PMID- 28688954 OWN - NLM STAT- MEDLINE DCOM- 20180523 LR - 20231213 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 112 DP - 2017 Nov TI - Rifampicin-induced injury in HepG2 cells is alleviated by TUDCA via increasing bile acid transporters expression and enhancing the Nrf2-mediated adaptive response. PG - 24-35 LID - S0891-5849(17)30675-5 [pii] LID - 10.1016/j.freeradbiomed.2017.07.003 [doi] AB - Bile acid transporters and the nuclear factor erythroid 2-related factor (Nrf-2)-mediated adaptive response play important roles in the development of drug-induced liver injury (DILI). However, little is known about the contribution of the adaptive response to rifampicin (RFP)-induced cell injury. In this study, we found RFP decreased the survival rate of HepG2 cells and increased the levels of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), gamma-glutamyl-transferase (gamma-GT), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), total bile acid (TBA) and adenosine triphosphate (ATP) in the cell culture supernatants in both a concentration- and a time-dependent manner. RFP increased the expression levels of bile acid transporter proteins and mRNAs, such as bile salt export pump (BSEP), multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2), Na(+)/taurocholate cotransporter (NTCP), organic anion transporting protein 2 (OATP2), organic solute transporter beta (OSTbeta) and Nrf2. Following the transient knockdown of Nrf2 and treatment with RFP, the expression levels of the BSEP, MDR1, MRP2, NTCP, OATP2 and OSTbeta proteins and mRNAs were decreased to different degrees. Moreover, the cell survival was decreased, whereas the LDH level in the cell culture supernatant was increased. Overexpression of the Nrf2 gene produced the opposite effects. Treatment with tauroursodeoxycholic acid (TUDCA) increased the expression levels of the bile acid transporters and Nrf2, decreased the expression levels of glucose-regulated protein 78 (GRP78), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4), and C/EBP-homologous protein (CHOP), and inhibited RFP-induced oxidative stress. Moreover, TUDCA reduced cell apoptosis, increased cell survival and decreased the levels of LDH, ALT, AST, AKP, gamma-GT, TBIL, DBIL, IBIL, TBA and ATP in the cell culture supernatant. Therefore, TUDCA alleviates RFP-induced injury in HepG2 cells by enhancing bile acid transporters expression and the Nrf2-mediated adaptive response. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Zhang, Weiping AU - Zhang W AD - Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, People's Republic of China; The First Affliated Hospital of AUTCM, 117 Meishan Road, Hefei 230031, People's Republic of China. FAU - Chen, Lihong AU - Chen L AD - Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, People's Republic of China. FAU - Feng, Hui AU - Feng H AD - Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, People's Republic of China. FAU - Wang, Wei AU - Wang W AD - Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, People's Republic of China. FAU - Cai, Yi AU - Cai Y AD - Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, People's Republic of China. FAU - Qi, Fen AU - Qi F AD - Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, People's Republic of China. FAU - Tao, Xiaofang AU - Tao X AD - School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei 230032, People's Republic of China; Biopharmaceutical Institute, Anhui Medical University, 81 Meishan Road, Hefei 230032, People's Republic of China. FAU - Liu, Jun AU - Liu J AD - School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei 230032, People's Republic of China; Biopharmaceutical Institute, Anhui Medical University, 81 Meishan Road, Hefei 230032, People's Republic of China. FAU - Shen, Yujun AU - Shen Y AD - School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei 230032, People's Republic of China; Biopharmaceutical Institute, Anhui Medical University, 81 Meishan Road, Hefei 230032, People's Republic of China. FAU - Ren, Xiaofei AU - Ren X AD - Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, People's Republic of China. FAU - Chen, Xi AU - Chen X AD - Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, People's Republic of China. FAU - Xu, Jianming AU - Xu J AD - Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, People's Republic of China. Electronic address: xujm1017@163.com. FAU - Shen, Yuxian AU - Shen Y AD - School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei 230032, People's Republic of China; Biopharmaceutical Institute, Anhui Medical University, 81 Meishan Road, Hefei 230032, People's Republic of China. Electronic address: shenyx@ahmu.edu.cn. LA - eng PT - Journal Article DEP - 20170706 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (ABCB1 protein, human) RN - 0 (ABCB11 protein, human) RN - 0 (ABCC2 protein, human) RN - 0 (ATP Binding Cassette Transporter, Subfamily B) RN - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 11) RN - 0 (Antibiotics, Antitubercular) RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (HSPA5 protein, human) RN - 0 (Liver-Specific Organic Anion Transporter 1) RN - 0 (Membrane Transport Proteins) RN - 0 (Multidrug Resistance-Associated Protein 2) RN - 0 (Multidrug Resistance-Associated Proteins) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NFE2L2 protein, human) RN - 0 (Organic Anion Transporters, Sodium-Dependent) RN - 0 (RNA, Small Interfering) RN - 0 (SLCO1B1 protein, human) RN - 0 (Symporters) RN - 0 (SLC51B protein, human) RN - 145420-23-1 (sodium-bile acid cotransporter) RN - 516-35-8 (Taurochenodeoxycholic Acid) RN - 60EUX8MN5X (ursodoxicoltaurine) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - EC 1.1.1.27 (L-Lactate Dehydrogenase) RN - EC 2.3.2.2 (gamma-Glutamyltransferase) RN - EC 2.6.1.1 (Aspartate Aminotransferases) RN - EC 2.6.1.2 (Alanine Transaminase) RN - EC 3.1.3.1 (Alkaline Phosphatase) RN - RFM9X3LJ49 (Bilirubin) RN - VJT6J7R4TR (Rifampin) SB - IM MH - ATP Binding Cassette Transporter, Subfamily B/agonists/antagonists & inhibitors/genetics/metabolism MH - ATP Binding Cassette Transporter, Subfamily B, Member 11/agonists/antagonists & inhibitors/*genetics/metabolism MH - Adaptation, Physiological MH - Adenosine Triphosphate MH - Alanine Transaminase/genetics/metabolism MH - Alkaline Phosphatase/genetics/metabolism MH - Antibiotics, Antitubercular/*pharmacology MH - Aspartate Aminotransferases/genetics/metabolism MH - Bilirubin MH - Endoplasmic Reticulum Chaperone BiP MH - Gene Expression Regulation MH - Hep G2 Cells MH - Humans MH - L-Lactate Dehydrogenase/genetics/metabolism MH - Liver-Specific Organic Anion Transporter 1/genetics/metabolism MH - Membrane Transport Proteins/genetics/metabolism MH - Multidrug Resistance-Associated Protein 2 MH - Multidrug Resistance-Associated Proteins/agonists/antagonists & inhibitors/*genetics/metabolism MH - NF-E2-Related Factor 2/agonists/*genetics/metabolism MH - Organic Anion Transporters, Sodium-Dependent/genetics/metabolism MH - RNA, Small Interfering/genetics/metabolism MH - Rifampin/antagonists & inhibitors/*pharmacology MH - Signal Transduction MH - Stress, Physiological MH - Symporters/genetics/metabolism MH - Taurochenodeoxycholic Acid/*pharmacology MH - gamma-Glutamyltransferase/genetics/metabolism OTO - NOTNLM OT - Adaptive response OT - Bile acid transporters OT - HepG2 cells OT - Nrf2 OT - Rifampicin OT - TUDCA EDAT- 2017/07/10 06:00 MHDA- 2018/05/24 06:00 CRDT- 2017/07/10 06:00 PHST- 2017/01/17 00:00 [received] PHST- 2017/06/19 00:00 [revised] PHST- 2017/07/05 00:00 [accepted] PHST- 2017/07/10 06:00 [pubmed] PHST- 2018/05/24 06:00 [medline] PHST- 2017/07/10 06:00 [entrez] AID - S0891-5849(17)30675-5 [pii] AID - 10.1016/j.freeradbiomed.2017.07.003 [doi] PST - ppublish SO - Free Radic Biol Med. 2017 Nov;112:24-35. doi: 10.1016/j.freeradbiomed.2017.07.003. Epub 2017 Jul 6.