Received for publication November 1, 2007.
Revised April 21, 2008.
Accepted for publication April 22, 2008.

Inhibitory effects of terpenoids on multidrug resistance-associated protein 2- and breast cancer resistance protein-mediated transport

Abstract

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--D-glucuronide (E₂17G) into membrane vesicles collected by a rapid filtration technique. The effects of (R)-(+)-citronellal, (S)-(-)--citronellol, -terpinene, terpinolene, (-)--pinene, abietic acid and glycyrrhetic acid on the intravesicular accumulation of [³H]E₂17G were examined. Large decreases in the [³H]E₂17G accumulation into vesicles from MRP2-expressing Sf9 cells were observed in the presence of glycyrrhetic acid and abietic acid, and their IC₅₀ values were about 20 µM and 51 µM, respectively. [³H]E₂17G 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]E₂17G. 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.

Key words: ABC transporters, drug interactions, multi-drug resistance