Use of a Bile Salt Export Pump Knockdown Rat Susceptibility Model to Interrogate Mechanism of Drug-Induced Liver Toxicity. (23rd March 2019)

• Record Type: Journal Article
• Authors: Li, Yutai; Evers, Raymond; Hafey, Michael J; Cheon, Kyeongmi; Duong, Hong; Lynch, Donna; LaFranco-Scheuch, Lisa; Pacchione, Stephen; Tamburino, Alex M; Tanis, Keith Q; Geddes, Kristin; Holder, Daniel; Zhang, Nanyan Rena; Kang, Wen; Gonzalez, Raymond J; Galijatovic-Idrizbegovic, Alema; Pearson, Kara M; Lebron, Jose A; Glaab, Warren E; Sistare, Frank D
• Is Part Of: Toxicological sciences. Volume 170:Number 1(2019)
• Page Start: 180
• Page End: 198
• Publication Date: 2019-03-23
• Subjects: bile acids -- bile salt export pump (BSEP) -- knockdown -- liquid chromatography-mass spectrometry (LC-MS) -- biomarkers -- transporters -- microbiome; Toxicology -- Periodicals; Toxicology -- Periodicals; Toxicology; Periodicals; 615.9
• DOI: 10.1093/toxsci/kfz079
• Languages: English
• ISSNs: 1096-6080

Abstract

Abstract: Inhibition of the bile salt export pump (BSEP) may be associated with clinical drug-induced liver injury, but is poorly predicted by preclinical animal models. Here we present the development of a novel rat model using siRNA knockdown (KD) of Bsep that displayed differentially enhanced hepatotoxicity to 8 Bsep inhibitors and not to 3 Bsep noninhibitors when administered at maximally tolerated doses for 7 days. Bsep KD alone resulted in 3- and 4.5-fold increases in liver and plasma levels, respectively, of the sum of the 3 most prevalent taurine conjugated bile acids (T3-BA), approximately 90% decrease in plasma and liver glycocholic acid, and a distinct bile acid regulating gene expression pattern, without resulting in hepatotoxicity. Among the Bsep inhibitors, only asunaprevir and TAK-875 resulted in serum transaminase and total bilirubin increases associated with increases in plasma T3-BA that were enhanced by Bsep KD. Benzbromarone, lopinavir, and simeprevir caused smaller increases in plasma T3-BA, but did not result in hepatotoxicity in Bsep KD rats. Bosentan, cyclosporine A, and ritonavir, however, showed no enhancement of T3-BA in plasma in Bsep KD rats, as well as Bsep noninhibitors acetaminophen, MK-0974, or clarithromycin. T3-BA findings were further strengthened through monitoring TCA-d4 converted from cholic acid-d4 overcoming interanimal variability in endogenous bile acids. Bsep KD also altered liver and/or plasma levels of asunaprevir, TAK-875, TAK-875 acyl-glucuronide, benzbromarone, and bosentan. The Bsep KD rat model has revealed differences in the effects on bile acid homeostasis among Bsep inhibitors that can best be monitored using measures of T3-BA and TCA-d4 in plasma. However, the phenotype caused by Bsep inhibition is complex due to the involvement of several compensatory mechanisms.