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

James J Beaudoin et al., Toxicological Sciences (2020) - PMID: 32294204

Product(s) used in this publication:  Reference Peptides for Targeted Proteomics - SpikeTides™ & SpikeMix™

Abstract

Organic solute transporter (OST) α/β is a key bile acid transporter expressed in various organs, including the liver under cholestatic conditions. However, little is known about the involvement of OSTα/β in bile acid-mediated drug-induced liver injury (DILI), a major safety concern in drug development. This study investigated whether OSTα/β preferentially transports more hepatotoxic conjugated primary bile acids, and to what extent xenobiotics inhibit this transport. Kinetic studies with OSTα/β-overexpressing cells revealed that OSTα/β preferentially transported bile acids in the following order: taurochenodeoxycholate>glycochenodeoxycholate>taurocholate>glycocholate. The apparent half-maximal inhibitory concentrations for OSTα/β-mediated bile acid (5µM) transport inhibition by fidaxomicin, troglitazone sulfate and ethinyl estradiol were: 210, 334 and 1050µM, respectively, for taurochenodeoxycholate; 97.6, 333 and 337µM, respectively, for glycochenodeoxycholate; 140, 265 and 527µM, respectively, for taurocholate; 59.8, 102 and 117µM, respectively, for glycocholate. The potential role of OSTα/β 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 (100µM) resulted in substantial OSTα/β 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 OSTα/β inhibition may accentuate DILI. In conclusion, this study provides insights into the role of OSTα/β in preferential disposition of bile acids associated with hepatotoxicity, the impact of xenobiotics on OSTα/β-mediated bile acid transport, and the role of this transporter in SCHH and cholestatic DILI.

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