Effects of plant sterols on human multidrug transporters ABCB1 and ABCC1

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Abstract

The effects of dietary plant sterols on human drug efflux transporters P-glycoprotein (P-gp, ABCB1) and multidrug resistance protein 1 (MRP1, ABCC1) were investigated using P-gp-overexpressing human carcinoma KB-C2 cells and human MRP1 gene-transfected KB/MRP cells. The effects of natural phytosterols found in foods, herbs, and dietary supplements such as β-sitosterol, campesterol, stigmasterol, fucosterol, and z-guggulsterone were investigated. The accumulation of daunorubicin or rhodamine 123, fluorescent substrates of P-gp, increased in the presence of guggulsterone in KB-C2 cells. The efflux of rhodamine 123 from KB-C2 cells was inhibited by guggulsterone. Guggulsterone also increased the accumulation of calcein, a fluorescent substrate of MRP1, in KB/MRP cells. The ATPase activities of P-gp and MRP1 were stimulated by guggulsterone. These results suggest that guggulsterone, a natural dietary hypolipidemic agent have dual inhibitory effects on P-gp and MRP1 and the potencies to cause food–drug interactions.

Section snippets

Materials and methods

Materials. Dulbecco’s modified Eagle’s medium (D-MEM) and fetal bovine serum (FBS) were purchased from Invitrogen Corp. (Carlsbad, CA). Colchicine, daunorubicin, rhodamine 123, and indomethacin were obtained from Wako Pure Chemical Industries, Ltd (Osaka, Japan). Calcein-AM was provided by Dojindo Laboratories (Kumamoto, Japan). β-Sitosterol, stigmasterol, β-sitostanol, β-cholestanol, N-ethylmaleimide (NEM), and glutathione (GSH) were purchased from Sigma Chemical (St. Louis, MO). MK-571 was

Effects of plant sterols on daunorubicin accumulation in KB-C2 cells

Fig. 1A shows the accumulation of daunorubicin in KB-C2 cells in the presence of 50 μM dietary phytosterols. Guggulsterone increased the cellular accumulation of daunorubicin, which indicates that this phytosterol inhibit the P-gp-mediated efflux of daunorubicin. In contrast, β-sitosterol, campesterol, stigmasterol, β-sitostanol, β-cholestanol, and fucosterol had no effect on the cellular accumulation of daunorubicin. Higher concentrations (100 μM) of β-sitosterol, campesterol, stigmasterol,

Discussion

It is now established that nutrients and phytochemicals can have pronounced impacts on drug absorption, disposition and elimination [15]. Grapefruit juice and the herbal mild antidepressant St. John’s wort (Hypericum perforatum) are a well known example of a food–drug interaction. Some dietary phytochemicals, such as the bioflavonoid quercetin, tea catechins, and ginsenosides, have been evaluated for their potential P-gp inhibitory effects [16], [17]. We have previously reported the inhibitory

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