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However, little is known about the involvement of OST\u03b1\/\u03b2 in bile acid-mediated drug-induced liver injury (DILI), a major safety concern in drug development. This study investigated whether OST\u03b1\/\u03b2 preferentially transports more hepatotoxic, conjugated, primary bile acids and to what extent xenobiotics inhibit this transport. Kinetic studies with OST\u03b1\/\u03b2-overexpressing cells revealed that OST\u03b1\/\u03b2 preferentially transported bile acids in the following order: taurochenodeoxycholate &amp;gt; glycochenodeoxycholate &amp;gt; taurocholate &amp;gt; glycocholate. The apparent half-maximal inhibitory concentrations for OST\u03b1\/\u03b2-mediated bile acid (5\u2009\u00b5M) transport inhibition by fidaxomicin, troglitazone sulfate, and ethinyl estradiol were: 210, 334, and 1050\u2009\u00b5M, respectively, for taurochenodeoxycholate; 97.6, 333, and 337\u2009\u00b5M, respectively, for glycochenodeoxycholate; 140, 265, and 527\u2009\u00b5M, respectively, for taurocholate; 59.8, 102, and 117\u2009\u00b5M, respectively, for glycocholate. The potential role of OST\u03b1\/\u03b2 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\u2009\u00b5M) resulted in substantial OST\u03b1\/\u03b2 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\u03b1\/\u03b2 inhibition may accentuate DILI. In conclusion, this study provides insights into the role of OST\u03b1\/\u03b2 in preferential disposition of bile acids associated with hepatotoxicity, the impact of xenobiotics on OST\u03b1\/\u03b2-mediated bile acid transport, and the role of this transporter in SCHH and cholestatic DILI.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa052","type":"journal-article","created":{"date-parts":[[2020,4,9]],"date-time":"2020-04-09T03:42:30Z","timestamp":1586403750000},"page":"34-45","source":"Crossref","is-referenced-by-count":24,"title":["Role of Organic Solute Transporter Alpha\/Beta in Hepatotoxic Bile Acid Transport and Drug Interactions"],"prefix":"10.1093","volume":"176","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6926-8844","authenticated-orcid":false,"given":"James J","family":"Beaudoin","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9977-1184","authenticated-orcid":false,"given":"Jacqueline","family":"Bezen\u00e7on","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6960-7757","authenticated-orcid":false,"given":"Noora","family":"Sj\u00f6stedt","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1848-0121","authenticated-orcid":false,"given":"John K","family":"Fallon","sequence":"additional","affiliation":[{"name":"Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1945-4929","authenticated-orcid":false,"given":"Kim L R","family":"Brouwer","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,15]]},"reference":[{"key":"2020111008422859900_kfaa052-B1","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.ejps.2017.02.011","article-title":"Identification of novel MRP3 inhibitors based on computational models and validation using an in vitro membrane vesicle assay","volume":"103","author":"Ali","year":"2017","journal-title":"Eur. 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