A protective effect of pyrrolidine dithiocarbamate in a rat model of liver cirrhosis.
BACKGROUND
Nuclear factor kappa B (NF-kappaB) activation, proinflammatory cytokines, and reactive oxygen species have been implicated as mediators of liver injury and fibrogenesis. We have shown recently that pyrrolidine dithiocarbamate (PDTC), an antioxidant and inhibitor of NF-kappaB activation, was protective in a rat model of acute liver failure. The aim of the present study was to examine the efficacy of PDTC in a chronic rat model of thioacetamide (TAA)-induced hepatic fibrosis.


METHODS
Liver cirrhosis was induced by intraperitoneal injections of TAA (200 mg/kg) twice weekly for 12 weeks. Two groups of rats also received PDTC (either 20 or 60 mg/kg, i.p. for 12 weeks).


RESULTS
TAA administration induced liver cirrhosis, which was inhibited by PDTC in a dose-dependent manner. The histopathologic score of fibrosis, the spleen weight, and hepatic hydroxyproline were significantly lower in the rats treated with TAA+PDTC compared with TAA only (P<0.001). The hepatic levels of thiobarbituric acid reactive substances and protein carbonyls after 12 weeks of treatment were also lower in the rats treated with TAA+PDTC (P=0.02 and 0.01, respectively), indicating reduced oxidative stress. Immunohistochemical studies and in situ hybridization demonstrated inhibition of stellate cell (alpha smooth muscle actin positive) activation, tissue inhibitor of metalloproteinase-2, and collagen alpha1(I) gene expression in the livers of the PDTC-treated rats. As determined by Northern blot analysis, PDTC had no inhibitory effect on collagen alpha1(I) gene expression in the rat hepatic stellate cells-T6 cells in vitro.


CONCLUSIONS
PDTC inhibits the development of liver cirrhosis in TAA-treated rats. The mechanism of action is associated with decreased oxidative stress and hepatic necroinflammation.
Bruck
Rafael
R
Department of Gastroenterology, The E. Wolfson Medical Center, Holon, Israel. rbruck@wolfson.health.gov.il
Schey
Ron
R
Aeed
Hussein
H
Hochman
Ayala
A
Genina
Olga
O
Pines
Mark
M
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects; D011759:Pyrrolidines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide / Q000008:administration & dosage / Q000633:toxicity; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013859:Thiocarbamates / Q000008:administration & dosage / Q000627:therapeutic use*
D000975:Antioxidants; D016328:NF-kappa B; D011759:Pyrrolidines; D017392:Thiobarbituric Acid Reactive Substances; D013859:Thiocarbamates; D013853:Thioacetamide; C020972:pyrrolidine dithiocarbamic acid; D006909:Hydroxyproline