Transport by OATP1B1 and OATP1B3 Enhances the Cytotoxicity of Epigallocatechin 3‑<i>O</i>‑Gallate and Several Quercetin Derivatives

Organic anion transporting polypeptides (OATPs) 1B1 and 1B3 are transporters that are expressed selectively in human hepatocytes under normal conditions. OATP1B3 is also expressed in certain cancers. Flavonoids such as green tea catechins and quercetin glycosides have been shown to modulate the function of some OATPs. In the present study, the extent to which six substituted quercetin derivatives (<b>1</b>–<b>6</b>) affected the function of OATP1B1 and OATP1B3 was investigated. Uptake of the radiolabeled model substrates estradiol 17β-glucuronide, estrone 3-sulfate, and dehydroepiandrosterone sulfate (DHEAS) was determined in the absence and presence of compounds <b>1</b>–<b>6</b> using Chinese hamster ovary (CHO) cells stably expressing either OATP1B1 or OATP1B3. Several of compounds <b>1</b>–<b>6</b> inhibited OATP-mediated uptake of all three model substrates, suggesting that they could also be potential substrates. Compound <b>6</b> stimulated OATP1B3-mediated estradiol 17β-glucuronide uptake by increasing the apparent affinity of OATP1B3 for its substrate. Cytotoxicity assays demonstrated that epigallocatechin 3-<i>O</i>-gallate (EGCG) and most of compounds <b>1</b>–<b>6</b> killed preferentially OATP-expressing CHO cells. EGCG, <b>1</b>, and <b>3</b> were the most potent cytotoxic compounds, with EGCG and <b>3</b> selectively killing OATP1B3-expressing cells. Given that OATP1B3 is expressed in several cancers, EGCG and some of the quercetin derivatives studied might be promising lead compounds for the development of novel anticancer drugs