PMID- 23175273
OWN - NLM
STAT- MEDLINE
DCOM- 20130705
LR  - 20181202
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 57
IP  - 4
DP  - 2013 Apr
TI  - Oxidative stress plays a major role in chlorpromazine-induced cholestasis in 
      human HepaRG cells.
PG  - 1518-29
LID - 10.1002/hep.26160 [doi]
AB  - Drugs induce cholestasis by diverse and still poorly understood mechanisms in 
      humans. Early hepatic effects of chlorpromazine (CPZ), a neuroleptic drug known 
      for years to induce intrahepatic cholestasis, were investigated using the 
      differentiated human hepatoma HepaRG cells. Generation of reactive oxygen species 
      (ROS) was detected as early as 15 minutes after CPZ treatment and was associated 
      with an altered mitochondrial membrane potential and disruption of the 
      pericanalicular distribution of F-actin. Inhibition of [3H]-taurocholic acid 
      efflux was observed after 30 minutes and was mostly prevented by N-acetyl 
      cysteine (NAC) cotreatment, indicating a major role of oxidative stress in 
      CPZ-induced bile acid (BA) accumulation. Moreover, 24-hour treatment with CPZ 
      decreased messenger RNA (mRNA) expression of the two main canalicular bile 
      transporters, bile salt export pump (BSEP) and multidrug resistance protein 3 
      (MDR3). Additional CPZ effects included inhibition of Na+ -dependent taurocholic 
      cotransporting polypeptide (NTCP) expression and activity, multidrug 
      resistance-associated protein 4 (MRP4) overexpression and CYP8B1 inhibition that 
      are involved in BA uptake, basolateral transport, and BA synthesis, respectively. 
      These latter events likely represent hepatoprotective responses which aim to 
      reduce intrahepatic accumulation of toxic BA. Compared to CPZ effects, 
      overloading of HepaRG cells with high concentrations of cholic and 
      chenodeoxycholic acids induced a delayed oxidative stress and, similarly, after 
      24 hours it down-regulated BSEP and MDR3 in parallel to a decrease of NTCP and 
      CYP8B1 and an increase of MRP4. By contrast, low BA concentrations up-regulated 
      BSEP and MDR3 in the absence of oxidative stress. CONCLUSION: These data provide 
      evidence that, among other mechanisms, oxidative stress plays a major role as 
      both a primary causal and an aggravating factor in the early CPZ-induced 
      intrahepatic cholestasis in human hepatocytes.
CI  - Copyright (c) 2012 American Association for the Study of Liver Diseases.
FAU - Antherieu, Sebastien
AU  - Antherieu S
AD  - Inserm UMR991, Liver Metabolisms and Cancer, Rennes, France.
FAU - Bachour-El Azzi, Pamela
AU  - Bachour-El Azzi P
FAU - Dumont, Julie
AU  - Dumont J
FAU - Abdel-Razzak, Ziad
AU  - Abdel-Razzak Z
FAU - Guguen-Guillouzo, Christiane
AU  - Guguen-Guillouzo C
FAU - Fromenty, Bernard
AU  - Fromenty B
FAU - Robin, Marie-Anne
AU  - Robin MA
FAU - Guillouzo, Andre
AU  - Guillouzo A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130304
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (ABCB11 protein, human)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 11)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Actins)
RN  - 0 (Reactive Oxygen Species)
RN  - 5E090O0G3Z (Taurocholic Acid)
RN  - 9EI49ZU76O (multidrug resistance protein 3)
RN  - U42B7VYA4P (Chlorpromazine)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B/metabolism
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 11
MH  - ATP-Binding Cassette Transporters/metabolism
MH  - Actins/metabolism
MH  - Carcinoma, Hepatocellular/metabolism/*pathology
MH  - Cell Line, Tumor
MH  - Chlorpromazine/*adverse effects/pharmacology
MH  - Cholestasis/*chemically induced/metabolism/*physiopathology
MH  - Humans
MH  - In Vitro Techniques
MH  - Liver Neoplasms/metabolism/*pathology
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Oxidative Stress/drug effects/*physiology
MH  - Reactive Oxygen Species/metabolism
MH  - Taurocholic Acid/metabolism
EDAT- 2012/11/24 06:00
MHDA- 2013/07/06 06:00
CRDT- 2012/11/24 06:00
PHST- 2012/01/24 00:00 [received]
PHST- 2012/10/24 00:00 [accepted]
PHST- 2012/11/24 06:00 [entrez]
PHST- 2012/11/24 06:00 [pubmed]
PHST- 2013/07/06 06:00 [medline]
AID - 10.1002/hep.26160 [doi]
PST - ppublish
SO  - Hepatology. 2013 Apr;57(4):1518-29. doi: 10.1002/hep.26160. Epub 2013 Mar 4.