Therapeutic potential of dithiolethiones for hepatic diseases.
Comprehensive studies support the notion that oltipraz [4-methyl-5-(2-pyrazynyl)-1,2-dithiole-3-thione] and its congeners exert cancer chemopreventive effects by the prevention, inhibition or reversal of carcinogenic processes. Recently, it was found that dithiolethione compounds had the activities to prevent or treat fibrosis, insulin resistance, and mitochondrial protective effects in the liver by a mechanism involving AMP-activated protein kinase (AMPK) and/or 70-kDa ribosomal protein S6 kinase 1 (S6K1). Moreover, chemical regulation of the AMPK-S6K1 pathway was found to affect Liver X receptor (LXR) activity and lipogenesis, leading to the identification of AMPK and S6K1 as targets for treating hepatic steatosis. These biological activities of dithiolethiones may offer a novel approach to pharmaceutical intervention. This review focuses on the interaction between oltipraz and the AMPK-mTOR-S6K1 pathway, which regulates genes that confer hepatocyte protection from intoxication, disrupted energy metabolism, and inflammation. In terms of therapeutic potential, the findings reviewed here demonstrate a new therapeutic potential for dithiolethiones, which function in a unique manner, and offer the possibility of new treatments for hepatic diseases.
Brooks
Samuel Carroll
SC
Innovative Drug Research Center for Metabolic and Inflammatory Disease, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South, Korea.
Brooks
Janie Sue
JS
Lee
Woo Hyung
WH
Lee
Myung Gull
MG
Kim
Sang Geon
SG
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D005234:Fatty Liver / Q000517:prevention & control; D005982:Glutathione Transferase / Q000502:physiology; D006801:Humans; D008658:Inactivation, Metabolic; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects; D008103:Liver Cirrhosis / Q000517:prevention & control; D008107:Liver Diseases / Q000188:drug therapy*; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D013871:Thiones; D013876:Thiophenes
D022782:CCAAT-Enhancer-Binding Protein-beta; D005982:Glutathione Transferase; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D011719:Pyrazines; D018336:Receptors, Aryl Hydrocarbon; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; C546842:MTOR protein, human; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1