PMID- 34767876
OWN - NLM
STAT- MEDLINE
DCOM- 20220127
LR  - 20220127
IS  - 1873-6351 (Electronic)
IS  - 0278-6915 (Linking)
VI  - 158
DP  - 2021 Dec
TI  - Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 
      and FXR pathways.
PG  - 112664
LID - S0278-6915(21)00697-9 [pii]
LID - 10.1016/j.fct.2021.112664 [doi]
AB  - Treatment of beta-lactamase positive bacterial infections with a combination of 
      amoxicillin (AMOX) and clavulanic acid (CLAV) causes idiosyncratic drug-induced 
      liver injury (iDILI) in a relevant number of patients, often with features of 
      intrahepatic cholestasis. This study aims to determine serum bile acid (BA) 
      levels in amoxicillin/clavulanate (A+C)-iDILI patients and to investigate the 
      mechanism of cholestasis by A+C in human in vitro hepatic models. In six 
      A+C-iDILI patients, significant elevations of serum primary conjugated BA 
      definitely demonstrated A+C-induced cholestasis. In cultured human Upcyte 
      hepatocytes and HepG2 cells, CLAV was more cytotoxic than AMOX, and, at 
      subcytotoxic concentrations, it altered the expression of more than 1,300 genes. 
      CLAV, but not AMOX, downregulated the expression of key genes for BA transport 
      (BSEP, NTCP, OSTalpha and MDR2) and synthesis (CYP7A1 and CYP8B1). CLAV also caused 
      early oxidative stress, with reduced GSH/GSSG ratio, along with induction of 
      antioxidant nuclear factor erythroid 2-related factor 2 (NRF2) target genes. 
      Activation of NRF2 by sulforaphane also resulted in downregulation of NTCP, OSTalpha, 
      ABCG5, CYP7A1 and CYP8B1. CLAV also inhibited the BA-sensor farnesoid X receptor 
      (FXR), in agreement with the downregulation of FXR targets BSEP, OSTalpha and ABCG5. 
      We conclude that CLAV, the culprit molecule in A+C, downregulates several key 
      biliary transporters by modulating NRF2 and FXR signaling, thus likely promoting 
      intrahepatic cholestasis. On top of that, increased ROS production and GSH 
      depletion may aggravate the cholestatic injury by A+C.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Petrov, Petar D
AU  - Petrov PD
AD  - Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain; CIBERehd, 
      ISCIII, Madrid, Spain.
FAU - Soluyanova, Polina
AU  - Soluyanova P
AD  - Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain.
FAU - Sanchez-Campos, Sonia
AU  - Sanchez-Campos S
AD  - CIBERehd, ISCIII, Madrid, Spain; Biomedicine Institute (IBIOMED), University of 
      Leon, Spain.
FAU - Castell, Jose V
AU  - Castell JV
AD  - Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain; CIBERehd, 
      ISCIII, Madrid, Spain; Dep. Biochemistry & Molecular Biology, University of 
      Valencia, Spain.
FAU - Jover, Ramiro
AU  - Jover R
AD  - Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain; CIBERehd, 
      ISCIII, Madrid, Spain; Dep. Biochemistry & Molecular Biology, University of 
      Valencia, Spain. Electronic address: ramiro.jover@uv.es.
LA  - eng
PT  - Journal Article
DEP - 20211109
PL  - England
TA  - Food Chem Toxicol
JT  - Food and chemical toxicology : an international journal published for the British 
      Industrial Biological Research Association
JID - 8207483
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0C5V0MRU6P (farnesoid X-activated receptor)
RN  - 23521W1S24 (Clavulanic Acid)
SB  - IM
MH  - Aged
MH  - Cell Line
MH  - *Cholestasis, Intrahepatic/chemically induced/genetics/metabolism
MH  - Clavulanic Acid/*toxicity
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - *NF-E2-Related Factor 2/genetics/metabolism
MH  - *Receptors, Cytoplasmic and Nuclear/genetics/metabolism
MH  - Signal Transduction/drug effects/genetics
OTO - NOTNLM
OT  - Bile acid transporter
OT  - Cholestasis
OT  - Clavulanic acid
OT  - FXR
OT  - Hepatotoxicity
OT  - NRF2
EDAT- 2021/11/13 06:00
MHDA- 2022/01/28 06:00
CRDT- 2021/11/12 20:14
PHST- 2021/08/11 00:00 [received]
PHST- 2021/10/14 00:00 [revised]
PHST- 2021/11/04 00:00 [accepted]
PHST- 2021/11/13 06:00 [pubmed]
PHST- 2022/01/28 06:00 [medline]
PHST- 2021/11/12 20:14 [entrez]
AID - S0278-6915(21)00697-9 [pii]
AID - 10.1016/j.fct.2021.112664 [doi]
PST - ppublish
SO  - Food Chem Toxicol. 2021 Dec;158:112664. doi: 10.1016/j.fct.2021.112664. Epub 2021 
      Nov 9.