Applied nutritional investigationAntiatherosclerotic effects of licorice extract supplementation on hypercholesterolemic patients: increased resistance of LDL to atherogenic modifications, reduced plasma lipid levels, and decreased systolic blood pressure
Introduction
Coronary artery disease develops as a result of risk factors such as increased plasma low-density lipoprotein (LDL) level and hypertension or LDL atherogenic modifications such as retention, oxidation, and aggregation. During early atherogenesis, circulating LDLs invade the arterial wall, where it binds to extracellular matrix proteoglycans, a process known as “LDL retention”.1 LDL retention in the arterial wall may be a prerequisite to lipoprotein oxidative modification because retention of LDL to arterial proteoglycans increases its susceptibility to oxidation.2 The process of LDL oxidation appears to occur within the artery wall, and all major artery wall cells including endothelial cells, smooth muscle cells and monocyte-derived macrophages, can oxidize LDL.3 Extensive oxidation of LDL also leads to its aggregation,4 and oxidized and aggregated LDL have been found in atherosclerotic lesions.5 These LDL modifications are considered atherogenic because they contribute to macrophage cholesterol accumulation and foam cell formation, the hallmark of early atherosclerosis.
High-density lipoprotein (HDL), in contrast, is associated with antiatherogenic activity, and HDL levels are inversely related to the risk of developing atherosclerosis. Paraoxonase (PON1) is an enzyme physically associated in serum with HDL and has been shown to protect LDL and HDL against oxidation.6
Consumption of polyphenolic flavonoids in the diet was inversely associated with morbidity and mortality from coronary heart disease.7 Polyphenolic flavonoids may prevent coronary artery disease by reducing plasma cholesterol levels and their ability to inhibit LDL oxidation.8, 9, 10, 11 The antioxidant activity of flavonoids is related to their chemical structure.12 We previously demonstrated the beneficial effects of flavonoids from red wine,13, 14 pomegranate juice,15 ginger extract,16 and olive oil17 against LDL oxidation. Further, flavonoids were shown to preserve PON1 activity18 and increase its activity in mice14 and humans15 after consumption.
Licorice root derived from the plant Glycyrrhiza glabra is used widely in Asia as a sweetener or a spice. Licorice root contains flavonoids from the flavan and chalcone subclasses, which have lipophilic characteristics and antioxidative properties.19 Among several flavonoids that were isolated and purified from licorice-root extract, the isoflavan glabridin constituted the major flavonoid.20 We previously demonstrated that in vitro licorice extract and purified glabridin protect LDL from oxidation induced by copper ions or free radical-generating systems.21 Mechanistic studies have shown that licorice-derived glabridin binds to the LDL particle and protects it from oxidation because of its capacity to scavenge free radicals.21, 22 Structural studies have found that the antioxidant effect of glabridin resides mainly in the 2′-hydroxyl group of the isoflavan ring B.23 Glabridin accumulates in macrophages and inhibits cell-mediated oxidation of LDL due to the inhibition of macrophage nicotinamide adenine dinucleotide phosphate oxidase activity.24 In vivo studies have shown that supplementation of licorice extract or glabridin to atherosclerotic mice deficient in apolipoprotein E (E0) reduces the susceptibility of their LDL to oxidation and significantly reduces the development of aortic atherosclerotic lesions.21, 24 In another study, licorice extract was administered to healthy normolipidemic subjects for 2 wk; consumption of 100 mg/d of licorice root extract increased their LDL resistance against oxidation.21
In the present study we extended our investigation on the antiatherogenic properties of licorice-root extract in moderately hypercholesterolemic patients. We found that licorice-root extract consumption by mildly hypercholesterolemic patients increases the resistance of their LDL against major atherogenic modifications and moderately reduces their plasma lipid levels and systolic blood pressures.
Section snippets
Materials
Licorice ethanolic extract free of glycyrrhizinic acid was provided by Fertilizers & Chemicals Ltd. (Haifa, Israel). Powdered roots of commercial Glycyrrhiza glabra were extracted in ethanol to obtain, after solvent evaporation, a brown solid extract. The powder was encapsulated in a soft-gel capsule (RP Scherer, Miami, FL, USA). Placebo capsules without licorice contained innertic gelatinous material normally included in soft-gel capsules. Na2 ethylene-diaminetetraacetic acid (EDTA) was
Results
After 1 mo of licorice-root ethanolic extract consumption, blood chemistry analyses showed no significant changes in markers for liver, kidney, and heart functions as measured by serum blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, bilirubin, and creatine phosphokinase (Table I). Placebo treatment for 1 mo did not significantly affect those markers (Table I). In addition, serum electrolytes, including kalium and natrium, and serum alkaline phosphatase
Discussion
Consumption of licorice-root extract was shown to inhibit oxidative modification of LDL in healthy human volunteers and accelerated development of atherosclerotic lesions in E0 mice.21 The present study expanded those findings to hypercholesterolemic patients and showed that consumption of licorice extract increases the resistance of LDL to atherogenic modifications, including CS binding ability, oxidation, and aggregation, and moderately reduced their plasma lipids levels and systolic blood
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