Inhibition of dimethylnitrosamine-induced liver fibrosis by [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] (oltipraz) in rats: suppression of transforming growth factor-beta1 and tumor necrosis factor-alpha expression.
Oltipraz is a cancer chemopreventive agent active against a wide variety of chemical carcinogens. In spite of the intense chemoprevention and toxicology studies on oltipraz, no information is available on its antifibrotic efficacy. In the present study, the effects of oltipraz on dimethylnitrosamine (DMN)-induced liver fibrogenesis were assessed in rats. As part of mechanistic studies, the expression of transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha) was monitored. Treatment of rats with DMN (10 microl/kg body weight, i.p., three times per week for 4 weeks) resulted in marked increases in plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (gamma-GT) activities. DMN also caused an increase in the plasma bilirubin content, whereas total plasma protein and albumin levels were rather decreased. Oltipraz (50 mg/kg body weight, p.o., three times per week for 4 weeks) inhibited the increases in plasma ALT, AST, gamma-GT and bilirubin by DMN. DMN increased liver fibrosis as histopathologically assessed by Van Gieson's staining and Masson's trichrome staining (fibrosis score, 3.7; Knodell score, 16), which was reduced by oltipraz treatment (fibrosis score, 2.5; Knodell score, 8.0). Reverse transcription-polymerase chain reaction analysis revealed that oltipraz inhibited an increase in the TGF-beta1 mRNA by DMN. Oltipraz was also active in reducing the production of plasma TNF-alpha by DMN or lipopolysaccharide (LPS), which would contribute to its cytoprotective effect. These results demonstrated that oltipraz inhibited hepatocyte injury and impairment of liver function induced by DMN, and reduces DMN-induced liver fibrosis possibly through suppression of TGF-beta1 and TNF-alpha production.
Kang
Keon Wook
KW
National Research Laboratory (MDT), College of Pharmacy, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, South Korea.
Choi
Sung Hee
SH
Ha
Jong Ryul
JR
Kim
Choon Won
CW
Kim
Sang Geon
SG
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004128:Dimethylnitrosamine / Q000633:toxicity*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013871:Thiones; D013876:Thiophenes; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D017931:DNA Primers; D011719:Pyrazines; D012333:RNA, Messenger; D013871:Thiones; D013876:Thiophenes; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C026209:oltipraz; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D004128:Dimethylnitrosamine