PMID- 30903168 OWN - NLM STAT- MEDLINE DCOM- 20200724 LR - 20200724 IS - 1096-0929 (Electronic) IS - 1096-0929 (Linking) VI - 170 IP - 1 DP - 2019 Jul 1 TI - Use of a Bile Salt Export Pump Knockdown Rat Susceptibility Model to Interrogate Mechanism of Drug-Induced Liver Toxicity. PG - 180-198 LID - 10.1093/toxsci/kfz079 [doi] AB - 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. CI - (c) The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Li, Yutai AU - Li Y AD - Safety Assessment and Laboratory Animal Resources. FAU - Evers, Raymond AU - Evers R AD - Pharmacokinetics, Pharmacodynamics and Drug Metabolism. FAU - Hafey, Michael J AU - Hafey MJ AD - Pharmacokinetics, Pharmacodynamics and Drug Metabolism. FAU - Cheon, Kyeongmi AU - Cheon K AD - Biometrics Research. FAU - Duong, Hong AU - Duong H AD - Safety Assessment and Laboratory Animal Resources. FAU - Lynch, Donna AU - Lynch D AD - Safety Assessment and Laboratory Animal Resources. FAU - LaFranco-Scheuch, Lisa AU - LaFranco-Scheuch L AD - Safety Assessment and Laboratory Animal Resources. FAU - Pacchione, Stephen AU - Pacchione S AD - Safety Assessment and Laboratory Animal Resources. FAU - Tamburino, Alex M AU - Tamburino AM AD - Genetics and Pharmacogenomics, MRL, West Point, PA 19486. FAU - Tanis, Keith Q AU - Tanis KQ AD - Genetics and Pharmacogenomics, MRL, West Point, PA 19486. FAU - Geddes, Kristin AU - Geddes K AD - Pharmacokinetics, Pharmacodynamics and Drug Metabolism. FAU - Holder, Daniel AU - Holder D AD - Biometrics Research. FAU - Zhang, Nanyan Rena AU - Zhang NR AD - Pharmacokinetics, Pharmacodynamics and Drug Metabolism. FAU - Kang, Wen AU - Kang W AD - Safety Assessment and Laboratory Animal Resources. FAU - Gonzalez, Raymond J AU - Gonzalez RJ AD - Safety Assessment and Laboratory Animal Resources. FAU - Galijatovic-Idrizbegovic, Alema AU - Galijatovic-Idrizbegovic A AD - Safety Assessment and Laboratory Animal Resources. FAU - Pearson, Kara M AU - Pearson KM AD - Safety Assessment and Laboratory Animal Resources. FAU - Lebron, Jose A AU - Lebron JA AD - Safety Assessment and Laboratory Animal Resources. FAU - Glaab, Warren E AU - Glaab WE AD - Safety Assessment and Laboratory Animal Resources. FAU - Sistare, Frank D AU - Sistare FD AD - Safety Assessment and Laboratory Animal Resources. LA - eng PT - Journal Article PL - United States TA - Toxicol Sci JT - Toxicological sciences : an official journal of the Society of Toxicology JID - 9805461 RN - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 11) RN - 0 (Abcb11 protein, rat) RN - 0 (Pharmaceutical Preparations) RN - 0 (RNA, Small Interfering) RN - 516-35-8 (Taurochenodeoxycholic Acid) RN - EC 2.6.1.- (Transaminases) RN - RFM9X3LJ49 (Bilirubin) SB - IM MH - ATP Binding Cassette Transporter, Subfamily B, Member 11/*antagonists & inhibitors/genetics MH - Animals MH - Bilirubin/blood MH - Chemical and Drug Induced Liver Injury/*etiology/*metabolism MH - *Disease Models, Animal MH - Gene Knockdown Techniques MH - Male MH - Pharmaceutical Preparations/*administration & dosage MH - RNA, Small Interfering/genetics MH - Rats MH - Rats, Wistar MH - Taurochenodeoxycholic Acid/blood MH - Transaminases/blood OTO - NOTNLM OT - bile acids OT - bile salt export pump (BSEP) OT - biomarkers OT - knockdown OT - liquid chromatography-mass spectrometry (LC-MS) OT - microbiome OT - transporters EDAT- 2019/03/25 06:00 MHDA- 2020/07/25 06:00 CRDT- 2019/03/24 06:00 PHST- 2019/03/25 06:00 [pubmed] PHST- 2020/07/25 06:00 [medline] PHST- 2019/03/24 06:00 [entrez] AID - 5418523 [pii] AID - 10.1093/toxsci/kfz079 [doi] PST - ppublish SO - Toxicol Sci. 2019 Jul 1;170(1):180-198. doi: 10.1093/toxsci/kfz079.