Planta Med 2021; 87(12/13): 1101-1109
DOI: 10.1055/a-1408-9338
Pharmacokinetic Investigations
Original Papers

Development, Validation and Application of a UHPLC-MS Method for the Quantification of Chios Mastic Gum Triterpenoids in Human Plasma[ # ]

Vincent Brieudes
1   Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens, Greece
,
Eleni V. Mikropoulou
1   Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens, Greece
,
Errikos Kallergis
1   Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens, Greece
,
Andriana C. Kaliora
2   Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece
,
Efstathia Papada
2   Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece
,
Petros Gkiouvetidis
1   Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens, Greece
,
Apostolis Angelis
1   Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens, Greece
,
Maria Halabalaki
1   Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens, Greece
› Author Affiliations
Supported by: Stavros Niarchos Foundation 14320
Supported by: European Regional Development Fund 5002803
Supported by: Greek national funds through the Operational Program “Competitiveness, Entrepreneurship and Innovation” “STRENGTHENING RESEARCH AND INNOVATION INFRASTRUCTURES”

Abstract

Chios mastic gum is the resinous secretion obtained from the barks of the shrub Pistacia lentiscus var. Chia, which is endemic to the Greek island of Chios. Since antiquity, Chios mastic gum has found several uses as a phytotherapeutic remedy, primarily for the treatment of gastrointestinal disorders while recently, Chios mastic gum was also recognized by EMA as an herbal medicinal product with specific indications. Chios mastic gumʼs biological properties are attributed to triterpenes which comprise the major chemical group (approx. 70%) and notably isomasticadienonic acid and masticadienonic acid. However, due to their structural characteristics, the isolation thereof in high yield and purity is challenging and since they are not commercially available, pharmacological studies aiming to assess their biological properties are limited. In the present work, masticʼs phytochemical investigation by UPLC-HRMS is followed by the isolation and characterization of isomasticadienonic acid and masticadienonic acid to be used as analytical standards for their accurate and reliable quantification in human plasma. A UHPLC-tQ-MS method that was developed and validated (in terms of specificity, linearity, limit of quantification, accuracy and precision), for the direct quantification of the targeted compounds in the low ng/mL range of concentration, was subsequently implemented on plasma samples of healthy volunteers thus demonstrating its fitness for purpose. The results presented herein might provide insight to the understanding of this traditional natural product consumed notably for its anti-inflammatory, antioxidant and lipid lowering properties. Moreover, this method might serve as a starting point for any study aiming to monitor bioactive triterpenes in biological fluids.

# Dedicated to Professor Arnold Vlietinck on the occasion of his 80th birthday.


Supporting Information



Publication History

Received: 14 December 2020

Accepted after revision: 25 February 2021

Article published online:
30 March 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Browicz K. Pistacia lentiscus cv. Chia (Anacardiaceae) on Chios island. Pl Syst Evol 1987; 155: 189-195
  • 2 Ierapetritis DG. The geography of the Chios mastic trade from the 17th through to the 19th century. Ethnobot Res Appl 2010; 8: 153-167
  • 3 UNESCO. Decision of the Intergovernmental Committee: 9.COM 10.18, Inscribing the Know-how of cultivating mastic on the island of Chios on the Representative List of the Intangible Cultural Heritage of Humanity. Accessed November 25, 2020 at: https://ich.unesco.org/en/decisions/9.COM/10.18
  • 4 Pachi VK, Mikropoulou EV, Gkiouvetidis P, Siafakas K, Argyropoulou A, Angelis A, Mitakou S, Halabalaki M. Traditional uses, phytochemistry and pharmacology of Chios mastic gum (Pistacia lentiscus var. Chia, Anacardiaceae): A review. J Ethnopharmacol 2020; 254: 112485
  • 5 Al-Said MS, Ageel AM, Parmar NS, Tariq M. Evaluation of mastic, a crude drug obtained from Pistacia lentiscus for gastric and duodenal anti-ulcer activity. J Ethnopharmacol 1986; 15: 271-278
  • 6 Dabos KJ, Sfika E, Vlatta LJ, Frantzi D, Amygdalos GI, Giannikopoulos G. Is Chios mastic gum effective in the treatment of functional dyspepsia? A prospective randomised double-blind placebo controlled trial. J Ethnopharmacol 2010; 127: 205-209
  • 7 Magiatis P, Melliou E, Skaltsounis AL, Chinou IB, Mitaku S. Chemical composition and antimicrobial activity of the essential oils of Pistacia lentiscus var. chia . Planta Med 1999; 65: 749-752
  • 8 Tassou CC, Nychas GJE. Antimicrobial activity of the essential oil of mastic gum (Pistacia lentiscus var. chia) on Gram positive and Gram negative bacteria in broth and in Model Food System. Int Biodeterior Biodegrad 1995; 36: 411-420
  • 9 Koutsoudaki C, Krsek M, Rodger A. Chemical composition and antibacterial activity of the essential oil and the gum of Pistacia lentiscus Var. chia . J Agric Food Chem 2005; 53: 7681-7685
  • 10 EMA. Assessment report on Pistacia lentiscus L., resin (mastix). Accessed November 25, 2020 at: http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2015/07/WC500190097.pdf
  • 11 EMA. Herbal Monograph on Pistacia lentiscus L., resin (mastix). Accessed November 20, 2020 at: https://www.ema.europa.eu/en/documents/herbal-monograph/final-european-union-herbal-monograph-pistacia-lentiscus-l-resin-mastic_en.pdf
  • 12 Paraschos S, Magiatis P, Mitakou S, Petraki K, Kalliaropoulos A, Maragkoudakis P, Mentis A, Sgouras D, Skaltsounis AL. In vitro and in vivo activities of Chios mastic gum extracts and constituents against Helicobacter pylori . Antimicrob Agents Chemother 2007; 51: 551-559
  • 13 Kaliora AC, Stathopoulou MG, Triantafillidis JK, Dedoussis GVZ, Andrikopoulos NK. Chios mastic treatment of patients with active Crohnʼs disease. World J Gastroenterol 2007; 13: 748-753
  • 14 Balan KV, Demetzos C, Prince J, Dimas K, Cladaras M, Han Z, Wyche JH, Pantazis P. Induction of apoptosis in human colon cancer HCT116 cells treated with an extract of the plant product, chios mastic gum. In Vivo (Brooklyn) 2005; 19: 93-102
  • 15 Dimas K, Hatziantoniou S, Wyche JH, Pantazis P. A mastic gum extract induces suppression of growth of human colorectal tumor xenografts in immunodeficient mice. In Vivo (Brooklyn) 2009; 23: 63-68
  • 16 He M, Li A, Xu C, Wang S, Zhang M, Gu H, Yang Y, Tao H. Mechanisms of antiprostate cancer by gum mastic: NF-κB signal as target. Acta Pharmacol Sin 2007; 28: 446-452
  • 17 He ML, Chen WW, Zhang PJ, Jiang AL, Fan W, Yuan HQ, Liu WW, Zhang JY. Gum mastic increases maspin expression in prostate cancer cells. Acta Pharmacol Sin 2007; 28: 567-572
  • 18 Spyridopoulou K, Tiptiri-Kourpeti A, Lampri E, Fitsiou E, Vasileiadis S, Vamvakias M, Bardouki H, Goussia A, Malamou-Mitsi V, Panayiotidis MI, Galanis A, Pappa A, Chlichlia K. Dietary mastic oil extracted from Pistacia lentiscus var. chia suppresses tumor growth in experimental colon cancer models. Sci Rep 2017; 7: 3782
  • 19 Abdel-Rahman AHY, Youssef AM, Youssef AM. Mastich as an antioxidant. J Am Oil Chem Soc 1975; 52: 423-423
  • 20 Assimopoulou AN, Zlatanos SN, Papageorgiou VP. Antioxidant activity of natural resins and bioactive triterpenes in oil substrates. Food Chem 2005; 92: 721-727
  • 21 Andrikopoulos NK, Kaliora AC, Assimopoulou AN, Papapeorgiou VP. Biological activity of some naturally occurring resins, gums and pigments against in vitro LDL oxidation. Phytother Res 2003; 17: 501-507
  • 22 Loizou S, Paraschos S, Mitakou S, Chrousos GP, Lekakis I, Moutsatsou P. Chios mastic gum extract and isolated phytosterol tirucallol exhibit anti-inflammatory activity in human aortic endothelial cells. Exp Biol Med 2009; 234: 553-561
  • 23 Dedoussis GVZ, Kaliora AC, Psarras S, Chiou A, Mylona A, Papadopoulos NG, Andrikopoulos NK. Antiatherogenic effect of Pistacia lentiscus via GSH restoration and downregulation of CD36 mRNA expression. Atherosclerosis 2004; 174: 293-303
  • 24 Triantafyllou A, Chaviaras N, Sergentanis TN, Protopapa E, Tsaknis J. Chios mastic gum modulates serum biochemical parameters in a human population. J Ethnopharmacol 2007; 111: 43-49
  • 25 Andreadou I, Mitakou S, Paraschos S, Efentakis P, Magiatis P, Kaklamanis L, Halabalaki M, Skaltsounis L, Iliodromitis EK. Pistacia lentiscus L. reduces the infarct size in normal fed anesthetized rabbits and possess antiatheromatic and hypolipidemic activity in cholesterol fed rabbits. Phytomedicine 2016; 23: 1220-1226
  • 26 Kartalis A, Didagelos M, Georgiadis I, Benetos G, Smyrnioudis N, Marmaras H, Voutas P, Zotika C, Garoufalis S, Andrikopoulos G. Effects of Chios mastic gum on cholesterol and glucose levels of healthy volunteers: A prospective, randomized, placebo-controlled, pilot study (CHIOS-MASTIHA). Eur J Prev Cardiol 2015; 23: 722-729
  • 27 González-Burgos E, Gomez-Serranillos MP. Terpene compounds in nature: a review of their potential antioxidant activity. Curr Med Chem 2012; 19: 5319-5341
  • 28 de Cássia da Silveira e Sá R. Andrade LN, de Sousa DP. A review on anti-inflammatory activity of monoterpenes. Molecules 2013; 18: 1227-1254
  • 29 Yadav VR, Prasad S, Sung B, Kannappan R, Aggarwal BB. Targeting inflammatory pathways by triterpenoids for prevention and treatment of cancer. Toxins (Basel) 2010; 2: 2428-2466
  • 30 Barton DHR, Seoane E. Triterpenoids. Part XXII. The constitution and stereochemistry of masticadienonic acid. J Chem Soc 1956; 189: 4150-4157
  • 31 Assimopoulou AN, Papageorgiou VP. GC-MS analysis of penta- and tetra-cyclic triterpenes from resins of Pistacia species. Part I. Pistacia lentiscus var. Chia . Biomed Chromatogr 2005; 19: 285-311
  • 32 Marner FJ, Freyer A, Lex J. Triterpenoids from gum mastic, the resin of Pistacia lentiscus . Phytochemistry 1991; 30: 3709-3712
  • 33 van den Berg KJ, van der Horst J, Boon JJ, Sudmeijer OO. Cis-1,4-poly-β-myrcene: the structure of the polymeric fraction of mastic resin (Pistacia Lentiscus L.) elucidated. Tetrahedron Lett 1998; 39: 2645-2648
  • 34 Lemonakis N, Magiatis P, Kostomitsopoulos N, Skaltsounis AL, Tamvakopoulos C. Oral administration of chios mastic gum or extracts in mice: quantification of triterpenic acids by liquid chromatography-tandem mass spectrometry. Planta Med 2011; 77: 1916-1923
  • 35 Brieudes V, Kallergis E, Papada E, Gioxari A, Kaliora A, Mitakou S, Skaltsounis L, Halabalaki M. Bioavailability study and impact of Chios mastic supplementation on oxidative stress in healthy humans. PMIO 2017; 4 (S 01): S1-S202
  • 36 Papada E, Gioxari A, Brieudes V, Amerikanou C, Halabalaki M, Skaltsounis AL, Smyrnioudis I, Kaliora AC. Bioavailability of terpenes and postprandial effect on human antioxidant potential. An open-label study in healthy subjects. Mol Nutr Food Res 2018; 62: 1-9
  • 37 ICH. Validation of analytical procedures: text and methodology, Q2(R1). Accessed September 25, 2020 at: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-2-r1-validation-analytical-procedures-text-methodology-step-5_en.pdf
  • 38 Xynos N, Termentzi A, Fokialakis N, Skaltsounis LA, Aligiannis N. Supercritical CO2 extraction of mastic gum and chemical characterization of bioactive fractions using LC-HRMS/MS and GC-MS. J Supercrit Fluids 2018; 133: 349-356
  • 39 Hamzaoui M, Angelis A, Laskari V, Termentzi A, Hubert J, Fokialakis N, Aligiannis N, Renault J, Skaltsounis A. Separation of neutral and acidic triterpenes from Mastic gum using Centrifugal Partition Chromatography (CPC) and Supercritical Fluid Chromatography (SFC-CO2). Planta Med 2015; 81: PW_62
  • 40 Wojdyło A, Oszmiański J, Czemerys R. Antioxidant activity and phenolic compounds in 32 selected herbs. Food Chem 2007; 105: 940-949
  • 41 International Vocabulary of Metrology – basic and general Concepts and associated Terms (VIM, 3rd Edition). Accessed September 25, 2020 at: https://www.bipm.org/utils/common/documents/jcgm/JCGM_200_2012.pdf
  • 42 Haug LS, Thomsen C, Becher G. A sensitive method for determination of a broad range of perfluorinated compounds in serum suitable for large-scale human biomonitoring. J Chromatogr A 2009; 1216: 385-393