PMID- 17602960
OWN - NLM
STAT- MEDLINE
DCOM- 20070918
LR  - 20220331
IS  - 0891-5849 (Print)
IS  - 0891-5849 (Linking)
VI  - 43
IP  - 3
DP  - 2007 Aug 1
TI  - De novo synthesis of glutathione is a prerequisite for curcumin to inhibit 
      hepatic stellate cell (HSC) activation.
PG  - 444-53
AB  - On liver injury, quiescent hepatic stellate cells (HSC), the most relevant cell 
      type for hepatic fibrogenesis, become active, characterized by enhanced cell 
      growth and overproduction of extracellular matrix (ECM). Oxidative stress 
      facilitates HSC activation and the pathogenesis of hepatic fibrosis. Glutathione 
      (GSH) is the most important intracellular antioxidant. We previously showed that 
      curcumin, the yellow pigment in curry from turmeric, significantly inhibited HSC 
      activation. The aim of this study is to elucidate the underlying mechanisms. It 
      is hypothesized that curcumin might inhibit HSC activation mainly by its 
      antioxidant capacity. Results from this study demonstrate that curcumin dose and 
      time dependently attenuates oxidative stress in passaged HSC demonstrated by 
      scavenging reactive oxygen species and reducing lipid peroxidation. Curcumin 
      elevates the level of cellular GSH and induces de novo synthesis of GSH in HSC by 
      stimulating the activity and gene expression of glutamate-cysteine ligase (GCL), 
      a key rate-limiting enzyme in GSH synthesis. Depletion of cellular GSH by the 
      inhibition of GCL activity using L-buthionine sulfoximine evidently eliminates 
      the inhibitory effects of curcumin on HSC activation. Taken together, our results 
      demonstrate, for the first time, that the antioxidant property of curcumin mainly 
      results from increasing the level of cellular GSH by inducing the activity and 
      gene expression of GCL in activated HSC in vitro. De novo synthesis of GSH is a 
      prerequisite for curcumin to inhibit HSC activation. These results provide novel 
      insights into the mechanisms of curcumin as an antifibrogenic candidate in the 
      prevention and treatment of hepatic fibrosis.
FAU - Zheng, Shizhong
AU  - Zheng S
AD  - Department of Pharmacology, Nanjing Medical University, China.
FAU - Yumei, Fu
AU  - Yumei F
FAU - Chen, Anping
AU  - Chen A
LA  - eng
GR  - R01 DK047995-10A2/DK/NIDDK NIH HHS/United States
GR  - R01 DK047995/DK/NIDDK NIH HHS/United States
GR  - R01 DK 047995/DK/NIDDK NIH HHS/United States
GR  - R01 DK047995-12/DK/NIDDK NIH HHS/United States
GR  - R01 DK047995-11/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20070429
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Antioxidants)
RN  - 0 (Lipid Peroxides)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 6.3.2.2 (Glutamate-Cysteine Ligase)
RN  - GAN16C9B8O (Glutathione)
RN  - IT942ZTH98 (Curcumin)
SB  - IM
MH  - Animals
MH  - Antioxidants/*pharmacology
MH  - Cells, Cultured
MH  - Curcumin/*pharmacology
MH  - Gene Expression/drug effects
MH  - Glutamate-Cysteine Ligase/drug effects/metabolism
MH  - Glutathione/*biosynthesis
MH  - Hepatocytes/*metabolism/*physiology
MH  - Lipid Peroxides/metabolism
MH  - Male
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reactive Oxygen Species/metabolism
PMC - PMC2562715
MID - NIHMS27375
EDAT- 2007/07/03 09:00
MHDA- 2007/09/19 09:00
PMCR- 2008/10/07
CRDT- 2007/07/03 09:00
PHST- 2006/09/13 00:00 [received]
PHST- 2007/02/21 00:00 [revised]
PHST- 2007/04/25 00:00 [accepted]
PHST- 2007/07/03 09:00 [pubmed]
PHST- 2007/09/19 09:00 [medline]
PHST- 2007/07/03 09:00 [entrez]
PHST- 2008/10/07 00:00 [pmc-release]
AID - S0891-5849(07)00283-3 [pii]
AID - 10.1016/j.freeradbiomed.2007.04.016 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2007 Aug 1;43(3):444-53. doi: 
      10.1016/j.freeradbiomed.2007.04.016. Epub 2007 Apr 29.