Oltipraz regenerates cirrhotic liver through CCAAT/enhancer binding protein-mediated stellate cell inactivation.
Liver cirrhosis (LC) is a chronic disease with high mortality rate. In the United States and Western world as well as Asian countries, LC is the major leading cause of death by disease. Yet, no effective therapeutic agent is available for LC treatment. Laboratory cirrhotic rats produced by dimethylnitrosamine administrations simulate the clinical features of human LC such as mortality, ascites, hepatic parenchymal cell destruction, and formation of connective tissue and nodular regeneration, providing a preclinical model to evaluate therapeutic efficacy of drugs and the underlying mechanisms. Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] has been used clinically and is of little toxicity. Comprehensive mechanistic and phase IIa clinical studies supported the notion that oltipraz exerts chemopreventive effects against chemical carcinogenesis. We report here that oltipraz within the clinical dose range regenerates cirrhotic liver in the established LC rats as a result of reduction of the intensities of cirrhotic nodules, elimination of accumulated extracellular matrix, and inactivation of stellate cells, thereby improving survival rate. We also reveal that activation of CCAAT/enhancer binding protein by oltipraz inhibits transforming growth factor b1 gene expression in stellate cells, which provides a molecular target for pharmacological treatment of LC. Oltipraz is the first therapeutic agent that regenerates cirrhotic liver.
Kang
Keon Wook
KW
National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Kim
Yoon Gyoon
YG
Cho
Min Kyong
MK
Bae
Soo Kyung
SK
Kim
Choon Won
CW
Lee
Myung Gull
MG
Kim
Sang Geon
SG
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D005109:Extracellular Matrix / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects*; D008954:Models, Biological; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D016019:Survival Analysis; D013871:Thiones; D013876:Thiophenes; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1
D022762:CCAAT-Enhancer-Binding Proteins; D011719:Pyrazines; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D013871:Thiones; D013876:Thiophenes; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C026209:oltipraz