Transport in Caco-2 Cell Monolayers of Antidiabetic Cucurbitane Triterpenoids from Momordica charantia Fruits

Abstract

Bitter melon, the fruit of Momordica charantia L. (Cucurbitaceae), is a widely-used treatment for diabetes in traditional medicine systems throughout the world. Various compounds have been shown to be responsible for this reputed activity, and, in particular, cucurbitane triterpenoids are thought to play a significant role. The objective of this study was to investigate the gastrointestinal transport of a triterpenoid-enriched n-butanol extract of M. charantia using a two-compartment transwell human intestinal epithelial cell Caco-2 monolayer system, simulating the intestinal barrier. Eleven triterpenoids in this extract were transported from the apical to basolateral direction across Caco-2 cell monolayers, and were identified or tentatively identified by HPLC-TOF-MS. Cucurbitane triterpenoids permeated to the basolateral side with apparent permeability coefficient (P _app) values for 3-β-7-β,25-trihydroxycucurbita-5,23(E)-dien-19-al and momordicines I and II at 9.02 × 10⁻⁶, 8.12 × 10⁻⁶, and 1.68 × 10⁻⁶ cm/s, respectively. Also, small amounts of these triterpenoids were absorbed inside the Caco-2 cells. This is the first report of the transport of the reputed antidiabetic cucurbitane triterpenoids in human intestinal epithelial cell monolayers. Our findings, therefore, further support the hypothesis that cucurbitane triterpenoids from bitter melon may explain, at least in part, the antidiabetic activity of this plant in vivo.

Key words

Momordica charantia - Cucurbitaceae - bitter melon - cucurbitane triterpenoid - Caco-2 cells - diabetes treatments

^* These authors contributed equally to this work.

• References

• 1 Yuwai KE, Rao KS, Kaluwin C, Jones GP, Rivett DE. Chemical composition of Momodica charantia L. fruits. J Agric Food Chem 1991; 39: 1762-1763
• 2 Ma J, Whittaker P, Keller AC, Mazzola EP, Pawar RS, White KD, Callahan JH, Kennelly EJ, Krynitsky AJ, Rader JI. Cucurbitane-type triterpenoids from Momordica charantia. Planta Med 2010; 76: 1758-1761
• 3 Basch E, Gabardi S, Ulbricht C. Bitter melon (Momordica charantia): a review of efficacy and safety. Am J Health Syst Pharm 2003; 60: 356-359
• 4 Akihisa T, Higo N, Tohuda H, Ukiya M, Akazawa H, Tochigi Y, Kimura Y, Suzuki T, Nishino H. Cucurbitane-type triterpenoids from the fruits of Momordica charantia and their cancer chemopreventive effects. J Nat Prod 2007; 70: 1233-1239
• 5 Liu Y, Ali Z, Khan IA. Cucurbitane-type triterpene glycosides from the fruits of Momordica charantia . Planta Med 2008; 74: 1291-1294
• 6 Okabe H, Miyahara Y, Yamaguchi T, Miyahara K, Kawasaki T. Studies on the constituents of Momordica charantia L. I. Isolation and characterization of momordicosides A and B, glycosides of a pentahydroxy-cucurbitane triterpene. Chem Pharm Bull 1980; 28: 2753-2762
• 7 Miyahara Y, Okabe H, Yamaguchi T. Studies on the constituents of Momordica charantia L. II. Isolation and characterization of minor seed glycosides, momordicosides C, D and E. Chem Pharm Bull 1981; 29: 1561-1566
• 8 Fatope MO, Takeda Y, Yamashita H, Okabe H, Yamaguchi T. New cucurbitane triterpenoids from Momordica charantra . J Nat Prod 1990; 53: 1491-1497
• 9 Chang CI, Chen CR, Liao YW, Cheng HL, Chen YC, Chou CH. Cucurbitane-type triterpenoids from the stems of Momordica charantia . J Nat Prod 2008; 71: 1327-1330
• 10 Chen J, Tian R, Qiu M, Lu L, Zheng Y, Zhang Z. Trinorcucurbitane and cucurbitane triterpenoids from the roots of Momordica charantia . Phytochemistry 2008; 69: 1043-1048
• 11 Chen JC, Chiu MH, Nie RL, Cordell GA, Qiu SX. Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat Prod Rep 2005; 22: 386-399
• 12 Keller AC, Ma J, Kavalier A, He K, Brillantes AB, Kennelly EJ. Saponins from the traditional medicinal plant Momordica charantia stimulate insulin secretion in vitro . Phytomedicine 2011; 19: 32-37
• 13 Harinantenaina L, Tanaka M, Takaoka S, Oda M, Mogami O, Uchida M, Asakawa Y. Momordica charantia constituents and antidiabetic screening of the isolated major compounds. Chem Pharm Bull 2006; 54: 1017-1021
• 14 Akhtar MS, Athar MA, Yaqub M. Effect of Momordica charantia on blood glucose level of normal and alloxan-diabetic rabbits. Planta Med 1981; 42: 205-212
• 15 Mahomoodally MF, Fakim AG, Subratty AH. Momordica charantia extracts inhibit uptake of monosaccharide and amino acid across rat everted gut sacs in-vitro . Biol Pharm Bull 2004; 27: 216-218
• 16 Mahomoodally MF, Gurib-Fakim A, Subratty AH. Experimental evidence for in vitro fluid transport in the presence of a traditional medicinal fruit extract across rat everted intestinal sacs. Fundam Clin Pharmacol 2005; 19: 87-92
• 17 Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun 1991; 175: 880-885
• 18 Yee S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man–fact or myth. Pharm Res 1997; 14: 763-766
• 19 Konishi T, Satsu H, Hatsugai Y, Aizawa K, Inakuma T, Nagata S, Sakuda SH, Nagasawa H, Shimizu M. Inhibitory effect of a bitter melon extract on the P-glycoprotein activity in intestinal Caco-2 cells. Br J Pharmacol 2004; 143: 379-387
• 20 Hsiao PC, Liaw CC, Hwang SY, Cheng HL, Zhang LJ, Shen CC, Hsu FL, Kuo YH. Antiproliferative and hypoglycemic cucurbitane-type glycosides from the fruits of Momordica charantia . J Agri Food Chem 2013; 61: 2979-2986
• 21 Shimizu K, Ozeki M, Iino A, Nakajyo S, Urakawa N, Atsuchi M. Structure-activity relationships of triterpenoid derivatives extracted from Gymnema inodorum leaves on glucose absorption. Jpn J Pharmacol 2001; 86: 223-229
• 22 Limtrakul P, Khantamat O, Pintha K. Inhibition of P-glycoprotein activity and reversal of cancer multidrug resistance by Momordica charantia extract. Cancer Chemother Pharmacol 2004; 54: 525-530
• 23 Pitchakarn P, Ohnuma S, Pintha K, Pompimon W, Ambudkar SV, Limtrakul P. Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance. J Nutr Biochem 2012; 23: 76-84
• 24 Welihinda J, Karunanayake EH, Sheriff MH, Jayasinghe KS. Effect of Momordica charantia on the glucose tolerance in maturity onset diabetes. J Ethnopharmacol 1986; 17: 277-282
• 25 Srivastava Y, Venkatakrishna-Bhatt H, Verma Y, Venkaiah K, Raval BH. Antidiabetic and adaptogenic properties of Momordica charantia extract. An experimental and clinical evaluation. Phytother Res 1993; 7: 285-289
• 26 Dans AM, Villarruz MV, Jimeno CA, Javelosa MA, Chua J, Bautista R, Velez GG. The effect of Momordica charantia capsule preparation on glycemic control in type 2 diabetes mellitus needs further studies. J Clin Epidemiol 2007; 60: 554-559
• 27 Popovich DG, Li L, Zhang W. Bitter melon (Momordica charantia) triterpenoid extract reduces preadipocyte viability, lipid accumulation and adiponectin expression in 3T3-L1 cells. Food Chem Toxicol 2010; 48: 1619-1626
• 28 Wu SB, Yue GGL, Keller AC, To MH, Lau CBS, Kennelly EJ. Transport in Caco-2 cell monolayers of cucurbitane triterpenoids from Momordica charantia . Planta Med 2012; 78: PD81
• 29 Yue GGL, Cheng SW, Yu H, Xu ZS, Lee JKM, Hon PM, Lee MYH, Kennelly EJ, Deng G, Yeung SK, Cassileth BR, Fung KP, Leung PC, Lau CBS. The role of turmerones on curcumin transportation and P-glycoprotein activities in intestinal Caco-2 cells. J Med Food 2012; 15: 242-252