.W., Brem A.S., Morris D.J. 11 beta-hydroxysteroid dehydrogenase antisense affects vascular contractile response and glucocorticoid metabolism. Steroids. 2002;67:195–201. doi: 10.1016/S0039-128X(01)00148-9.
    1. Latif S.A., Conca T.J., Morris D.J. The effects of the licorice derivative, glycyrrhetinic acid, on hepatic 3α- and 3β-hydroxysteroid dehydrogenases and 5α- and 5β-reductase pathways of metabolism of aldosterone in male rats. Steroids. 1990;55:52–58. doi: 10.1016/0039-128X(90)90024-6.
    1. Chanda D., Prieto-Lloret J., Singh A., Iqbal H., Yadav P., Snetkov V., Aaronson P.I. Glabridin-induced vasorelaxation: Evidence for a role of bkca channels and cyclic gmp. Life Sci. 2016;165:26–34. doi: 10.1016/j.lfs.2016.09.018.
    1. Farese R.V., Jr., Biglieri E.G., Shackleton C.H., Irony I., Gomez-Fontes R. Licorice-induced hypermineralocorticoidism. N. Engl. J. Med. 1991;325:1223–1227. doi: 10.1056/NEJM199110243251706.
    1. Tarjus A., Amador C., Michea L., Jaisser F. Vascular mineralocorticoid receptor and blood pressure regulation. Curr. Opin. Pharmacol. 2015;21:138–144. doi: 10.1016/j.coph.2015.02.004.
    1. Ohtake M., Hattori T., Murase T., Takahashi K., Takatsu M., Ohtake M., Miyachi M., Watanabe S., Cheng X.W., Murohara T., et al. Glucocorticoids activate cardiac mineralocorticoid receptors in adrenalectomized dahl salt-sensitive rats. Nagoya J. Med. Sci. 2014;76:59–72.
    1. Quaschning T., Ruschitzka F., Shaw S., Luscher T.F. Aldosterone receptor antagonism normalizes vascular function in liquorice-induced hypertension. Hypertension. 2001;37:801–805. doi: 10.1161/01.HYP.37.2.801.
    1. Schiffrin E.L., Deng L.Y., Sventek P., Day R. Enhanced expression of endothelin-1 gene in resistance arteries in severe human essential hypertension. J. Hypertens. 1997;15:57–63. doi: 10.1097/00004872-199715010-00005.
    1. Ergul S., Parish D.C., Puett D., Ergul A. Racial differences in plasma endothelin-1 concentrations in individuals with essential hypertension. Hypertension. 1996;28:652–655. doi: 10.1161/01.HYP.28.4.652.
    1. Gomez-Sanchez E.P., Gomez-Sanchez C.E. Central hypertensinogenic effects of glycyrrhizic acid and carbenoxolone. Am. J. Physiol. 1992;263:E1125–E1130. doi: 10.1152/ajpendo.1992.263.6.E1125.
    1. Hautaniemi E.J., Tahvanainen A.M., Koskela J.K., Tikkakoski A.J., Kähönen M., Uitto M., Sipilä K., Niemelä O., Mustonen J., Pörsti I.H. Voluntary liquorice ingestion increases blood pressure via increased volume load, elevated peripheral arterial resistance, and decreased aortic compliance. Sci. Rep. 2017;7:10947. doi: 10.1038/s41598-017-11468-7.
    1. Penninkilampi R., Eslick E.M., Eslick G.D. The association between consistent licorice ingestion, hypertension and hypokalaemia: A systematic review and meta-analysis. J. Hum. Hypertens. 2017;31:699–707. doi: 10.1038/jhh.2017.45.
    1. Van Gelderen C.E., Bijlsma J.A., van Dokkum W., Savelkoul T.J. Glycyrrhizic acid: The assessment of a no effect level. Hum. Exp. Toxicol. 2000;19:434–439. doi: 10.1191/096032700682694251.
    1. Basso A., Dalla Paola L., Erle G., Boscaro M., Armanini D. Licorice ameliorates postural hypotension caused by diabetic autonomic neuropathy. Diabetes Care. 1994;17:1356. doi: 10.2337/diacare.17.11.1356.
    1. Van der Zwan A. Hypertension encephalopathy after liquorice ingestion. Clin. Neurol. Neurosurg. 1993;95:35–37. doi: 10.1016/0303-8467(93)90089-Y.
    1. Russo S., Mastropasqua M., Mosetti M.A., Persegani C., Paggi A. Low doses of liquorice can induce hypertension encephalopathy. Am. J. Nephrol. 2000;20:145–148. doi: 10.1159/000013572.
    1. Bramont C., Lestradet C., Godart L., Faivre R., Narboni G. cerebral vascular accident caused by alcohol-free licorice. Presse Med. 1985;14:746.
    1. Chamberlain J.J., Abolnik I.Z. Pulmonary edema following a licorice binge. West J. Med. 1997;167:184–185.
    1. Chamberlain T.J. Licorice poisoning, pseudoaldosteronism, and heart failure. JAMA. 1970;213:1343. doi: 10.1001/jama.1970.03170340065018.
    1. Hasegawa J., Suyama Y., Kinugawa T., Morisawa T., Kishimoto Y. Echocardiographic findings of the heart resembling dilated cardiomyopathy during hypokalemic myopathy due to licorice-induced pseudoaldosteronism. Cardiovasc. Drugs Ther. 1998;12:599–600. doi: 10.1023/A:1007708025567.
    1. Sailler L., Juchet H., Ollier S., Nicodeme R., Arlet P. generalized edema caused by licorice: A new syndrome. Apropos of 3 cases. Rev. Med. Interne. 1993;14:984. doi: 10.1016/S0248-8663(05)80102-X.
    1. Johns C. Glycyrrhizic acid toxicity caused by consumption of licorice candy cigars. CJEM. 2009;11:94–96. doi: 10.1017/S1481803500010988.
    1. Francini-Pesenti F., Puato M., Piccoli A., Brocadello F. Liquorice-induced hypokalaemia and water retention in the absence of hypertension. Phytother. Res. 2008;22:563–565. doi: 10.1002/ptr.2402.
    1. Negro A., Rossi E., Regolisti G., Perazzoli F. Liquorice-induced sodium retention. Merely an acquired condition of apparent mineralocorticoid excess? A case report. Ann. Ital. Med. Int. 2000;15:296–300.
    1. Luis A., Domingues F., Pereira L. Metabolic changes after licorice consumption: A systematic review with meta-analysis and trial sequential analysis of clinical trials. Phytomedicine. 2018;39:17–24. doi: 10.1016/j.phymed.2017.12.010.
    1. Forslund T., Fyhrquist F., Froseth B., Tikkanen I. Effects of licorice on plasma atrial natriuretic peptide in healthy volunteers. J. Intern. Med. 1989;225:95–99. doi: 10.1111/j.1365-2796.1989.tb00046.x.
    1. Mattarello M.J., Benedini S., Fiore C., Camozzi V., Sartorato P., Luisetto G., Armanini D. Effect of licorice on PTH levels in healthy women. Steroids. 2006;71:403–408. doi: 10.1016/j.steroids.2006.01.005.
    1. Sigurjonsdottir H.A., Axelson M., Johannsson G., Manhem K., Nyström E., Wallerstedt S. The liquorice effect on the RAAS differs between the genders. Blood Press. 2006;15:169–172. doi: 10.1080/08037050600593060.
    1. Ruszymah B.H., Nabishah B.M., Aminuddin S., Khalid B.A. Effects of glycyrrhizic acid on right atrial pressure and pulmonary vasculature in rats. Clin. Exp. Hypertens. 1995;17:575–591. doi: 10.3109/10641969509037425.
    1. Yang P.-S., Kim D.-H., Lee Y.J., Lee S.-E., Kang W.J., Chang H.-J., Shin J.-S. Glycyrrhizin, inhibitor of high mobility group box-1, attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling in rats. Respir. Res. 2014;15:148. doi: 10.1186/s12931-014-0148-4.
    1. Ottenbacher R., Blehm J. An unusual case of licorice-induced hypertensive crisis. S. D. Med. 2015;68:346–347.
    1. Schulze zur Wiesch C., Sauer N., Aberle J. hypertension and hypokalemia—A reninoma as the cause of suspected liquorice-induced arterial hypertension. Dtsch. Med. Wochenschr. 2011;136:882–884. doi: 10.1055/s-0031-1275821.
    1. Epstein M.T., Espiner E.A., Donald R.A., Hughes H. Liquorice toxicity and the renin-angiotensin-aldosterone axis in man. BMJ. 1977;1:209–210. doi: 10.1136/bmj.1.6055.209.
    1. Sigurjonsdottir H.A., Manhem K., Axelson M., Wallerstedt S. Subjects with essential hypertension are more sensitive to the inhibition of 11 beta-hsd by liquorice. J. Hum. Hypertens. 2003;17:125–131. doi: 10.1038/sj.jhh.1001504.
    1. Epstein M.T., Espiner E.A., Donald R.A., Hughes H. Effect of eating liquorice on the renin-angiotensin aldosterone axis in normal subjects. Br. Med. J. 1977;1:488–490. doi: 10.1136/bmj.1.6059.488.
    1. MacKenzie M.A., Hoefnagels W.H., Jansen R.W., Benraad T.J., Kloppenborg P.W. The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers. J. Clin. Endocrinol. Metab. 1990;70:1637–1643. doi: 10.1210/jcem-70-6-1637.
    1. Kageyama Y., Suzuki H., Saruta T. Glycyrrhizin induces mineralocorticoid activity through alterations in cortisol metabolism in the human kidney. J. Endocrinol. 1992;135:147–152. doi: 10.1677/joe.0.1350147.
    1. Bernardi M., D’Intino P.E., Trevisani F., Cantelli-Forti G., Raggi M.A., Turchetto E., Gasbarrini G. Effects of prolonged ingestion of graded doses of licorice by healthy volunteers. Life Sci. 1994;55:863–872. doi: 10.1016/0024-3205(94)90042-6.
    1. Armanini D., Lewicka S., Pratesi C., Scali M., Zennaro M.C., Zovato S., Gottardo C., Simoncini M., Spigariol A., Zampollo V. Further studies on the mechanism of the mineralocorticoid action of licorice in humans. J. Endocrinol. Invest. 1996;19:624–629. doi: 10.1007/BF03349029.
    1. Sobieszczyk P., Borlaug B.A., Gornik H.L., Knauft W.D., Beckman J.A. Glycyrrhetinic acid attenuates vascular smooth muscle vasodilatory function in healthy humans. Clin. Sci. 2010;119:437–442. doi: 10.1042/CS20100087.
    1. Tu J.H., He Y.J., Chen Y., Fan L., Zhang W., Tan Z.R., Huang Y.F., Guo D., Hu D.L., Wang D., et al. Effect of glycyrrhizin on the activity of cyp3a enzyme in humans. Eur. J. Clin. Pharmacol. 2010;66:805–810. doi: 10.1007/s00228-010-0814-5.
    1. Yan M., Fang P.-F., Li H.-D., Xu P., Liu Y.-P., Wang F., Cai H.-L., Tan Q.-Y. Lack of effect of continuous glycyrrhizin administration on the pharmacokinetics of the p-glycoprotein substrate talinolol in healthy volunteers. Eur. J. Clin. Pharmacol. 2013;69:515–521. doi: 10.1007/s00228-012-1391-6.
    1. Bocker D., Breithardt G. induction of arrhythmia by licorice abuse. Z. Kardiol. 1991;80:389–391.
    1. Eriksson J.W., Carlberg B., Hillorn V. Life-threatening ventricular tachycardia due to liquorice-induced hypokalaemia. J. Intern. Med. 1999;245:307–310. doi: 10.1046/j.1365-2796.1999.00476.x.
    1. Bannister B., Ginsburg R., Shneerson J. Cardiac arrest due to liquorice induced hypokalaemia. BMJ. 1977;2:738–739. doi: 10.1136/bmj.2.6089.738-a.
    1. Crean A.M., Abdel-Rahman S.E., Greenwood J.P. A sweet tooth as the root cause of cardiac arrest. Can. J. Cardiol. 2009;25:e357–e358. doi: 10.1016/S0828-282X(09)70723-8.
    1. Campana A., Manzo M., Brigante M., Marrazzo N., Melchiorre G. an unusual cause of cardiac arrest. Ital. Heart J. Suppl. 2003;4:510–513.
    1. Konik E., Kurtz E.G., Sam F., Sawyer D. Coronary artery spasm, hypertension, hypokalemia and licorice. J. Clin. Case Rep. 2012;2:143. doi: 10.4172/2165-7920.1000143.
    1. Tąpolska M., Spałek M., Szybowicz U., Domin R., Owsik K., Sochacka K., Skrypnik D., Bogdański P., Owecki M. Arterial Stiffness Parameters Correlate with Estimated Cardiovascular Risk in Humans: A Clinical Study. Int. J. Environ. Res. Public Health. 2019;16:2547. doi: 10.3390/ijerph16142547.
    1. Banerjee A., Giri R. Chapter 9—Nutraceuticals in gastrointestinal disorders. In: Gupta R.C., editor. Nutraceuticals. Academic Press; Boston, MA, USA: 2016. pp. 109–122.
    1. Ojha S.K., Sharma C., Golechha M.J., Bhatia J., Kumari S., Arya D.S. Licorice treatment prevents oxidative stress, restores cardiac function, and salvages myocardium in rat model of myocardial injury. Toxicol. Ind. Health. 2015;31:140–152. doi: 10.1177/0748233713491800.
    1. Ojha S., Golechha M., Kumari S., Bhatia J., Arya D.S. Glycyrrhiza glabra protects from myocardial ischemia–reperfusion injury by improving hemodynamic, biochemical, histopathological and ventricular function. Exp. Toxicol. Pathol. 2013;65:219–227. doi: 10.1016/j.etp.2011.08.011.
    1. Haleagrahara N., Varkkey J., Chakravarthi S. Cardioprotective effects of glycyrrhizic acid against isoproterenol-induced myocardial ischemia in rats. Int. J. Mol. Sci. 2011;12:7100–7113. doi: 10.3390/ijms12107100.
    1. Fuhrman B., Buch S., Vaya J., Belinky P.A., Coleman R., Hayek T., Aviram M. Licorice extract and its major polyphenol glabridin protect low-density lipoprotein against lipid peroxidation: In vitro and ex vivo studies in humans and in atherosclerotic apolipoprotein e-deficient mice. Am. J. Clin. Nutr. 1997;66:267–275. doi: 10.1093/ajcn/66.2.267.
    1. 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;274:13790–13799. doi: 10.1074/jbc.274.20.13790.
    1. Somjen D., Knoll E., Vaya J., Stern N., Tamir S. Estrogen-like activity of licorice root constituents: Glabridin and glabrene, in vascular tissues in vitro and in vivo. J. Steroid Biochem. Mol. Biol. 2004;91:147–155. doi: 10.1016/j.jsbmb.2004.04.003.
    1. Somjen D., Kohen F., Jaffe A., Amir-Zaltsman Y., Knoll E., Stern N. Effects of gonadal steroids and their antagonists on DNA synthesis in human vascular cells. Hypertension. 1998;32:39–45. doi: 10.1161/01.HYP.32.1.39.
    1. Huang K., Liu Y., Tang H., Qiu M., Li C., Duan C., Wang C., Yang J., Zhou X. Glabridin prevents doxorubicin-induced cardiotoxicity through gut microbiota modulation and colonic macrophage polarization in mice. Front. Pharmacol. 2019 doi: 10.3389/fphar.2019.00107.
    1. Meyer R. Pseudohyperaldosteronismus: Lakritzverzehr mit Folgen. Dtsch. Arztebl. Int. 2000;97:A-596.
    1. Wang X., Zhang H., Chen L., Shan L., Fan G., Gao X. Liquorice, a unique “guide drug” of traditional chinese medicine: A review of its role in drug interactions. J. Ethnopharmacol. 2013;150:781–790. doi: 10.1016/j.jep.2013.09.055.
    1. Tsukamoto S., Aburatani M., Yoshida T., Yamashita Y., El-Beih A.A., Ohta T. Cyp3a4 inhibitors isolated from licorice. Biol. Pharm Bull. 2005;28:2000–2002. doi: 10.1248/bpb.28.2000.
    1. Kent U.M., Aviram M., Rosenblat M., Hollenberg P.F. The licorice root derived isoflavan glabridin inhibits the activities of human cytochrome p450s 3a4, 2b6, and 2c9. Drug Metab. Dispos. 2002;30:709–715. doi: 10.1124/dmd.30.6.709.
    1. Lv Q.L., Wang G.H., Chen S.H., Hu L., Zhang X., Ying G., Qin C.Z., Zhou H.H. In vitro and in vivo inhibitory effects of glycyrrhetinic acid in mice and human cytochrome p450 3a4. Int. J. Environ. Res. Public Health. 2015;13:84. doi: 10.3390/ijerph13010084.
    1. Paolini M., Barillari J., Broccoli M., Pozzetti L., Perocco P., Cantelli-Forti G. Effect of liquorice and glycyrrhizin on rat liver carcinogen metabolizing enzymes. Cancer Lett. 1999;145:35–42. doi: 10.1016/S0304-3835(99)00225-6.
    1. Paolini M., Pozzetti L., Sapone A., Cantelli-Forti G. Effect of licorice and glycyrrhizin on murine liver cyp-dependent monooxygenases. Life Sci. 1998;62:571–582. doi: 10.1016/S0024-3205(97)01154-5.
    1. Hou Y.C., Lin S.P., Chao P.D. Liquorice reduced cyclosporine bioavailability by activating p-glycoprotein and cyp 3a. Food Chem. 2012;135:2307–2312. doi: 10.1016/j.foodchem.2012.07.061.
    1. Heck A.M., DeWitt B.A., Lukes A.L. Potential interactions between alternative therapies and warfarin. Am. J. Health Syst. Pharm. 2000;57:1221–1227. doi: 10.1093/ajhp/57.13.1221. quiz 1228–1230.
    1. Matsumoto T., Kaifuchi N., Mizuhara Y., Warabi E., Watanabe J. Use of a caco-2 permeability assay to evaluate the effects of several kampo medicines on the drug transporter p-glycoprotein. J. Nat. Med. 2018;72:897–904. doi: 10.1007/s11418-018-1222-x.
    1. Kerstens M.N., Dullaart R.P. 11 beta-hydroxysteroid-dehydrogenase: Characteristics and the clinical significance of a key enzyme in cortisol metabolism. Ned. Tijdschr. Geneeskd. 1999;143:509–514.
    1. Buhl L.F., Pedersen F.N., Andersen M.S., Glintborg D. Licorice-induced apparent mineralocorticoid excess compounded by excessive use of terbutaline and high water intake. BMJ Case Rep. 2018 doi: 10.1136/bcr-2017-223918.
    1. Harada T., Ohtaki E., Misu K., Sumiyoshi T., Hosoda S. Congestive heart failure caused by digitalis toxicity in an elderly man taking a licorice-containing chinese herbal laxative. Cardiology. 2002;98:218. doi: 10.1159/000067316.
    1. Scientific Committee on Food . Opinion of the Scientific Committee on Food on Glycyrrhizinic acid and Its Ammonium Salt. Scientific Committee on Food; Brussels, Belgium: 2003.
    1. Shimada S., Arai T., Tamaoka A., Homma M. Liquorice-induced hypokalaemia in patients treated with yokukansan preparations: Identification of the risk factors in a retrospective cohort study. BMJ Open. 2017;7:e014218. doi: 10.1136/bmjopen-2016-014218.
    1. Nazari S., Rameshrad M., Hosseinzadeh H. Toxicological effects of Glycyrrhiza glabra (licorice): A review. Phytother. Res. 2017;31:1635–1650. doi: 10.1002/ptr.5893.
    1. Steinberg D., Sgan-Cohen H.D., Stabholz A., Pizanty S., Segal R., Sela M.N. The anticariogenic activity of glycyrrhizin: Preliminary clinical trials. Isr. J. Dent. Sci. 1989;2:153–157.
    1. Segal R., Pisanty S., Wormser R., Azaz E., Sela M.N. Anticariogenic activity of licorice and glycyrrhizine i: Inhibition of in vitro plaque formation by streptococcus mutans. J. Pharm. Sci. 1985;74:79–81. doi: 10.1002/jps.2600740121.
    1. Jia J., Li Y., Lei Z., Hao Y., Wu Y., Zhao Q., Wang H., Ma L., Liu J., Zhao C., et al. Relaxative effect of core licorice aqueous extract on mouse isolated uterine horns. Pharm. Biol. 2013;51:744–748. doi: 10.3109/13880209.2013.764536.
    1. Yang L., Chai C.Z., Yan Y., Duan Y.D., Henz A., Zhang B.L., Backlund A., Yu B.Y. Spasmolytic mechanism of aqueous licorice extract on oxytocin-induced uterine contraction through inhibiting the phosphorylation of heat shock protein 27. Molecules. 2017;22:1392. doi: 10.3390/molecules22091392.
    1. Peskar B.M. Effect of carbenoxolone on prostaglandin synthesizing and metabolizing enzymes and correlation with gastric mucosal carbenoxolone concentrations. Scand. J. Gastroenterol. Suppl. 1980;65:109–114.
    1. Wang L.J., Geng C.A., Ma Y.B., Huang X.Y., Luo J., Chen H., Zhang X.M., Chen J.J. Synthesis, biological evaluation and structure-activity relationships of glycyrrhetinic acid derivatives as novel anti-hepatitis b virus agents. Bioorg. Med. Chem. Lett. 2012;22:3473–3479. doi: 10.1016/j.bmcl.2012.03.081.
    1. Hibasami H., Iwase H., Yoshioka K., Takahashi H. Glycyrrhizin induces apoptosis in human stomach cancer kato iii and human promyelotic leukemia hl-60 cells. Int. J. Mol. Med. 2005;16:233–236. doi: 10.3892/ijmm.16.2.233.
    1. Asl M.N., Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. And its bioactive compounds. Phytother. Res. 2008;22:709–724. doi: 10.1002/ptr.2362.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit