PMID- 31571363
OWN - NLM
STAT- MEDLINE
DCOM- 20210323
LR  - 20210323
IS  - 1478-3231 (Electronic)
IS  - 1478-3223 (Linking)
VI  - 40
IP  - 1
DP  - 2020 Jan
TI  - Tanshinone IIA prevents rifampicin-induced liver injury by regulating BSEP/NTCP 
      expression via epigenetic activation of NRF2.
PG  - 141-154
LID - 10.1111/liv.14262 [doi]
AB  - BACKGROUND & AIMS: Rifampicin (RFP)-induced cholestatic liver injury is 
      characterized by impaired hepatic bile acid (BA) transport. Bile salt efflux pump 
      (BSEP) and Na+/taurocholate cotransporter (NTCP) are the major BA transporters. 
      However, little is known about the mechanisms underlying these transporters. 
      METHODS: The role of tanshinone IIA (TAN IIA) in preventing RFP-induced liver 
      injury was evaluated in vitro and in vivo, based on the regulatory mechanism of 
      nuclear factor erythroid 2-related factor 2 (NRF2)-BSEP/NTCP signalling. The 
      epigenetic induction of NRF2 by TAN IIA was investigated as well as the influence 
      on BSEP and NTCP transcriptional activation and NRF2 DNA-binding ability. 
      RESULTS: TAN IIA strongly induced BSEP and NTCP expression in hepatocytes. NRF2 
      knockdown abrogated the induction. We found two NRF2 binding sites on the human 
      BSEP promoter, called musculoaponeurotic fibrosarcoma recognition elements 
      (MAREs), and one MARE on the NTCP promoter. Human BSEP and NTCP promoter 
      luciferase reporter gene plasmids were stimulated by NRF2. Mutations of the 
      predicted MAREs abolished NRF2 transcriptional activation. TAN IIA induced the 
      expression of ten-eleven translocation 2 (TET2) to mediate the demethylation of 
      NRF2, which promoted NRF2 DNA-binding on the BSEP and NTCP promoters and their 
      transcriptional activation. Finally, in vivo, Nrf2 played an important role in 
      RFP-induced liver injury (more serious liver injury in Nrf2-/- mice), and TAN IIA 
      prevented it. CONCLUSIONS: These results indicate that NRF2 regulates the target 
      transporters BSEP and NTCP, depending on the DNA demethylation by TET2. 
      Pharmacological activation of NRF2 by TAN IIA may be beneficial for RFP-induced 
      liver injury.
CI  - (c) 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
FAU - Yang, Yujie
AU  - Yang Y
AD  - Department of Clinical Pharmacy and Pharmacy Administration, Key Laboratory of 
      Drug-Targeting and Drug Delivery System of the Education Ministry, West China 
      School of Pharmacy, Sichuan University, Chengdu, China.
AD  - Department of Pharmacy, The Third People's Hospital of Chengdu, College of 
      Medicine, Southwest Jiaotong University, Chengdu, China.
FAU - Liu, Lei
AU  - Liu L
AD  - Department of Clinical Pharmacy and Pharmacy Administration, Key Laboratory of 
      Drug-Targeting and Drug Delivery System of the Education Ministry, West China 
      School of Pharmacy, Sichuan University, Chengdu, China.
FAU - Zhang, Xiqian
AU  - Zhang X
AUID- ORCID: 0000-0002-4486-8042
AD  - Department of Pharmacy, The Third People's Hospital of Chengdu, College of 
      Medicine, Southwest Jiaotong University, Chengdu, China.
FAU - Jiang, Xuehua
AU  - Jiang X
AD  - Department of Clinical Pharmacy and Pharmacy Administration, Key Laboratory of 
      Drug-Targeting and Drug Delivery System of the Education Ministry, West China 
      School of Pharmacy, Sichuan University, Chengdu, China.
FAU - Wang, Ling
AU  - Wang L
AUID- ORCID: 0000-0003-3220-6065
AD  - Department of Clinical Pharmacy and Pharmacy Administration, Key Laboratory of 
      Drug-Targeting and Drug Delivery System of the Education Ministry, West China 
      School of Pharmacy, Sichuan University, Chengdu, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191007
PL  - United States
TA  - Liver Int
JT  - Liver international : official journal of the International Association for the 
      Study of the Liver
JID - 101160857
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 11)
RN  - 0 (Abcb11 protein, mouse)
RN  - 0 (Abietanes)
RN  - 0 (Bile Acids and Salts)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (Organic Anion Transporters, Sodium-Dependent)
RN  - 0 (Symporters)
RN  - 03UUH3J385 (tanshinone)
RN  - 145420-23-1 (sodium-bile acid cotransporter)
RN  - VJT6J7R4TR (Rifampin)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
MH  - Abietanes/*pharmacology
MH  - Animals
MH  - Bile Acids and Salts/metabolism
MH  - Chemical and Drug Induced Liver Injury, Chronic/*genetics/pathology
MH  - *Epigenesis, Genetic
MH  - Female
MH  - HEK293 Cells
MH  - Hepatocytes/metabolism
MH  - Humans
MH  - Liver/drug effects/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-E2-Related Factor 2/*genetics/metabolism
MH  - Organic Anion Transporters, Sodium-Dependent/*metabolism
MH  - Rifampin/*toxicity
MH  - Symporters/*metabolism
OTO - NOTNLM
OT  - BSEP
OT  - NRF2
OT  - NTCP
OT  - TET2
OT  - rifampicin
OT  - tanshinone IIA
EDAT- 2019/10/02 06:00
MHDA- 2021/03/24 06:00
CRDT- 2019/10/02 06:00
PHST- 2019/07/02 00:00 [received]
PHST- 2019/08/17 00:00 [revised]
PHST- 2019/09/15 00:00 [accepted]
PHST- 2019/10/02 06:00 [pubmed]
PHST- 2021/03/24 06:00 [medline]
PHST- 2019/10/02 06:00 [entrez]
AID - 10.1111/liv.14262 [doi]
PST - ppublish
SO  - Liver Int. 2020 Jan;40(1):141-154. doi: 10.1111/liv.14262. Epub 2019 Oct 7.