Oltipraz regenerates cirrhotic liver through CCAAT/enhancer binding protein-mediated stellate cell inactivation
KEON WOOK KANG*#, YOON GYOON KIM*#, MIN KYONG CHO*#, SOO KYUNG BAE#, CHOON WON KIM+, MYUNG GULL LEE and SANG GEON KIM*#2
*National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul; and Department of Clinical Pathology, Hanyang University Medical School, Seoul, Korea
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.
2 Correspondence: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, Korea.