Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibitory Effect of 1-O-Hexyl-2,3,5-Trimethylhydroquinone on Dimethylnitrosamine-induced Liver Fibrosis in Male SD Rats

  • Jung, Yu-Ri (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Lee, Young-Jung (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Lee, Nam-Jin (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Lin, Chun-Mai (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Moon, Jun-Hawn (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Chai, Hee-Yul (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Kang, Jong-Koo (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University)
  • Received : 2010.06.27
  • Accepted : 2010.08.14
  • Published : 2010.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Hepatic fibrosis represents the main complication of most chronic liver disorders and, regardless of its etiology, is characterized by excessive deposition of extracellular matrix components. In this study, we examined that 1-O-Hexyl-2,3,5-Trimethylhydroquinone (HTHQ), a potent anti-oxidative agent, could prevent experimental hepatic fibrosis induced by dimethylnitrosamine (DMN) in male SD rats. Except for vehicle control group, other groups were induced hepatic fibrosis by intraperitoneal injection with DMN (10 mg/ml/kg) on 3 consecutive days weekly for 4 weeks. During the same 4 weeks, control and DMN groups were given vehicle and HTHQ 50, 100 and 200 groups were orally administered HTHQ (50, 100, 200 mg/kg respectively). In HTHQ 100 and 200 groups, relative liver weight and serum chemistry level improved significantly. HTHQ reduced hydroxyproline (p < 0.05) and malondialdehyde (p < 0.05) level in the liver. Histopathological examination of H&E, Masson's trichrome stain showed the reduced fibrotic septa in HTHQ 100 and 200 groups. HTHQ administration showed reduced mRNA level of PDGF (Platelet-derived growth factor), $\alpha$-SMA ($\alpha$-smooth muscle actin) and TGF-$\beta$ (transforming growth factor-$\beta$) than DMN-induced hepetic fibrosis animals in the liver tissue. In this study, we showed that HTHQ improves against DMN-induced liver fibrosis in male SD rats.

Keywords

References

  1. Ahmed, A. and Keeffe, E.B. (2004). Chronic hepatitis C with normal aminotransferase levels. Gastroenterology, 126, 1409-1415. https://doi.org/10.1053/j.gastro.2004.02.073
  2. Baskol, G., Atmaca, H., Tanriverdi, F., Baskol, M., Kocer, D. and Bayram, F. (2007). Oxidative stress and enzymatic antioxidant status in patients with hypothyroidism before and after treatment. Exp. Clin. Endocrinol. Diabetes, 115, 522-526. https://doi.org/10.1055/s-2007-981457
  3. Bertelli, A.A., Giovannini, L., Stradi, R., Bertelli, A. and Tillement,J.P. (1996). Plasma, urine and tissue levels of trans- and cis-resveratrol (3,4',5-trihydroxystilbene) after short-term or prolonged administration of red wine to rats. Int. J. Tissue React., 18, 67-71.
  4. Britton, R.S. and Bacon, B.R. (1994). Role of free radicals in liver diseases and hepatic fibrosis. Hepatogastroenterology, 41, 343-348.
  5. Cooksley, W.G., Bradbear, R.A., Robinson, W., Harrison, M., Halliday,J.W., Powell, L.W., Ng, H.S., Seah, C.S., Okuda, K.,Scheuer, P.J. and Sherlock, S. (1986). The prognosis of chronicactive hepatitis without cirrhosis in relation to bridging necrosis. Hepatology, 6, 345-348. https://doi.org/10.1002/hep.1840060302
  6. Edwards, C.K., 3rd, Myers, M.J., Kelley, K.W. and Schook, L.B.(1991). Enhanced macrophage anti-microbial activity followingdimethylnitrosamine exposure in vivo is related to augmentedproduction of reactive oxygen metabolites. Immunopharmacol.Immunotoxicol., 13, 395-411. https://doi.org/10.3109/08923979109019713
  7. Elsharkawy, A.M., Wright, M.C., Hay, R.T., Arthur, M.J., Hughes,T., Bahr, M.J., Degitz, K. and Mann, D.A. (1999). Persistentactivation of nuclear factor-kappaB in cultured rat hepatic stellate cells involves the induction of potentially novel Rel-like factors and prolonged changes in the expression of IkappaBfamily proteins. Hepatology, 30, 761-769. https://doi.org/10.1002/hep.510300327
  8. Farber, E. (1996). Orientation in Liver Toxicity by Drugs, Handbook of Experimental Pharmacology, Springer-Verlag, Berlin,Germany.
  9. Friedman, S.L. (1990). Cellular sources of collagen and regulation of collagen production in liver. Semin. Liver Dis., 10, 20-29. https://doi.org/10.1055/s-2008-1040454
  10. Friedman, S.L. (2000). Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J. Biol. Chem., 275, 2247-2250. https://doi.org/10.1074/jbc.275.4.2247
  11. Friedman, S.L., Roll, F.J., Boyles, J. and Bissell, D.M. (1985).Hepatic lipocytes: the principal collagen-producing cells of normal rat liver. Proc. Natl. Acad. Sci. USA, 82, 8681-8685. https://doi.org/10.1073/pnas.82.24.8681
  12. Gressner, A.M. and Bachem, M.G. (1990). Cellular sources ofnoncollagenous matrix proteins: role of fat-storing cells in fibrogenesis. Semin. Liver Dis., 10, 30-46. https://doi.org/10.1055/s-2008-1040455
  13. Haggerty, H.G. and Holsapple, M.P. (1990). Role of metabolism indimethylnitrosamine-induced immunosuppression: a review. Toxicology, 63, 1-23. https://doi.org/10.1016/0300-483X(90)90064-N
  14. Hashimoto, N., Ishikawa, Y. and Utsunomiya, J. (1989). Effects of portacaval shunt, transposition, and dimethylnitrosamine-induced chronic liver injury on pancreatic hormones and amino acids in dog. J. Surg. Res., 46, 35-40. https://doi.org/10.1016/0022-4804(89)90179-0
  15. Hirose, M., Akagi, K., Hasegawa, R., Yaono, M., Satoh, T., Hara,Y., Wakabayashi, K. and Ito, N. (1995a). Chemoprevention of2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP)-induced mammary gland carcinogenesis by antioxidants inF344 female rats. Carcinogenesis, 16, 217-221. https://doi.org/10.1093/carcin/16.2.217
  16. Hirose, M., Hasegawa, R., Kimura, J., Akagi, K., Yoshida, Y.,Tanaka, H., Miki, T., Satoh, T., Wakabayashi, K., Ito, N. andShirai, T. (1995b). Inhibitory effects of 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), green tea catechins and other antioxidants on 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole(Glu-P-1)-induced rat hepatocarcinogenesis and dose-dependentinhibition by HTHQ of lesion induction by Glu-P-1 or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). Carcinogenesis,16, 3049-3055. https://doi.org/10.1093/carcin/16.12.3049
  17. Hirose, M., Ito, T., Takahashi, S., Ozaki, M., Ogiso, T., Nihro, Y.,Miki, T. and Shirai, T. (1998). Prevention by synthetic phenolic antioxidants of 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)- or activated MeIQx-induced mutagenesis and MeIQx-induced rat hepatocarcinogenesis, and role of antioxidant activity in the prevention of carcinogenesis. Eur. J. Cancer Prev., 7, 233-241. https://doi.org/10.1097/00008469-199806000-00008
  18. Hirose, M., Iwata, S., Ito, E., Nihro, Y., Takahashi, S., Mizoguchi,Y., Miki, T., Satoh, T., Ito, N. and Shirai, T. (1995c). Strong anti-mutagenic activity of the novel lipophilic antioxidant 1-Ohexyl-2,3,5-trimethylhydroquinone against heterocyclic amineinduced mutagenesis in the Ames assay and its effect on metabolic activation of 2-amino-6-methyldipyrido[1,2-a:3',2'-d] imidazole (Glu-p-1). Carcinogenesis, 16, 2227-2232. https://doi.org/10.1093/carcin/16.9.2227
  19. Jezequel, A.M., Mancini, R., Rinaldesi, M.L., Ballardini, G., Fallani, M., Bianchi, F. and Orlandi, F. (1989). Dimethylnitrosamine-induced cirrhosis. Evidence for an immunological mechanism. J. Hepatol., 8, 42-52. https://doi.org/10.1016/0168-8278(89)90160-8
  20. Lang, A., Schoonhoven, R., Tuvia, S., Brenner, D.A. and Rippe,R.A. (2000). Nuclear factor kappaB in proliferation, activation,and apoptosis in rat hepatic stellate cells. J. Hepatol., 33, 49-58. https://doi.org/10.1016/S0168-8278(00)80159-2
  21. Li, B.L., Zhao, X.X., Liu, X.Y., Kim, H.S., Raska, K., Jr., Ortaldo,J.R., Schwartz, B. and Pestka, S. (1990). Alpha-interferon structure and natural killer cell stimulatory activity. Cancer Res., 50, 5328-5332.
  22. Luckey, S.W. and Petersen, D.R. (2001). Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. Exp. Mol. Pathol., 71, 226-240. https://doi.org/10.1006/exmp.2001.2399
  23. Magee, P.N. and Barnes, J.M. (1967). Carcinogenic nitroso compounds. Adv. Cancer Res., 10, 163-246. https://doi.org/10.1016/S0065-230X(08)60079-2
  24. Mancuso, C., Pani, G. and Calabrese, V. (2006). Bilirubin: anendogenous scavenger of nitric oxide and reactive nitrogen species. Redox Rep., 11, 207-213. https://doi.org/10.1179/135100006X154978
  25. Marra, F., Gentilini, A., Pinzani, M., Choudhury, G.G., Parola, M., Herbst, H., Dianzani, M.U., Laffi, G., Abboud, H.E. and Gentilini,P. (1997). Phosphatidylinositol 3-kinase is required for platelet-derived growth factor’s actions on hepatic stellate cells. Gastroenterology, 112, 1297-1306. https://doi.org/10.1016/S0016-5085(97)70144-6
  26. Maton, A., Hopkins J., McLaughlin, C.W., Johnson, S., Warner,M.Q., LaHart, D. and Wright, J.D. (1993). Human Biology andHealth. Englewood Cliffs, New Jersey, USA: Prentice Hall.
  27. McGavin, M.D. and Zachary, J.F. (2007). Pathologic basis of veterinary disease, Elsevier Mosby, St.Louis.
  28. Nihro, Y., Furukawa, H., Sogawa, S., Wang, T.C., Miyataka, H., Matsumoto, H., Miki, T. and Satoh, T. (1994). Synthesis and anti lipid-peroxidation activity of hydroquinone monoalkyl ethers. Chem. Pharm. Bull. (Tokyo), 42, 576-579. https://doi.org/10.1248/cpb.42.576
  29. Pinzani, M., Marra, F. and Carloni, V. (1998). Signal transduction in hepatic stellate cells. Liver, 18, 2-13.
  30. Saile, B., Matthes, N., Knittel, T. and Ramadori, G. (1999). Transforming growth factor beta and tumor necrosis factor alphainhibit both apoptosis and proliferation of activated rat hepatic stellate cells. Hepatology, 30, 196-202. https://doi.org/10.1002/hep.510300144
  31. Shiba, M., Shimizu, I., Yasuda, M., Ii, K. and Ito, S. (1998).Expression of type I and type III collagens during the course ofdimethylnitrosamine-induced hepatic fibrosis in rats. Liver, 18,196-204.
  32. Shimizu, I., Mizobuchi, Y., Yasuda, M., Shiba, M., Ma, Y.R.,Horie, T., Liu, F. and Ito, S. (1999). Inhibitory effect of oestradiol on activation of rat hepatic stellate cells in vivo and in vitro. Gut, 44, 127-136. https://doi.org/10.1136/gut.44.1.127
  33. Strain, A. and Anna, M.D. (1998). Liver Growth and Repair,Chapman & Hall, London.
  34. Trump, B.F. and Berezesky, I.K. (1992). The role of cytosolicCa2+ in cell injury, necrosis and apoptosis. Curr. Opin. Cell Biol., 4, 227-232.

Cited by

  1. Expression vol.118, pp.10, 2017, https://doi.org/10.1002/jcb.25993
  2. Lactobacillus Aggravate Bile Duct Ligation-Induced Liver Inflammation and Fibrosis in Mice vol.34, pp.3, 2018, https://doi.org/10.5487/TR.2018.34.3.241