Transport of Schisandra chinensis extract and its biologically-active constituents across Caco-2 cell monolayers — an in-vitro model of intestinal transport

Abstract

We have determined the intestinal transport of Schisandra chinensis extract and its lignans (gomisin A, gomisin N and schisandrin C) in the Caco-2 cell monolayer model. The transport across monolayers was examined for 2 h in absorptive and secretory directions. Quantitation of lignans was performed by HPLC. Out of the three lignans, gomisin A exhibited bi-directional transport, with P(app) values in the range of 25-29 x 10(-6) cm s(-1), indicating a passive diffusion. Gomisin N, mixture and Schisandra extract displayed a higher transport in the secretory direction with efflux ratios in the range of 2.2-5.2. The efflux was decreased in the presence of inhibitors of multidrug resistance protein (MRP) transporter (MK-571) and P-glycoprotein (verapamil) indicating a possible involvement of an efflux pump and MRP in the transport of Schisandra lignans. Poor transport of schisandrin C was observed which could not be quantitated. The permeability of gomisin A in the isolated form was significantly different compared with the mixture or extract.

Inhibitory effects of schisandrin A and schisandrin B on CYP3A activity

“…The active ingredients in the alkaloid fraction of the decoction were identified and the water extract of schisandra fruit significantly inhibited rat CYP3A in vitro in a concentration-dependent manner, with an IC 50 of 123 µg/mL, which was similar to the value for inhibition of erythromycin N-demethylation in human liver microsomes (13). It has also been found that several constituents, gomisins B, C, G and N and γ-shizandrin, isolated from Schisandra sphenanthera can interact with CYP3A4 (13)(14)(15)(16).…”

Gomisin A is a Novel Isoform-Specific Probe for the Selective Sensing of Human Cytochrome P450 3A4 in Liver Microsomes and Living Cells

“…Because of toxicity, the application of bufalin in measuring CYP3A4 activity in living cells is limited. Additionally, GA exhibits high membrane permeability with a passive diffusion manner [45], which provides the possibility of performing a cell-based assay. The CYP3A4 mRNA level was significantly upregulated in the rifampin-treated group, while the CYP3A5 mRNA level was not remarkably induced, possibly because CYP3A5 is far less susceptible to induction than CYP3A4 [46].…”

Inhibitory Effects of Continuous Ingestion of Schisandrin A on CYP3A in the Rat

“…Based on these results, we suggested that the clinically beneficial drug interaction of S. sphenanthera is likely a result of its inhibition of CYP3A4. Consistent with this hypothesis, a number of recent in vitro studies also suggest that the components isolated from S. chinensis or S. sphenanthera are capable of altering CYP activity [10][11][12]. …”

“…Based on these results, we suggested that the clinically beneficial drug interaction of S. sphenanthera is likely a result of its inhibition of CYP3A4. Consistent with this hypothesis, a number of recent in vitro studies also suggest that the components isolated from S. chinensis or S. sphenanthera are capable of altering CYP activity [10][11][12]. In recent years, several CYP3A4 substrates have been proposed in the literature as metabolic probes to evaluate the catalytic activity of CYP3A4 in vivo and in vitro, including testosterone, MDZ and 7-benzyloxy-4-trifluoromethylcoumarin.…”