Prevention of liver cirrhosis in rats by curcumin.
OBJECTIVE
Curcumin, the major polyphenolic compound in turmeric, has been shown to attenuate hepatic damage in several animal models of liver injury. The aim of the present study was to examine the efficacy of curcumin in preventing thioacetamide-induced cirrhosis and to unravel the mechanism of curcumin's effect on hepatic fibrosis in rats.


METHODS
Liver cirrhosis was induced by thioacetamide (TAA; 200 mg/kg, i.p.) twice weekly for 12 weeks. One group of rats concomitantly received curcumin (300 mg/kg/day, by gavage for 12 weeks); the control group received the solvent at identical amounts and duration.


RESULTS
TAA administration induced liver cirrhosis, which was inhibited by curcumin. Liver histopathology, hydroxyproline levels and spleen weights were significantly lower in the rats treated with TAA+curcumin compared with TAA only (P<0.001). Immunohistochemical studies and in situ hybridization demonstrated inhibition of hepatic stellate cell (alpha smooth muscle actin-positive) activation and collagen alpha1 (I) gene expression in the livers of the TAA+curcumin-treated rats. Curcumin reduced oxidative stress as shown by the decreased hepatic nitrotyrosine staining in the curcumin+TAA-treated rats. Curcumin treatment had no effect on pre existing liver cirrhosis. As determined by in vitro studies using the rat HSC-T6 cell line, curcumin had no direct inhibitory effect on collagen alpha1 (I) messenger RNA expression. Further studies in these cells using reverse transcriptase-polymerase chain reaction demonstrated that curcumin had no effect on the expression of PDGF-induced TIMP-1 and TIMP-2, TGFbeta1, TGFbeta2 and MCP-1 but significantly inhibited tumor necrosis factor alpha expression. Curcumin had no effect on hepatic stellate cells proliferation. Zymography showed that curcumin had no effect on matrix metalloproteinase-2 activity.


CONCLUSIONS
Curcumin inhibited the development of TAA-induced liver cirrhosis mainly due to its anti-inflammatory activities and not by a direct anti-fibrotic effect. As curcumin ingestion is safe in humans, it may be reasonable to assess in clinical studies the beneficial effect of curcumin in slowing the development of liver cirrhosis.
Bruck
Rafael
R
The Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel. rafib@tasmc.health.gov.il
Ashkenazi
Michal
M
Weiss
Sigal
S
Goldiner
Ilana
I
Shapiro
Haim
H
Aeed
Hussein
H
Genina
Olga
O
Helpern
Zamir
Z
Pines
Mark
M
D000199:Actins / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003474:Curcumin / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects; D013853:Thioacetamide; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D024042:Collagen Type I; D016207:Cytokines; D013853:Thioacetamide; C002744:3-nitrotyrosine; D014443:Tyrosine; D020778:Matrix Metalloproteinase 2; D003474:Curcumin; D006909:Hydroxyproline