PMID- 11786960
OWN - NLM
STAT- MEDLINE
DCOM- 20020125
LR  - 20181130
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 35
IP  - 1
DP  - 2002 Jan
TI  - Stimulation and proliferation of primary rat hepatic stellate cells by cytochrome 
      P450 2E1-derived reactive oxygen species.
PG  - 62-73
AB  - The alcohol-inducible cytochrome P450 2E1 (CYP2E1) is expressed mainly in 
      hepatocytes and generates reactive oxygen species (ROS). To better understand how 
      hepatic stellate cells (HSC) become activated in the presence of oxidative stress 
      and evaluate whether CYP2E1-derived ROS activate stellate cells, we coincubated 
      primary stellate cells with HepG2 cells, which do (E47 cells) or do not (C34 
      cells) express CYP2E1. Morphologic changes and loss of lipid droplets were more 
      apparent in the stellate cells cocultured with E47 cells. There was a more 
      pronounced increase in alpha-smooth muscle actin (alpha-sma), intracellular and 
      secreted collagen type I protein, and intra- and extracellular H(2)O(2) and lipid 
      peroxidation products in stellate cells coincubated with E47 cells. Expression of 
      collagen in stellate cells did not change when cocultured with HepG2 cells 
      expressing a different P450, CYP3A4. Stellate cells cultured on Matrigel 
      expressed increased alpha-sma and collagen when incubated with E47 cells. The 
      increase in collagen production by coculture with E47 cells was prevented by 
      antioxidants, by CYP2E1 inhibitors, and by transfected antisense CYP2E1. The 
      addition of arachidonic acid plus ferric nitrilotriacetate (Fe-NTA), agents that 
      potentiate oxidative stress, further induced collagen protein in the E47 
      coculture. Stellate cell proliferation was greater in the E47 coculture, and this 
      was partially abrogated by catalase and vitamin E. These results show that 
      hepatocytes containing CYP2E1 release diffusible mediators including ROS, which 
      can activate HSC. Thus, besides perturbing the homeostasis of hepatocytes, 
      CYP2E1-derived diffusible oxidants may also interact with stellate cells and 
      contribute to hepatic fibrosis.
FAU - Nieto, Natalia
AU  - Nieto N
AD  - Department of Biochemistry, Mount Sinai School of Medicine, One Gustave L. Levy 
      Place, New York, NY 10029, USA.
FAU - Friedman, Scott L
AU  - Friedman SL
FAU - Cederbaum, Arthur I
AU  - Cederbaum AI
LA  - eng
GR  - AA 03312/AA/NIAAA NIH HHS/United States
GR  - AA 06610/AA/NIAAA NIH HHS/United States
GR  - DK37340/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Actins)
RN  - 0 (Antioxidants)
RN  - 0 (Collagen Type I)
RN  - 0 (Drug Combinations)
RN  - 0 (Ferric Compounds)
RN  - 0 (Laminin)
RN  - 0 (Proteoglycans)
RN  - 0 (Reactive Oxygen Species)
RN  - 119978-18-6 (matrigel)
RN  - 1406-18-4 (Vitamin E)
RN  - 27YG812J1I (Arachidonic Acid)
RN  - 9007-34-5 (Collagen)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.11.1.6 (Catalase)
RN  - EC 1.14.13.- (Cytochrome P-450 CYP2E1)
RN  - KA90006V9D (Nitrilotriacetic Acid)
RN  - Z3U5ED15B9 (ferric nitrilotriacetate)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - Arachidonic Acid/pharmacology
MH  - Catalase/pharmacology
MH  - *Cell Division
MH  - Cell Line
MH  - Coculture Techniques
MH  - Collagen
MH  - Collagen Type I/biosynthesis/metabolism
MH  - Cytochrome P-450 CYP2E1/genetics/*metabolism
MH  - Drug Combinations
MH  - Ferric Compounds/pharmacology
MH  - Fluorescent Antibody Technique
MH  - Gene Expression
MH  - Hepatocytes/cytology/drug effects/*physiology
MH  - Humans
MH  - Hydrogen Peroxide/metabolism
MH  - Iron/pharmacology
MH  - Laminin
MH  - Lipid Peroxidation
MH  - Nitrilotriacetic Acid/*analogs & derivatives/pharmacology
MH  - Oxidative Stress
MH  - Proteoglycans
MH  - Rats
MH  - Reactive Oxygen Species/metabolism/*pharmacology
MH  - Vitamin E/pharmacology
EDAT- 2002/01/12 10:00
MHDA- 2002/01/26 10:01
CRDT- 2002/01/12 10:00
PHST- 2002/01/12 10:00 [pubmed]
PHST- 2002/01/26 10:01 [medline]
PHST- 2002/01/12 10:00 [entrez]
AID - S0270913902808837 [pii]
AID - 10.1053/jhep.2002.30362 [doi]
PST - ppublish
SO  - Hepatology. 2002 Jan;35(1):62-73. doi: 10.1053/jhep.2002.30362.