Bioactive Candy: Effects of Licorice on the Cardiovascular System

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.

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

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

(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).