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

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