Abstract
Tanshinone IIA is one of the most abundant constituents of the root of Salvia miltiorrhiza BUNGE which exerts antioxidant and anti-inflammatory actions in many experimental disease models. In the present study, we demonstrated that the standardized fraction of S. miltiorrhiza (Sm-SF) was able to protect RAW 264.7 cells from ethanol-and lipopolysaccharide (LPS)-induced production of superoxide radical, activation of NADPH oxidase and subsequently death of the cells. Among four main components of Sm-SF, tanshinone IIA was the most potent in protecting cells from LPS-and ethanol-induced cytotoxicity. LPS or ethanol induced the expression of CD14, iNOS, and SCD1 and decreased RXR-α, which was completely reversed by tanshinone IIA. In H4IIEC3 cells, 10 μM tanshinone IIA effectively blocked ethanol-induced fat accumulation as evidenced by Nile Red binding assay. These results indicate that tanshinone IIA may have potential to inhibit alcoholic liver disease by reducing LPS-and ethanol-induced Kupffer cell sensitization, inhibiting synthesis of reactive oxygen/nitrogen species, inhibiting fatty acid synthesis and stimulating fatty acid oxidation.
Similar content being viewed by others
References
Adachi, Y., Bradford, B. U., Gao, W., Bojes, H. K., and Thurman, R. G., Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology, 20, 453–460 (1994).
Babior, B. M., NADPH Oxidase: An Update. Blood, 93, 1464–1476 (1999).
Borenfreund, E. and Puerner, J. A., A simple quantitative procedure using monolayer cultures for cytotoxicity assays (HTD/NR-90). Methods Cell Sci., 9, 7–9 (1985).
Butler, J., Jayson, G. G., and Swallow, A. J., The reaction between the superoxide anion radical and cytochrome c. Biochim. Biophys. Acta., 408, 215–222 (1975).
Cao, E. H., Liu, X. Q., Wang, J. J., and Xu, N. F., Effect of natural antioxidant tanshinone II-A on DNA damage by lipid peroxidation in liver cells. Free Radic. Biol. Med., 20, 801–806 (1996).
Cathcart, M. K., Regulation of superoxide anion production by NADPH oxidase in monocytes/macrophages: contributions to atherosclerosis. Arterioscler. Thromb. Vasc. Biol., 24, 23–28 (2004).
Cheng, T. O., Cardiovascular effects of Danshen. Int. J. Cardiol., 121, 9–22 (2007).
Dobrzyn, P. and Dobrzyn, A., Stearoyl-CoA desaturase: A new therapeutic target of liver steatosis. Drug. Dev. Res., 67, 643 (2006).
Fu, J., Huang, H., Liu, J., Pi, R., Chen, J., and Liu, P., Tanshione IIA protects cardiac myocytes against oxidative stress-triggered damage and apoptosis. Eur. J. Pharmacol., 568, 213–221 (2007).
Gyamfi, M. A., Kocsis, M. G., He, L., Dai, G., Mendy, A. J., and Wan, Y. J., The role of retinoid X receptor alpha in regulating alcohol metabolism. J. Pharmacol. Exp. Ther., 319, 360–368 (2006).
Heitzer, T., Wenzel, U., Hink, U., Krollner, D., Skatchkov, M, Stahl, R. A., Macharzina, R., Brasen, J., Meinertz, T., and Munzel, T., Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: Evidence for an involvement of protein kinase C. Kidney Int., 55, 252–260 (1999).
Heyman, R. A., Mangelsdorf, D. J., Dyck, J. A., Stein, R. B., Eichele, G., Evans, R. M., and Thaller, C., 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell, 68, 397–406 (1992).
Hines, I. N. and Wheeler, M. D., Recent Advances in Alcoholic Liver Disease III. Role of the innate immune response in alcoholic hepatitis. Am. J. Physiol. Gastrointest. Liver Physiol., 287, 310–314 (2004).
IJpenberg, A., Tan, N.S., Gelman, L., Kersten, S., Seydoux, J., Xu, J., Metzger, D., Canaple, L., Chambon, P., and Wahli, W., In vivo activation of PPAR target genes by RXR homodimers. EMBO J., 23, 2083–2091 (2004).
Jang, S. I., Jeong, S. I., Kim, K. J., Kim, H. J., Yu, H. H., Park, R., Kim, H. M., and You, Y. O., Tanshione IIA from Salvia miltiorrhiza inhibits inducible nitric oxide synthase expression and production of TNF-alpha, IL-1beta and IL-6 in activated RAW 264.7 cells. Planta Med., 69, 1057–1959 (2003)
Karaa, A., Kamoun, W. S., and Clemens, M. G., chronic ethanol sensitizes the liver to endotoxin via effects on endothelial nitric oxide synthase regulation. Shock, 24, 447–454 (2005)
Kim, D. D., Sanchez, F. A., Duran, R. G., Kanetaka, T., and Duran, W. N., Endothelial nitric oxide synthase is a molecular vascular target for the Chinese herb Danshen in hypertension. Am. J. Physiol. Heart Circ. Physiol., 292, H2131–H2137 (2007).
Liu, Y., Wang, X., and Liu, Y., Protective effects of tanshinone IIA on injured primary cultured rat hepatocytes induced by CCI4. Zhong.Yao.Cai., 26, 415–417 (2003)
Miyazaki, M., Dobrzyn, A., Man, W.C., Chu, K., Sampath, H., Kim, H.J., and Ntambi, J.M., Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and-independent mechanisms. J. Biol. Chem., 279, 25164–25171 (2004).
Moldeus, P., Hogberg, J., and Orrenius, S., Isolation and use of liver cells. Methods Enzymol., 52,60–71(1978)
Nagy, L. E., Recent insights into the role of the innate immune systems in the development of alcoholic liver disease. Exp. Biol. Med., 228, 882–890 (2003).
Ng, T. B., Liu, F., and Wang, Z. T., Antioxidative activity of natural products from plants. Life Sci., 66, 709–723 (2000).
Ntambi, J. M., Miyazaki, M., Stoehr, J. P., Lan, H., Kendziorski, C. M., Yandell, B. S., Song, Y., Cohen, P., Friedman, J. M. and Attie, A. D., Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc. Natl. Acad. Sci., 99, 11482–11486 (2002).
Park, E. J., Zhao, Y. Z., Kim, Y. C., and Sohn, D. H., PF2401-SF, standardized fraction of Salvia miltiorrhiza and its constituents, tanshinone I, tanshinone IIA, and cryptotanshinone, protect primary cultured rat hepatocytes from bile acid-induced apoptosis by inhibiting jNK phosphorylation. Food Chem. Toxicol., 45, 1891–1898 (2007).
Pervaiz, S. and Clement, M. V., Superoxide anion: Oncogenic reactive oxygen species. Int. J. Biochem. Cell. Biol., 39, 1297–1304 (2007).
Ryu, S. Y., Lee, C. O., and Choi, S. U., In vitro cytotoxicity of tanshinones from Salvia miltiorrhiza. Planta Med., 63, 339–342 (1997).
Smith, S. A., Peroxisome proliferator-activated receptors and the regulation of mammalian lipid metabolism. Biochem. Soc. Trans., 30, 1086–1090 (2002).
Spitzer, J. A., Zheng, M., Kolls, J. K., Vande Stouwe, C., and Spitzer, J. J., Ethanol and LPS modulate NF-kappaB activation, inducible NO synthase and COX-2 gene expression in rat liver cells in vivo. Front. Biosci., 7, a99–a108 (2002).
Thurman, R. G., Mechanisms of hepatotoxicity II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Am. J. Physiol. Gastrointest. Liver Physiol., 275, 605–611 (1998).
Wang, X., Wei, Y., Yuan, S., Liu, G., Lu, Y., Zhang, J., and Wang, W., Potential anticancer activity of tanshinone IIA against human breast cancer. Int. J. Cancer, 116, 799–807 (2005).
Wheeler, M.D., Endotoxin and Kupffer cell activation in alcoholic liver disease. Alcohol Res. Health, 27, 300–306 (2003).
Xing, H. C., Li, L. J., Xu, K. J., Shen, T., Chen, Y. B., Chen, Y., Fu, S. Z., Sheng, J. F., Chen, C. L., Wang, J. G., Yan, D., Dai, F. W., and Sha, X. Y., Effects of Salvia miltiorrhiza on intestinal microflora in rats with ischemia/reperfusion liver injury. Hepatobiliary Pancreat. Dis. Int., 4, 274–280 (2005).
Yokoyama, H., Fukuda, M., Okamura, Y., Mizukami, T., Ohgo, H., Kamegaya, Y., Kato, S., and Ishii, H., Superoxide anion release into the hepatic sinusoid after an acute ethanol challenge and its attenuation by Kupffer cell depletion. Alcohol. Clin. Exp. Res., 23, 71S–75S (1999).
You, M., Fischer, M., Deeg, M. A., and Crabb, D. W., Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP). J. Biol. Chem., 277, 29342–29347 (2002).
Zhang, H. S. and Wang, S. Q., Nrf2 is involved in the effect of tanshinone IIA on intracellular redox status in human aortic smooth muscle cells. Biochem. Pharmacol., 73, 1358–1366 (2007).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yin, HQ., Kim, YS., Choi, YJ. et al. Effects of tanshinone IIA on the hepatotoxicity and gene expression involved in alcoholic liver disease. Arch. Pharm. Res. 31, 659–665 (2008). https://doi.org/10.1007/s12272-001-1209-2
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-001-1209-2