Hepatoprotective effects of 18beta-glycyrrhetinic acid on carbon tetrachloride-induced liver injury: inhibition of cytochrome P450 2E1 expression.
The protective effects of 18beta-glycyrrhetinic acid (GA), the aglycone of glycyrrhizin (GL) derived from licorice, on carbon tetrachloride-induced hepatotoxicity and the possible mechanisms involved in this protection were investigated in mice. Pretreatment with GA prior to the administration of carbon tetrachloride significantly prevented an increase in serum alanine, aspartate aminotransferase activity and hepatic lipid peroxidation in a dose-dependent manner. In addition, pretreatment with GA also significantly prevented the depletion of glutathione (GSH) content in the livers of carbon tetrachloride-intoxicated mice. However, reduced hepatic GSH levels and glutathione-S-transferase activities were unaffected by treatment with GA alone. Carbon tetrachloride-induced hepatotoxicity was also prevented, as indicated by a liver histopathologic study. The effects of GA on the cytochrome P450 (P450) 2E1, the major isozyme involved in carbon tetrachloride bioactivation, were also investigated. Treatment of mice with GA resulted in a significant decrease of the P450 2E1-dependent hydroxylation of p-nitrophenol and aniline in a dose-dependent manner. Consistent with these observations, the P450 2E1 expressions were also decreased, as determined by immunoblot analysis. GA also showed antioxidant effects upon FeCl(2)-ascorbate-induced lipid peroxidation in mice liver homogenate and upon superoxide radical scavenging activity. These results show that protective effects of GA against the carbon tetrachloride-induced hepatotoxicity may be due to its ability to block the bioactivation of carbon tetrachloride, primarily by inhibiting the expression and activity of P450 2E1, and its free radical scavenging effects.
Jeong
Hye Gwang
HG
Department of Pharmacy and Research Center for Proteineous Materials, Chosun University, 375 Seosuk-dong, Kwangju 501-759, South Korea. hgjeong@mail.chosun.ac.kr
You
Ho Jin
HJ
Park
Sung Jun
SJ
Moon
Ae Ran
AR
Chung
Young Chul
YC
Kang
Shin Keon
SK
Chun
Hyo Kon
HK
D000287:Administration, Topical; D000409:Alanine / Q000097:blood / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000008:administration & dosage; D002712:Chlorides; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis / Q000187:drug effects; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D005290:Ferric Compounds / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D006035:Glycyrrhiza; D019695:Glycyrrhizic Acid / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D002712:Chlorides; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D005290:Ferric Compounds; D016166:Free Radical Scavengers; D010936:Plant Extracts; D013481:Superoxides; D019695:Glycyrrhizic Acid; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D001219:Aspartate Aminotransferases; D005978:Glutathione; D000409:Alanine; D006034:Glycyrrhetinic Acid; D001205:Ascorbic Acid; C024555:ferric chloride