PMID- 36787806
OWN - NLM
STAT- MEDLINE
DCOM- 20230605
LR  - 20230612
IS  - 1099-1263 (Electronic)
IS  - 0260-437X (Linking)
VI  - 43
IP  - 7
DP  - 2023 Jul
TI  - The choleretic role of tauroursodeoxycholic acid exacerbates 
      alpha-naphthylisothiocyanate induced cholestatic liver injury through the 
      FXR/BSEP pathway.
PG  - 1095-1103
LID - 10.1002/jat.4446 [doi]
AB  - The aim of this study was to determine the effect of tauroursodeoxycholic acid 
      (TUDCA) on the alpha-naphthylisothiocyanate (ANIT)-induced model of cholestasis 
      in mice. Wild-type and farnesoid X receptor (FXR)-deficient (Fxr(-/-) ) mice were 
      used to generate cholestasis models by gavage with ANIT. Obeticholic acid (OCA) 
      was used as a positive control. In wild-type mice, treatment with TUDCA for 
      7 days resulted in a dramatic increase in serum levels of alanine 
      aminotransferase (ALT), with aggravation of bile infarcts and hepatocyte necrosis 
      with ANIT-induction. TUDCA activated FXR to upregulate the expression of bile 
      salt export pump (BSEP), increasing bile acids (BAs)-dependent bile flow, but 
      aggravating cholestatic liver injury when bile ducts were obstructed resulting 
      from ANIT. In contrast, TUDCA improved the liver pathology and decreased serum 
      ALT and alkaline phosphatase (ALP) levels in ANIT-induced Fxr(-/-) mice. 
      Furthermore, TUDCA inhibited the expression of cleaved caspase-3 and reduced the 
      area of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) 
      staining in the model mice. TUDCA also upregulated anion exchanger 2 (AE2) 
      protein expression, protecting cholangiocytes against excessive toxic BAs. Our 
      results showed that TUDCA aggravated cholestatic liver injury via the FXR/BSEP 
      pathway when bile ducts were obstructed, although TUDCA inhibited apoptotic 
      activity and protected cholangiocytes against excessive toxic BAs.
CI  - (c) 2023 John Wiley & Sons Ltd.
FAU - Zhao, Jing
AU  - Zhao J
AUID- ORCID: 0000-0003-0175-1319
AD  - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated with the 
      Shanghai University of Traditional Chinese Medicine, Shanghai, China.
FAU - Song, Guochao
AU  - Song G
AD  - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated with the 
      Shanghai University of Traditional Chinese Medicine, Shanghai, China.
FAU - Weng, Fengyi
AU  - Weng F
AD  - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated with the 
      Shanghai University of Traditional Chinese Medicine, Shanghai, China.
FAU - Li, Yue
AU  - Li Y
AD  - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated with the 
      Shanghai University of Traditional Chinese Medicine, Shanghai, China.
FAU - Zou, Bin
AU  - Zou B
AD  - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated with the 
      Shanghai University of Traditional Chinese Medicine, Shanghai, China.
FAU - Jin, Jingyi
AU  - Jin J
AD  - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated with the 
      Shanghai University of Traditional Chinese Medicine, Shanghai, China.
FAU - Yan, Dongming
AU  - Yan D
AD  - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated with the 
      Shanghai University of Traditional Chinese Medicine, Shanghai, China.
FAU - Sun, Xin
AU  - Sun X
AD  - Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang 
      Hospital Affiliated with the Shanghai University of Traditional Chinese Medicine, 
      Shanghai, China.
FAU - Liu, Chenghai
AU  - Liu C
AD  - Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang 
      Hospital Affiliated with the Shanghai University of Traditional Chinese Medicine, 
      Shanghai, China.
FAU - Qiu, Fu-Rong
AU  - Qiu FR
AD  - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated with the 
      Shanghai University of Traditional Chinese Medicine, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230227
PL  - England
TA  - J Appl Toxicol
JT  - Journal of applied toxicology : JAT
JID - 8109495
RN  - 60EUX8MN5X (ursodoxicoltaurine)
RN  - 0 (Cholagogues and Choleretics)
RN  - 551-06-4 (1-Naphthylisothiocyanate)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 11)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Bile Acids and Salts)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Cholagogues and Choleretics/adverse effects/metabolism
MH  - 1-Naphthylisothiocyanate/toxicity/metabolism
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
MH  - Receptors, Cytoplasmic and Nuclear/genetics/metabolism
MH  - Liver
MH  - *Cholestasis/chemically induced
MH  - Bile Acids and Salts/metabolism
OTO - NOTNLM
OT  - alpha-naphthyl isothiocyanate
OT  - bile salt export pump
OT  - cholestatic liver injury
OT  - farnesoid X receptor
OT  - tauroursodeoxycholic acid
EDAT- 2023/02/15 06:00
MHDA- 2023/06/05 06:42
CRDT- 2023/02/14 19:13
PHST- 2023/02/10 00:00 [revised]
PHST- 2022/12/16 00:00 [received]
PHST- 2023/02/10 00:00 [accepted]
PHST- 2023/06/05 06:42 [medline]
PHST- 2023/02/15 06:00 [pubmed]
PHST- 2023/02/14 19:13 [entrez]
AID - 10.1002/jat.4446 [doi]
PST - ppublish
SO  - J Appl Toxicol. 2023 Jul;43(7):1095-1103. doi: 10.1002/jat.4446. Epub 2023 Feb 
      27.