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SHORT COMMUNICATION

Inhibitory Effects of Terpenoids on Multidrug Resistance-Associated Protein 2- and Breast Cancer Resistance Protein-Mediated Transport

Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan (N.Y., J.K.); Department of Pharmacy, Toyama University Hospital, University of Toyama, Toyama, Japan (N.Y., I.A.); Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan (T.T., H.S.); and Department of Pharmacy, Tokyo Postal Service Agency Hospital, Chiyoda-ku, Tokyo, Japan (Y.Y.)

The possibility of interactions between natural products/supplements and conventional prescription medicines is one of the most important issues in pharmacotherapeutic safety. Recently, we reported that some terpenoids such as (R)-(+)-citronellal and glycyrrhetic acid, which are present in herbal medicines, can act as inhibitors of P-glycoprotein (MDR1/ABCB1). In the present study, the effects of seven terpenoids on multidrug resistance-associated protein 2 (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2)-mediated transport were investigated in vitro. Membrane vesicles were prepared from MRP2 cDNA transfected Sf9 cells derived from pupal ovarian tissue of Spodoptera frugiperda, a fall armyworm, and BCRP cDNA transfected LLC-PK1 cells derived from porcine kidney. MRP2- or BCRP-mediated efflux transport was measured as ATP-dependent accumulation of [³H]estradiol 17-β-D-glucuronide (E₂17βG) into membrane vesicles collected by a rapid filtration technique. The effects of (R)-(+)-citronellal, (S)-(-)-β-citronellol, -terpinene, terpinolene, (-)-β-pinene, abietic acid, and glycyrrhetic acid on the intravesicular accumulation of [³H]E₂17βG were examined. Large decreases in the [³H]E₂17βG accumulation into vesicles from MRP2-overexpressing Sf9 cells were observed in the presence of glycyrrhetic acid and abietic acid, and their IC₅₀ values were about 20 and 51 µM, respectively. [³H]E₂17βG accumulation into vesicles from BCRP-overexpressing LLC-PK1 cells was suppressed by only glycyrrhetic acid, with an IC₅₀ value of about 39 µM. Other terpenoids used in this study did not alter the ATP-dependent accumulation of [³H]E₂17βG. These findings suggest that glycyrrhetic acid and abietic acid can potently inhibit MRP2- or BCRP-mediated membrane transport and may interact with their substrates in pharmacokinetic processes.