Stronger Neo-Minophagen C, a glycyrrhizin-containing preparation, protects liver against carbon tetrachloride-induced oxidative stress in transgenic mice expressing the hepatitis C virus polyprotein.
OBJECTIVE
Stronger Neo-Minophagen C (SNMC), a glycyrrhizin-containing preparation, has been used as a treatment for chronic hepatitis for more than 30 years in Japan, and shown to be effective in preventing the development of hepatocellular carcinoma in chronic hepatitis C patients, but its underlying mechanisms remain elusive. The aim of this study was to investigate if SNMC had an anti-oxidative effect, as oxidative stress has been proposed to be one of the mechanisms of liver injury in hepatitis C virus (HCV)-associated chronic liver diseases.


METHODS
The protective effect of SNMC against carbon tetrachloride (CCl4)-induced liver injury was examined using transgenic mice expressing the HCV polyprotein.


RESULTS
A small dose of CCl4 (10 microl/kg of body weight) significantly increased the serum alanine aminotransferase (ALT) level and hepatic malondialdehyde content, decreased hepatic reduced glutathione (GSH) content and induced ultrastructural alterations of hepatic mitochondria in transgenic mice, but not in nontransgenic mice. A single SNMC treatment equivalent to a clinical dose significantly restored the serum ALT level and hepatic malondialdehyde and GSH contents, attenuated the ultrastructural alterations of hepatic mitochondria, and increased mRNA expression of gamma-glutamylcysteine synthetase (gamma-GCS).


CONCLUSIONS
Transgenic mice expressing the HCV polyprotein are abnormally vulnerable to oxidative stress. SNMC protects hepatocytes against CCl4-induced oxidative stress and mitochondrial injury in the presence of HCV proteins by restoring depleted cellular GSH.
Hidaka
Isao
I
Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Hino
Keisuke
K
Korenaga
Masaaki
M
Gondo
Toshikazu
T
Nishina
Sohji
S
Ando
Miye
M
Okuda
Michiari
M
Sakaida
Isao
I
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury; D003545:Cysteine / Q000494:pharmacology* / Q000627:therapeutic use; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004195:Disease Models, Animal; D004338:Drug Combinations; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005998:Glycine / Q000494:pharmacology* / Q000627:therapeutic use; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D008107:Liver Diseases / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects*; D020815:Polyproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D000975:Antioxidants; D004338:Drug Combinations; D020815:Polyproteins; D012333:RNA, Messenger; D014764:Viral Proteins; D008315:Malondialdehyde; C083319:stronger neominophagen C; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D000410:Alanine Transaminase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D003545:Cysteine; D006034:Glycyrrhetinic Acid; D005998:Glycine