Bioaccessibility and Absorption of Flavonoid C-glycosides from Abrus mollis Using Simulated Digestion, Caco-2 Cell, and In Situ Single-pass Perfusion Models

Abstract

Abrus mollis is commonly used as a traditional Chinese medicine for the treatment of liver diseases due to its hepatoprotection and anti-inflammation, but the absorption properties of its main bioactive ingredients remain unclear. Our previous studies verified that the flavonoid C-glycosides, including vicenin-2 (1), isoschaftoside (2), and schaftoside (3), were the major active components in A. mollis for hepatic protection against nonalcoholic fatty liver disease, hepatitis, and hepatic fibrosis. This study investigated the bioaccessibility and transport mechanisms of total flavonoid C-glycoside, as well as vicenin-2 (1), isoschaftoside (2), and schaftoside (3), in A. mollis by simulated digestion and use of the Caco-2 cell model. Moreover, this study attempted to verify their absorption properties by in situ gastrointestinal perfusion in rats. Total flavonoid C-glycoside and 1, 2, and 3 exhibited similar bioaccessibility of 84.58%, 85.13%, 83.05%, and 81.65% respectively after simulated digestion. The transport of total flavonoid C-glycoside in the Caco-2 cell model increased with the concentration, and the transport showed saturation characteristics with the time and concentration of total flavonoid C-glycoside to a certain degree. The Papp values of total flavonoid C-glycoside and the 3 flavonoid C-glycosides were significantly improved by verapamil, probenecid, and EDTA-Na₂. Their absorption properties in the gastrointestinal tract were consistent with that found in Caco-2 cells, and superior absorption rates were observed in the duodenum and jejunum. The absorption pattern of total flavonoid C-glycoside may involve multiple transport pathways, including active transport, passive diffusion, and the paracellular pathway. TFC was actively pumped out by P-glycoprotein and multidrug resistance-associated protein. These results revealed that the bioaccessibility and intestinal absorption characteristic of total flavonoid C-glycoside were consistent with the 3 major flavonoids.

Key words

Abrus pulchellus subsp. mollis - Leguminosae - flavonoid C-glycosides - intestinal absorption - bioaccessibility - simulated gastrointestinal digestion - Caco-2 cell - in situ single-pass perfusion

Publication History

Received: 31 May 2020

Accepted after revision: 14 January 2021

Article published online:
05 February 2021

• References

• 1 Committee of National Pharmacopoeia. Pharmacopoeia of the Peopleʼs Republic of China. Beijing: Medicine Science and Technology Press of China; 2010: 916-918
• 2 Zheng H, Li Z, Mu R. The research progress of the pharmacological effects of traditional Chinese medicine Abrus cantoniensis Hance. Chinaʼs Foreign Trade 2011; 12: 380
• 3 Xiao BD. Ling Nan Cai Yao Lu (Collection of Drugs in South of the Five Ridges of China). Guangzhou: Guangzhou Science Press; 2009: 80
• 4 Li TS, Huang SY. Chemical components and clinical application of Abri herba. Chin J Exp Trad Med Form 2019; 25: 226-234
• 5 Yan WY, Han QJ, Guo PP, Wang CY, Zhang ZJ. Simultaneous detection of flavonoids, phenolic acids and alkaloids in Abri herba and Abri mollis herba using liquid chromatography tandem mass spectrometry. Phytochem Anal 2016; 27: 50-56
• 6 Liu ZW, Que ZL, Ye ZW, Zhang XQ, Wang H, Ye WC, Zhao SX. Chemical constituents from the aerial parts of Abrus mollis . Chin J Nat Med 2008; 6: 415-417
• 7 Hu XL, Niu YJ, Chen M, Feng JH, Shen W, Jiang ZZ, Zhang XQ, Ye WC, Xiong F, Wang H. Preventive effects of total flavonoid C-glycosides from Abrus mollis on nonalcoholic fatty liver disease through activating the PPARalpha signaling pathway. Planta Med 2019; 85: 678-688
• 8 Chen M, Wang T, Jiang ZZ, Shan C, Wang H, Wu MJ, Zhang S, Zhang Y, Zhang LY. Anti-inflammatory and hepatoprotective effects of total flavonoid C-glycosides from Abrus mollis extracts. Chin J Nat Med 2014; 12: 590-598
• 9 Atala E, Fuentes J, Wehrhahn MJ, Speisky H. Quercetin and related flavonoids conserve their antioxidant properties despite undergoing chemical or enzymatic oxidation. Food Chem 2017; 234: 479-485
• 10 Chen XM, Tait AR, Kitts DD. Flavonoid composition of orange peel and its association with antioxidant and anti-inflammatory activities. Food Chem 2017; 218: 15-21
• 11 Luo LY, Fan MX, Zhao HY, Li MX, Wu X, Gao WY. Pharmacokinetics and bioavailability of the isoflavones formononetin and ononin and their in vitro absorption in Ussing chamber and Caco-2 cell models. J Agri Food Chem 2018; 66: 2917-2924
• 12 Zhang W, Jiang S, Qian DW, Shang EX, Guan HL, Ren H, Zhu ZH, Duan JA. The interaction between ononin and human intestinal bacteria. Acta Pharm Sin 2014; 49: 1162-1168
• 13 Xiao JB, Högger P. Advance on the pharmacokinetics of natural bioactive polyphenols. Curr Drug Metab 2014; 15: 1-2
• 14 Xiao JB, Högger P. Metabolism of dietary flavonoids in liver microsomes. Curr Drug Metab 2013; 14: 381-391
• 15 Xiao J, Capanoglu E, Jassbi AR, Miron A. Advance on the flavonoid C-glycosides and health benefits. Crit Rev Food Sci Nutr 2016; 56: S29-S45
• 16 Sameera S, Said A, Ken N. Simulated gastrointestinal digestion and in vitro colonic fermentation of date (Phoenix dactylifera L.) seed polyphenols. Int J Food Sci Tech 2018; 53: 412-422
• 17 Cardinali A, Linsalata V, Lattanzio V, Ferruzzi MG. Verbascosides from olive mill waste water: assessment of their bioaccessibility and intestinal uptake using an in vitro digestion/Caco-2 model system. J Food Sci 2011; 76: 48-54
• 18 Fu SS, Augustin MA, Shen ZP, Ng K, Sanguansri L, Ajlouni S. Bioaccessibility of curcuminoids in buttermilk in simulated gastrointestinal digestion models. Food Chem 2015; 179: 52-59
• 19 Yang H, Zhai BT, Fan Y, Wang J, Sun J, Shi YJ, Guo DY. Intestinal absorption mechanisms of araloside A in situ single-pass intestinal perfusion and in vitro Caco-2 cell model. Biomed Pharmacother 2018; 106: 1563-1569
• 20 Wu AG, Zeng B, Huang MQ, Li SM, Chen JN, Lai XP. The absorption and transport of magnolol in Caco-2 cell model. Chin J Integr Med 2013; 19: 206-211
• 21 Zhu ML, Liang XL, Zhao LJ, Liao ZG, Zhao GW, Cao YC, Zhang J, Luo Y. Elucidation of the transport mechanism of baicalin and the influence of a Radix Angelicae Dahuricae extract on the absorption of baicalin in a Caco-2 cell monolayer model. J Ethnopharmacol 2013; 150: 553-559
• 22 Day AJ, DuPont MS, Ridley S, Rhodes M, Rhodes MJ, Morgan MR, Williamson G. Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver β-glucosidase activity. FEBS Lett 1998; 436: 71-75
• 23 Yokooji T. Role of ABC efflux transporters in the oral bioavailability and drug-induced intestinal toxicity. Yakugaku Zasshi 2013; 133: 815-822
• 24 Yokooji T, Murakami T, Yumoto R, Nagai J, Takano M. Role of intestinal efflux transporters in the intestinal absorption of methotrexate in rats. J Pharm Pharmacol 2007; 59: 1263-1270
• 25 Zhao J, Liang AH. Caco-2 cell model and its application in the absorption and transportation research of Chinese materia medica. Chin J Exp Trad Med Form 2009; 15: 79-82
• 26 Noach ABJ, Kurosaki Y, Blom-Roosemalen MCM, de Boer AG, Breimer DD. Cell-polarity dependent effect of chelation on the paracellular permeability of confluent Caco-2 cell monolayers. Int J Pharm 1993; 90: 229-237
• 27 Fagerholm U, Johansson M, Lennernas H. Comparison between permeability coefficients in rat and human jejunum. Pharm Res 1996; 13: 1336-1342
• 28 Pang KS. Modeling of intestinal drug absorption: roles of transporters and metabolic enzymes (for the Gillette Review Series). Drug Metab Dispos 2003; 31: 1507-1519
• 29 Boisset M, Botham RP, Haegele KD, Lenfant B, Pachot JI. Absorption of angiotensin II antagonists in Ussing chambers, Caco-2, perfused jejunum loop and in vivo: importance of drug ionisation in the in vitro prediction of in vivo absorption. Eur J Pharm Sci 2000; 10: 215-224
• 30 Estudante M, Morais JG, Soveral G, Benet LZ. Intestinal drug transporters: An overview. Adv Drug Deliv Rev 2013; 65: 1340-1356
• 31 Murakami T, Takano M. Intestinal efflux transporters and drug absorption. Expert Opin. Drug Metab Toxicol 2008; 4: 923-939
• 32 Liang XL, Zhao LJ, Liao ZG, Zhao GW, Zhang J, Chao YC, Yang M, Yin RL. Transport properties of puerarin and effect of Radix Angelicae Dahuricae extract on the transport of puerarin in Caco-2 cell model. J Ethnopharmacol 2012; 144: 677-682
• 33 Du HB, Wang H, Yu J, Liang CY, Ye WC, Li P. Enrichment and purification of total flavonoid C-glycosides from Abrus mollis extracts with macroporous resins. Ind Eng Chem Res 2012; 51: 7349-7354
• 34 Xie C, Veitch NV, Houghton PJ, Simmonds MS. Flavone C-glycosides from Viola yedoensis Makino. Chem Pharm Bull 2003; 51: 1204-1207
• 35 Xiong F, Wang H, Jiang Z, Huo M, Yan C, Zheng C, Gu N. Integrated pharmacokinetics and biodistribution of multiple flavonoid C-glycosides components in rat after oral administration of Abrus mollis extract and correlations with bio-effects. J Ethnopharmacol 2015; 163: 290-296
• 36 Versantvoort CH, Oomen AG, Van de Kamp E, Rompelberg CJ, Sips AJ. Applicability of an in vitro digestion model in assessing the bioaccessibility of mycotoxins from food. Food Chem Toxicol 2005; 43: 31-40
• 37 Kim HW, Oh SH, Kim N, Nakazawa E, Rhyu IJ. Rapid method for electron tomographic reconstruction and 3-dimensional modeling of the murine synapse using an automated fiducial marker-free system. Microsc Microanal 2013; 19: 182-187
• 38 Kimura O, Kotaki Y, Hamaue N, Haraguchi K, Endo T. Transcellular transport of domoic acid across intestinal Caco-2 cell monolayers. Food Chem Toxicol 2011; 49: 2167-2171
• 39 Stewart BH, Chan OH, Lu RH, Reyner EL, Schmid HL, Hamilton HW, Steinbaugh BA, Taylor MD. Comparison of intestinal permeabilities determined in multiple in vitro and in situ models: relationship to absorption in humans. Pharm Res 1995; 12: 693-699
• 40 Liu Y, Hu M. Absorption and metabolism of flavonoids in the Caco-2 cell culture model and a perused rat intestinal model. Drug Metab Dispos 2002; 30: 370-377
• 41 Doluisio JT, Billups NF, Dittert LW, Sugita ET, Swintosky JV. Drug absorption. I. An in situ rat gut technique yielding realistic absorption rates. J Pharm Sci 1969; 58: 1196-1200
• 42 Tian XJ, Yang XD, Wang K, Yang XW. The efflux of flavonoids morin, isorhamnetin-3-O-rutinoside and diosmetin-7-O-β-D-Xylopyranosyl-(1–6)-β-D-glucopyranoside in the human intestinal cell line Caco-2. Pharm Res 2006; 23: 1721-1728
• 43 Zhai L, Shi J, Xu W, Heinrich M, Wang J, Deng W. Ex vivo and in situ evaluation of “Dispelling-Wind” Chinese medicine herb-drugs on intestinal absorption of chlorogenic acid. Phytother Res 2015; 29: 1974-1981
• 44 National Institutes of Health. Guide for the Care and Use of Laboratory Animals. 8th ed. Washington DC: National Research Council of the National Academies Press; 2011
• 45 Zhou F, Huang WS, Li MQ, Zhong YH, Wang MM, Lu BY. Bioaccessibility and absorption mechanism of phenylethanoid glycosides using simulated digestion/Caco-2 intestinal cell models. J Agri Food Chem 2018; 66: 4630-4637
• 46 Wang H, Jiang ZZ, Du HB, Liang CY, Wang YC, Zhang MH, Li P. Simultaneous determination of 3 flavonoid C-glycosides in mice biosamples by HPLC-ESI-MS method after oral administration of Abrus mollis extract and its application to biodistribution studies. J Chromatogr B Analyt Technol Biomed Life Sci 2012; 903: 68-74