N-acetylcysteine prevents carbon tetrachloride-induced liver cirrhosis: role of liver transforming growth factor-beta and oxidative stress.
OBJECTIVE
N-acetylcysteine (NAC) is an antioxidant, a precursor of reduced glutathione, and an inhibitor of the profibrotic cytokine liver transforming growth factor-beta (TGF-beta). Carbon tetrachloride (CCl4) cirrhosis is characterized by oxidative stress and fibrosis. Therefore, the aim of this work was to study the effect of NAC on experimental cirrhosis.


METHODS
CCl4 was chronically administered for 8 weeks along with 300 mg/kg of NAC orally once a day. Alkaline phosphatase, alanine aminotransferase, and gamma-glutamyltranspeptidase were measured in plasma. Hydroxyproline, glycogen, lipid peroxidation, glutathione were determined in liver samples by colorimetric methods. TGF-beta was evaluated by western blotting, and a histopathological analysis was performed.


RESULTS
Serum markers of liver damage increased by CCl4 intoxication (P<0.05), whereas cotreatment with NAC prevented these increases (P<0.05); glycogen was depleted in the cirrhotic group (P<0.05), but preserved by NAC (P<0.05). Lipid peroxidation increased and glutathione decreased by the administration of CCl4 (P<0.05), again NAC prevented both effects (P<0.05). Importantly, collagen increased by about seven-fold in the CCl4 group (P<0.05); administration of NAC preserved the normal levels of collagen (P<0.05). Biochemical determinations were corroborated by hematoxylin and eosin, and trichromic stains. Western blots revealed a four-fold increase in TGF-beta in the group receiving CCl4, NAC cotreatment abolished TGF-beta signal (P<0.05).


CONCLUSIONS
Our results strongly suggest that NAC prevents experimental cirrhosis by two mechanisms: by preventing oxidative stress and by downregulating the profibrogenic cytokine TGF-beta. As NAC is currently used in humans intoxicated with paracetamol, it can be tested in fibrotic or cirrhotic patients under controlled trials.
Galicia-Moreno
Marina
M
External Section of Pharmacology, Cinvestav-IPN, Mexico City, Mexico.
Rodríguez-Rivera
Adriana
A
Reyes-Gordillo
Karina
K
Segovia
José
J
Shibayama
Mineko
M
Tsutsumi
Victor
V
Vergara
Paula
P
Moreno
Mario G
MG
Muriel
Pablo
P
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002251:Carbon Tetrachloride; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000187:drug effects* / Q000378:metabolism
D000975:Antioxidants; D016212:Transforming Growth Factor beta; D002251:Carbon Tetrachloride; D000111:Acetylcysteine