Pharmacological characterization of liquiritigenin, a chiral flavonoid in licorice

Samaa Alrushaid, Neal M. Davies, Stephanie E. Martinez, Casey L. Sayre

Abstract


Liquiritigenin is a chiral flavonoid present in plant based food, nutraceuticals, and traditional medicines. It is also an important ingredient present in licorice. The purpose of this study is to explore the pharmacological activity of racemic liquiritigenin utilizing several in vitro assays with relevant roles in colon cancer and diabetes. Where possible, the pure enantiomers were tested to identify the stereospecific contribution to the activity. In vitro antioxidant, anticancer, anti-inflammatory activities (cyclooxygenase inhibition), antidiabetic activities (alpha-amylase and alpha-glucosidase inhibition) as well as cytochrome P450 (CYP450) inhibitory activities were assessed. Racemic liquiritigenin demonstrated a dose-dependent inhibition of alpha-amylase enzyme whereas its pure enantiomers did not. Racemic liquiritigenin showed moderate antiproliferative activity on a HT-29 (human colorectal adenocarcinoma) cancer cell line that was dose-dependent and potent inhibitory effects on the cyclooxygenase-2 enzyme. The flavonoid did not inhibit the activity of cytochrome CYP2D6 over the concentration range studied but was a potent antioxidant. The current study demonstrated the importance of understanding the stereospecific pharmacological effects of liquiritigenin enantiomers in alpha-amylase inhibition.


Keywords


Liquiritigenin; Flavonoid; Chiral; Stereospecific; Pharmacology

Full Text:

PDF

References


Haslam E. Practical polyphenolics: from structure to molecular recognition and physiological action. Cambridge University Press. 1998; pp 422.

Cook NC, Samman S. Flavonoids—Chemistry, metabolism, cardioprotective effects, and dietary sources. J Nutr Biochem. 1996;7(2):66-76.

Bhagwat S, Haytowitz DB, Holden JM. USDA database for the flavonoid content of selected foods, release 3.1 (2013). [Internet]. 2013. Available from: http://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/Flav/Flav3-1.pdf

Kawaii S, Tomono Y, Katase E, Ogawa K, Yano M. Quantitation of flavonoid constituents in citrus fruits. J Agric Food Chem. 1999;47(9):3565-3571.

Nielsen SE, Freese R, Kleemola P, Mutanen M. Flavonoids in human urine as biomarkers for intake of fruits and vegetables. Cancer Epidemiol Biomarkers Prev. 2002;11(5):459–466.

Bugianesi R, Catasta G, Spigno P, D’Uva A, Maiani G. Naringenin from cooked tomato paste is bioavailable in men. J Nutr. 2002;132(11):3349–3352.

Le Gall G, DuPont MS, Mellon FA, Davis AL, Collins GJ, Verhoeyen ME, et al. Characterization and content of flavonoid glycosides in genetically modified tomato (Lycopersicon esculentum) fruits. J Agric Food Chem . 2003;51(9):2438–2446.

Stewart AJ, Bozonnet S, Mullen W, Jenkins GI, Lean ME, Crozier A. Occurrence of flavonols in tomatoes and tomato-based products. J Agric Food Chem. 2000;48(7):2663–2669.

Daigle DJ, Conkerton EJ, Sanders TH, Mixon AC. Peanut hull flavonoids: their relationship with peanut maturity. J Agric Food Chem. 1988;36(6):1179–1181.

Manach C, Morand C, Gil-Izquierdo A, Bouteloup-Demange C, Rémésy C. Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice. Eur J Clin Nutr. 2003;57(2):235–242.

Krause M, Galensa R. Analysis of Enantiomeric Flavanones in Plant Extracts by High-Performance Liquid Chromatography on a Cellulose Triacetate Based Chiral Stationary Phase. Chromatographia. 1991;32(1):69–72.

Sayre CL, Davies NM. Quantification of three chiral flavonoids with reported bioactivity in selected licensed Canadian natural health products and US marketed dietary supplements. J Pharm Pharm Sci. 2013;16(2):272–278.

Corradini C, Borromei C, Cavazza A, Merusi C, De Rossi A, Nicoletti I. Determination of flavanones in citrus byproducts and nutraceutical products by a validated RP-HPLC method. J Liq Chromatogr Relat Technol. 2009;32(10):1448–1462.

Espin JC, Garcia-Conesa MT, Tomas-Barberan FA. Nutraceuticals: facts and fiction. Phytochemistry. 2007;68(22-24):2986–3008.

Yáñez JA, Andrews PK, Davies NM. Methods of analysis and separation of chiral flavonoids. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;848(2):159–181.

Sayre CL, Hopkins M, Takemoto JK, Davies NM. Chiral analytical method development of liquiritigenin with application to a pharmacokinetic study. Biomed Chromatogr. 2013;27(3):404–406.

Gan P, Huang X, Zhong M, Sun M, Qin F, Zhang C. Simultaneous determination of eight major constituents in the traditional Chinese medicine Shaoyao-Gancao-Tang by UPLC-PDA. J Med Plants Res. 2010;4(24):2615–2621.

Zhao C, Liu Y, Cong D, Zhang H, Yu J, Jiang Y, et al. Screening and determination for potential α-glucosidase inhibitory constituents from Dalbergia odorifera T. Chen using ultrafiltration-LC/ESI-MS(n). Biomed Chromatogr. 2013;27(12):1621–1629.

Yu JY, Ha JY, Kim KM, Jung YS, Jung JC, Oh S. Anti-Inflammatory activities of licorice extract and its active compounds, glycyrrhizic acid, liquiritin and liquiritigenin, in BV2 cells and mice liver. Molecules. 2015;20(7):13041–13054.

Zhang Y, He Y, Yu H, Ma F, Wu J, Zhang X. Liquiritigenin protects rats from carbon tetrachloride induced hepatic injury through PGC-1α pathway. Evid Based Complement Alternat Med. 2015;2015:649568.

Gaur R, Yadav KS, Verma RK, Yadav NP, Bhakuni RS. In vivo anti-diabetic activity of derivatives of isoliquiritigenin and liquiritigenin. Phytomedicine. 2014;21(4):415-422.

Wang D, Lu J, Liu Y, Meng Q, Xie J, Wang Z, et al. Liquiritigenin induces tumor cell death through mitogen-activated protein kinase- (MPAKs-) mediated pathway in hepatocellular carcinoma cells. Biomed Res Int. 2014;2014:965316.

Gaffield W. Circular dichroism, optical rotatory dispersion and absolute configuration of flavanones, 3-hydroxyflavanones and their glycosides. Tetrahedron. 1970;26(17):4093–4108.

Tadera K, Minami Y, Takamatsu K, Matsuoka T. Inhibition of alpha-glucosidase and alpha-amylase by flavonoids. J Nutr Sci Vitaminol (Tokyo). 2006;52(2):149–153.

Martinez SE, Sayre CL, Davies NM. Pharmacometrics of 3-methoxypterostilbene: a component of traditional chinese medicinal plants. Evid Based Complement Alternat Med. 2013;2013:261468.

Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev. 2006;58(3):521–590.

Yáñez JA, Chemuturi NV, Womble SW, Sayre CL, Davies NM. Flavonoids and Drug Interactions. In: Davies NM, Yanez JA, editors. Flavonoid Pharmacokinetics: Methods of Analysis, Pre-Clinical and Clinical Pharmacokinetics, Safety, and Toxicology. New York: John Wiley & Sons, Ltd; 2012. pp. 281–319.

Torres CA, Davies NM, Yanez JA, Andrews PK. Disposition of selected flavonoids in fruit tissues of various tomato (lycopersicon esculentum mill.) Genotypes. J Agric Food Chem. 2005;53(24):9536–9543.

Yanez JA, Remsberg CM, Miranda ND, Vega-Villa KR, Andrews PK, Davies NM. Pharmacokinetics of selected chiral flavonoids: hesperetin, naringenin and eriodictyol in rats and their content in fruit juices. Biopharm Drug Dispos. 2008;29(2):63–82.

Vega-Villa KR, Remsberg CM, Takemoto JK, Ohgami Y, Yanez JA, Andrews PK, et al. Stereospecific pharmacokinetics of racemic homoeriodictyol, isosakuranetin, and taxifolin in rats and their disposition in fruit. Chirality. 2011;23(4):339–348.

Sayre CL, Alrushaid S, Martinez SE, Anderson HD, Davies NM. Pre-Clinical pharmacokinetic and pharmacodynamic characterization of selected chiral flavonoids: pinocembrin and pinostrobin. J Pharm Pharm Sci. 2015;18(4):368–395.

Qiao X, Ji S, Yu S-W, Lin X-H, Jin H-W, Duan Y-K, et al. Identification of key licorice constituents which interact with cytochrome P450: evaluation by LC/MS/MS cocktail assay and metabolic profiling. AAPS J. 2014;16(1):101–13.


Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.