Protective Effect of Glycyrrhizin, Glycyrrhetic Acid and Matrine on Acute Cholestasis Induced by α-Naphthyl Isothiocyanate in Rats

Abstract

α-Naphthyl isothiocyanate (ANIT) is a known hepatotoxicant that causes acute cholestatic hepatitis characterized by the infiltration of neutrophils around bile ducts and necrotic hepatocytes. The effects of glycyrrhizin (GL), 18β-glycyrrhetinic acid (GA), matrine (MT), oxymatrine (OMT), salvianolic acid B (SAB), silymarin (SI) and dexamethasone (DEX) on ANIT-induced acute cholestasis in rats were investigated. Serological and histological data demonstrated that the administration of GL, GA or MT all protected against hepatocyte injury and cholestasis induced by ANIT. Furthermore, the bile flow and the accumulative bile excretion of ketoprofen glucuronide (KPG), that were significantly suppressed by ANIT, were preserved in rats administered GL, GA or MT. DEX protected against acute cholestasis but did not protect against hepatocyte necrosis and elevated serum alanine aminotransferase levels following ANIT administration. Rats administrated OMT, SAB or SI were not resistant to ANIT toxicity. In summary, the protective effect of DEX is directed toward cholangiocytes rather than hepatocytes whereas the natural products, GA, GL and MT, exhibit significantly better protective effects against ANIT-induced liver damage including the protection of hepatocytes as well as cholangiocytes.

Abbreviations

ANIT:α-naphthyl isothiocyanate

GL:glycyrrhizin

GA:18β-glycyrrhetinic acid

MT:matrine

OMT:oxymatrine

SAB:salvianolic acid B

SI:silymarin

DEX:dexamethasone

KPG:ketoprofen glucuronide

RP-HPLC:reversed-phase high-performance liquid chromatography

ALT:alanine aminotransferase

Tbil:total bilirubin

ALP:alkaline phosphatase

γ-GT:γ-glutamyl transpeptidase

Hibiscus sabdariffa - Malvaceae - antihypertensive - standardized herbal medicinal product - complementary and alternative medicine

References

• 1 Rutherford A E, Pratt D S. Cholestasis and cholestatic syndromes.  Curr Opin Gastroenterol. 2006;  22 209-14
• 2 Finney R S, Somers G F. The antiinflammatory activity of glycyrrhetinic acid and derivatives.  J Pharmacol. 1958;  10 613-20
• 3 Ohuchi K, Kamada Y, Levine L, Tsurufuji S. Glycyrrhizin inhibits prostaglandin E2 production by activated peritoneal macrophages from rats.  Prostaglandins Med. 1981;  7 457-63
• 4 Kiso Y, Tohkin M, Hikino H, Hattori M, Sakamoto T, Namba T. Mechanism of antihepatotoxic activity of glycyrrhizin. I: Effect of free radical generation and lipid peroxidation.  Planta Med. 1984;  50 298-302
• 5 Nose M, Ito M, Kamimura K, Shimizu M, Ogihara Y. A comparison of the antihepatotoxic activity between glycyrrhizin and glycyrrhetinic acid.  Planta Med. 1994;  60 136-9
• 6 Sasaki H, Takei M, Kobayashi M, Pollard R B, Suzuki F. Effect of glycyrrhizin, an active component of licorice roots, on HIV replication in cultures of peripheral blood mononuclear cells from HIV-seropositive patients.  Pathobiology. 2002 - 2003;  70 229-36
• 7 Abe N, Ebina T, Ishida N. Interferon induction by glycyrrhizin and glycyrrhetinic acid in mice.  Microbiol Immunol. 1982;  26 535-9
• 8 Cheng H, Xia B, Zhang L, Zhou F, Zhang Y X, Ye M. et al . Matrine improves 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice.  Pharmacol Res. 2006;  53 202-8
• 9 Lao Y. Clinical study of matrine injection on preventing liver function damage of anti-tumor drugs during chemotherapy of breast cancer.  Zhong Yoo Cai. 2005;  28 735-7
• 10 Pei R J, Xiao L, Fan X P, Liu X J. The effects of matrine on mouse immune functions.  Hai Xia Yao Xue. 1998;  10 7-8
• 11 Liu X S, Jiang J, Jiao X Y, Wu Y E, Lin J H. Matrine-induced apoptosis in leukemia U937 cells: involvement of caspases activation and MAPK-independent pathways.  Planta Med. 2006;  72 501-6
• 12 Zheng P, Niu F L, Liu W Z, Shi Y, Lu L G. Anti-inflammatory mechanism of oxymatrine in dextran sulfate sodium-induced colitis of rats.  World J Gastroenterol. 2005;  11 4912-5
• 13 Wu X N, Wang G J. Experimental studies of oxymatrine and its mechanisms of action in hepatitis B and C viral infections.  Chin J Dig Dis. 2004;  5 12-6
• 14 Yu X H, Zhu J S, Yu H F, Zhu L. Immunomodulatory effect of oxymatrine on induced CCl4-hepatic fibrosis in rats.  Chin Med J (Engl). 2004;  117 1856-8
• 15 Liu G T, Zhang T M, Wang B E, Wang Y W. Protective action of seven natural phenolic compounds against peroxidative damage to biomembranes.  Biochem Pharmacol. 1992;  43 147-52
• 16 Wasser S, Ho J M, Ang H K, Tan C E. Salvia miltiorrhiza reduces experimentally-induced hepatic fibrosis in rats.  J Hepatol. 1998;  29 760-71
• 17 Nan J X, Park E J, Kang H C, Park P H, Kim J Y, Sohn D H. Anti-fibrotic effects of a hot-water extract from Salvia miltiorrhiza roots on liver fibrosis induced by biliary obstruction in rats.  J Pharm Pharmacol. 2001;  53 197-204
• 18 Huang Y T, Lee T Y, Lin H C, Chou T Y, Yang Y Y, Hong C Y. Hemodynamic effects of Salvia miltiorrhiza on cirrhotic rats.  Can J Physiol Pharmacol. 2001;  79 566-72
• 19 Song Z, Deaciuc I, Song M, Lee D Y, Liu Y, Ji X. et al . Silymarin protects against acute ethanol-induced hepatotoxicity in mice.  Alcohol Clin Exp Res. 2006;  30 407-13
• 20 Letteron P, Labbe G, Degott C, Berson A, Fromenty B, Delaforge M. et al . Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant.  Biochem Pharmacol.. 1990;  39 2027-34
• 21 Dahm L J, Schultze A E, Roth R A. An antibody to neutrophils attenuates alpha-naphthyl isothiocyanate-induced liver injury.  J Pharmacol Exp Ther. 1991;  256 412-20
• 22 Roth R A, Dahm L J. Neutrophil- and glutathione-mediated hepatotoxicity of alpha-naphthyl isothiocyanate.  Drug Metab Rev. 1997;  29 153-65
• 23 Meunier C J, Verbeeck R K. Glucuronidation kinetics of R,S-ketoprofen in adjuvant-induced arthritic rats.  Pharmacol Res. 1999;  16 1081-6
• 24 Desmond P V, Smyth F E, Mashford M L. Release of latent glucuronosyltransferase activity contributes to the sparing of glucuronidation in experimental liver injuries.  J Gastroenterol Hepatol. 1994;  9 350-4
• 25 Elbekai R H, Korashy H M, El-Kadi A O. The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes.  Curr Drug Metab. 2004;  5 157-67