TY - JOUR T1 - Inhibitory Effects of Terpenoids on Multidrug Resistance-Associated Protein 2- and Breast Cancer Resistance Protein-Mediated Transport JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1206 LP - 1211 DO - 10.1124/dmd.107.019513 VL - 36 IS - 7 AU - Naoko Yoshida AU - Tappei Takada AU - Yoshikazu Yamamura AU - Isao Adachi AU - Hiroshi Suzuki AU - Junichi Kawakami Y1 - 2008/07/01 UR - http://dmd.aspetjournals.org/content/36/7/1206.abstract N2 - 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, α-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. The American Society for Pharmacology and Experimental Therapeutics ER -