Effects of Schisandra Lignans on P-Glycoprotein-Mediated Drug Efflux in Human Intestinal Caco-2 Cells

Abstract

Schisandra fruits (Schisandraceae) are often used in traditional medicine and can be taken concomitantly with conventional medicine. In this study, the effects of dibenzocyclooctadiene lignans from Schizandra chinensis on P-gp-mediated efflux were examined to investigate a possible interaction with P-gp substrates. The cellular accumulation of rhodamine-123 in Caco-2 cells was measured with 12 Schisandra lignans. Most compounds resulted in slight or moderate increases of rhodamin-123 cellular uptake, indicating their P-gp inhibitory activity. Among them, deoxyschizandrin exhibited the most potent effect on the accumulation of rhodamine-123. Subsequently, bidirectional transports of digoxin and rhodamine-123 in Caco-2 cells were determined with deoxyschizandrin, the most active compound for the rhodamine-123 assay. In the bidirectional transport study, apical-to-basal (A-to-B) transports of digoxin and rhodamine-123 were increased, whereas basal-to-apical (B-to-A) transports were decreased by deoxyschizandrin in concentration- and time-dependent manners. At 50 μM of deoxyschizandrin, the transport ratios (B-A/A-B) for digoxin and rhodamine-123 were 2.2 and 2.1 compared with the control ratios of 15.2 and 12.2, respectively. These results demonstrated that deoxyschizandrin effectively inhibited the P-gp-mediated efflux in Caco-2 cells, suggesting they could potentially increase the absorption of drugs that can act as a P-gp substrate.

Key words

Schisandra chinensis - Schisandraceae - P-glycoprotein - dibenzocyclooctadiene lignans - deoxyschizandrin - Caco-2 cells

References

• 1 Chang G T, Kang S K, Kim J H, Chung K H, Chang Y C, Kim C H. Inhibitory effect of the Korean herbal medicine, Dae-Jo-Whan, on platelet-activating factor-induced platelet aggregation.  J Ethnopharmacol. 2005;  102 430-9.
• 2 Wagner H, Bauer R, Peigen X, Jianming C, Nenninger A. Fructus Schisandrae (Wuweizi).  Chinese Drug Monographs and Analysis. 1996;  1 1-8.
• 3 Chinese herbal m edicine, Materia M edica. Seattle; Eastland Press 1990.
• 4 Hancke J L, Burgos R A, Ahumada F. Schisandra chinensis (Turcz.) Baill.  Fitoterapia. 1999;  70 451-71.
• 5 Seo S M, Lee H J, Park Y, Lee M K, Park J I, Paik K H. Lignans from the fruit of Schizandra chinensis and their inhibitory effects on dopamine content in PC12 cells.  Nat Prod Sci. 2004;  10 104-8.
• 6 Choi Y W, Takamatsu S, Khan S I, Srinivas P V, Ferreira D, Zhao J. et al . Schisandrene, a dibenzocyclooctadiene lignan from Schisandra chinensis: structure-antioxidant activity relationships of dibenzocyclooctadiene lignans.  J Nat Prod. 2006;  69 356-9.
• 7 Opletal L, Sovova H, Bartlova M. Dibenzo[a,c]cyclooctadiene lignans of the genus Schisandra: importance, isolation and determination.  J Chromatogr B. 2004;  812 357-71.
• 8 Chen D F, Zhang S X, Kozuka M, Sun Q Z, Feng J, Wang Q. et al . Interiotherins C and D, two new lignans from Kadsura interior and antitumor-promoting effects of related neolignans on Epstein-Barr virus activation.  J Nat Prod. 2002;  65 242-5.
• 9 Ohtaki Y, Hida T, Hiramatsu K, Kanitani M, Ohshima T, Nomura M. et al . Deoxycholic acid as an endogenous risk factor for hepatocarcinogenesis and effects of gomisin A, a lignan component of Schizandra fruits.  Anticancer Res. 1996;  16 751-5.
• 10 Nomura M, Ohtaki Y, Hida T, Aizawa T, Wakita H, Miyamoto K. Inhibition of early 3-methyl-4-dimethylaminoazobenzene-induced hepatocarcinogenesis by gomisin A in rats.  Anticancer Res. 1994;  14 1967-71.
• 11 Wu M D, Huang R L, Kuo L M, Hung C C, Ong C W, Kuo Y H. The anti-HBsAg (human type B hepatitis, surface antigen) and anti-HBeAg (human type B hepatitis, e antigen) C18 dibenzocyclooctadiene lignans from Kadsura matsudai and Schizandra arisanensis .  Chem Pharm Bull. 2003;  51 1233-6.
• 12 Chen D F, Zhang S X, Xie L, Xie J X, Chen K, Kashiwada Y. et al . Anti-AIDS agents-XXVI. Structure-activity correlations of gomisin-G-related anti-HIV lignans from Kadsura interior and of related synthetic analogues.  Bioorg Med Chem. 1997;  5 1715-23.
• 13 Lu H, Liu G T. Anti-oxidant activity of dibenzocyclooctene lignans isolated from Schisandraceae.  Planta Med. 1992;  58 311-3.
• 14 Zhao B L, Li X J, Liu G T, Jia W Y, Xin W J. Scavenging effect of schizandrins on active oxygen radicals.  Cell Biol Int Rep. 1990;  14 99-109.
• 15 Yasukawa K, Ikeya Y, Mitsuhashi H, Iwasaki M, Aburada M, Nakagawa S. et al . Gomisin A inhibits tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin.  Oncology. 1992;  49 68-71.
• 16 Qiangrong P, Wang T, Lu Q, Hu X. Schisandrin B - A novel inhibitor of P-glycoprotein.  Biochem Biophys Res Commun. 2005;  335 406-11.
• 17 Ambudkar S V, Dey S, Hrycyna C A, Ramachandra M, Pastan I, Gottesman M M. Biochemical, cellular, and pharmacological aspects of the multidrug transporter.  Annu Rev Pharmacol Toxicol. 1999;  39 361-98.
• 18 Luo F R, Paranjpe P V, Guo A, Rubin E, Sinko P. Intestinal transport of irinotecan in Caco-2 cells and MDCK II cells overexpressing efflux transporters Pgp, cMOAT, and MRP1.  Drug Metab Dispos. 2002;  30 763-70.
• 19 Fugh-Berman A. Herb-drug interactions.  Lancet. 2000;  355 134-8.
• 20 Fugh-Berman A, Ernst E. Herb-drug interactions: review and assessment of report reliability.  Br J Clin Pharmacol. 2001;  52 587-95.
• 21 Hu Z, Yang X, Ho P C, Chan S Y, Heng P W, Chan E. et al . Herb-drug interactions: a literature review.  Drugs. 2005;  65 1239-82.
• 22 Evans A M. Influence of dietary components on the gastrointestinal metabolism and transport of drugs.  Ther Drug Monit. 2000;  22 131-6.
• 23 Ioannides C. Pharmacokinetic interactions between herbal remedies and medicinal drugs.  Xenobiotica. 2002;  32 451-78.
• 24 Walter-Sack I, Klotz U. Influence of diet and nutritional status on drug metabolism.  Clin Pharmacokinet. 1996;  31 47-64.
• 25 Wilkinson G R. The effects of diet, aging and disease-states on presystemic elimination and oral drug bioavailability in humans.  Adv Drug Deliv Rev. 1997;  27 129-59.
• 26 Zhou S, Gao Y, Jiang W, Huang M, Xu A, Paxton J W. Interactions of herbs with cytochrome P450.  Drug Metab Rev. 2003;  35 35-98.
• 27 Laska D A, Houchins J O, Pratt S E, Horn J, Xia X, Hanssen B R. et al . Characterization and application of a vinblastine-selected Caco-2 cell line for evaluation of p-glycoprotein.  In Vitro Cell Dev Biol Anim. 2002;  38 401-10.
• 28 Iwata H, Tezuka Y, Usia T, Kadota S, Hiratsuka A, Watabe T. Inhibition of human liver microsomal CYP3A4 and CYP2D6 by extracts from 78 herbal medicines.  J Trad Med. 2004;  21 42-50.
• 29 Iwata H, Tezuka Y, Kadota S, Hiratsuka A, Watabe T. Identification and characterization of potent CYP3A4 inhibitors in Schizandra fruit extract.  Drug Metab Dispos. 2004;  32 1351-8.
• 30 Wacher V J, Wu C Y, Benet L Z. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy.  Mol Carcinog. 1995;  13 129-34.
• 31 Cummins C L, Jacobsen W, Benet L Z. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4.  J Pharmacol Exp Ther. 2002;  300 1036-45.