Role of Organic Solute Transporter Alpha/Beta in Hepatotoxic Bile Acid Transport and Drug Interactions

Abstract

Organic solute transporter (OST) alpha/beta is a key bile acid transporter expressed in various organs, including the liver under cholestatic conditions. However, little is known about the involvement of OST alpha/beta in bile acid-mediated drug-induced liver injury (DILI), a major safety concern in drug development. This study investigated whether OST alpha/beta preferentially transports more hepatotoxic, conjugated, primary bile acids and to what extent xenobiotics inhibit this transport. Kinetic studies with OST alpha/beta-overexpressing cells revealed that OST alpha/beta preferentially transported bile acids in the following order: taurochenodeoxycholate > glycochenodeoxycholate > taurocholate > glycocholate. The apparent half-maximal inhibitory concentrations for OST alpha/beta-mediated bile acid (5 mu M) transport inhibition by fidaxomicin, troglitazone sulfate, and ethinyl estradiol were: 210, 334, and 1050 mu M, respectively, for taurochenodeoxycholate; 97.6, 333, and 337 mu M, respectively, for glycochenodeoxycholate; 140, 265, and 527 mu M, respectively, for taurocholate; 59.8, 102, and 117 mu M, respectively, for glycocholate. The potential role of OST alpha/beta in hepatocellular glycine-conjugated bile acid accumulation and cholestatic DILI was evaluated using sandwich-cultured human hepatocytes (SCHH). Treatment of SCHH with the farnesoid X receptor agonist chenodeoxycholate (100 mu M) resulted in substantial OST alpha/beta induction, among other proteomic alterations, reducing glycochenodeoxycholate and glycocholate accumulation in cells+bile 4.0- and 4.5-fold, respectively. Treatment of SCHH with troglitazone and fidaxomicin together under cholestatic conditions resulted in increased hepatocellular toxicity compared with either compound alone, suggesting that OST alpha/beta inhibition may accentuate DILI. In conclusion, this study provides insights into the role of OST alpha/beta in preferential disposition of bile acids associated with hepatotoxicity, the impact of xenobiotics on OST alpha/beta-mediated bile acid transport, and the role of this transporter in SCHH and cholestatic DILI.