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The Anti-Fibrogenic Effect of a Pharmaceutical Composition of[5-(2-Pyrazinyl)-4-methyl-1,2-dithiol-3-thione] (Oltipraz) and Dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylene dioxybiphenyl-2,2′-dicarboxylate (DDB)  

Kang, Keon-Wook (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University)
Kim, Yoon-Gyoon (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University)
Kim, Choon-Won (Department of Clinical Pathology, Hanyang University Medical School)
Kim, Sang-Geon (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University)
Publication Information
Archives of Pharmacal Research / v.25, no.5, 2002 , pp. 655-663 More about this Journal
Abstract
Liver fibrosis is a prepathological state wherein damaged liver tissues in chronic liver diseases, such as hepatitis, are not repaired to normal tissues, but converted to fibrous tissue. 5-(2-Pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz), a cancer chemopreventive agent, is effective against a wide variety of chemical carcinogens. Recently, we reported that oltipraz inhibits liver fibrogenesis (Kang et al., 2002). In the present study, the effects of oltipraz in combination with dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDb) on dimethylnitrosamine (DMN)-induced liver fibrogenesis were assessed in rats. Oltipraz (30 mg/kg body weight, po, 3 times per week for 4 weeks) was found to inhibit the increases in plasma ALT, AST and bilirubin by DMN, whereas DDB (30 mg/kg body weight, po, 3 times per week for 4 weeks) attenuated the increases in the plasma ALT and bilirubin. The lowered plasma protein and albumin contents in DMN-treated rats were completely restored by oltipraz, but not by DDB. DDB decreases liver cell injury and inflammation through inhibition of nuclear factor-kB. DMN increased the accumulation of liver collagen, as indicated by the increase in the 4-hydroxyproline content in liver homogenates, which was reduced by treatment with oltipraz, but not by DDB. Given the differential effect between oltipraz and DDB, the potential enhancement of antifibrotic efficacy by the drugs was assessed in the animal model. Despite the minimal effect of DDB on DMN-induced fibrogenesis, DDB (5-25 mg/kg), administered together with oltipraz (25-5 mg/kg), showed an additive protective effect against hepatotoxicity and fibrosis induced by DMN, which was shown by the blood chemistry parameters and histopathological analysis. The adequate composition ratio of oltipraz to DDB was 5:1. These results provide information on the pharmaceutical composition, comprising of oltipraz and DDB as the active components, for the treatment and/or prevention of liver fibrosis and cirrhosis.
Keywords
Oltipraz; DDB; Fibrosis; Dimethylnitrosamine; Pharmaceutical composition;
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Times Cited By Web Of Science : 4  (Related Records In Web of Science)
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1 Kensler, T. W., Egner, P. A., Dolan, P. M., Groopman, J. D., and Roebuck, B. D., Mechanism of protection against aflatoxin tumorigenicity in rats fed 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) and related 1,2-dithiol-3-thiones and 1,2dithiol-3-ones. Cancer Res., 47, 4271-4277 (1987)   PUBMED
2 Kim, S. G., Nam, S. Y., Kim, C. W., Kim, J. H., Cho, C. K., and Yoo, S. Y., Enhancement of radiation-inducible hepatic glutathione S-transferase gene by oltipraz: possible role in radioprotection, Mol. Pharmacol., 51, 225-233 (1997)   PUBMED
3 Kim, S. G., Kwak, J. Y, Lee, J. W, Novak, R. F, Park, S. S., and Kim, N. D., Malotilate, a hepatoprotectant, suppresses CYP2E1 expression in rats. Biochem. Biaphys. Res. Commun., 200, 1414-1420 (1994)   DOI   ScienceOn
4 Mansuy, D., Sassi, A, Dansette, P. M., and Plat, M., A new potent inhibitor of lipid peroxidation in vitro and in vivo, the hepatoprotective drug anisyldithiolthione. Biochem. Biophys. Res Commun., 135, 1015-1021 (1986)   DOI   ScienceOn
5 Maxuitenko, Y. Y, Libby, A. H., Joyner, H. H., Curphey, T. J., Macmillan, D. L., and Kensler, T. W, Identification of dithiolthione with better chemopreventive properties than oltipraz. Carcinogenesis, 19, 1609-1615 (1998)   DOI   ScienceOn
6 Pendyala, L., Schwartz, G., Bolanowska-Higdon, W, Hitt, S., Zdanowicz, J., Murphy, M., Lawrence, D., and Creaven, P J., Phase I/pharmacodynamic study of N-acetylcysteine/oltipraz in smokers: early termination due to excessive toxicity. Cancer Epidemiol. Biomarkers Prev., 10, 269-272 (2001)   PUBMED
7 Stohs, S. J., Lawson, T A, Anderson, L., and Bueding, E., Effects of oltipraz, BHA, ADT and cabbage on glutathione metabolism, DNA damage and lipid peroxidation in old mice. Mech. Ageing Dev., 37, 137-145 (1986)   DOI   ScienceOn
8 Liu, K. T., and Lesca, P., Pharmacological properties of dibenzo[a,c]cyclooctene derivatives isolated from Fructus schizandrae chinensis Ⅲ. Inhibitory effects on carbon tetrachloride-induced lipid peroxidation, metabolism and covalent binding of carbon tetrachloride to lipids.. Chem. Biol. Interact., 41,39-47 (1982)   DOI   ScienceOn
9 Kim, J. Y., Baek, M., Lee, S., Kim, S. O., Dong, M. S., Kim, B. R., and Kim, D. H., Characterization of the selectivity and mechanism of cytochrome P450 inhibition by dimethyl-4,4'dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate. Drug Metab. Dispos., 29, 1555-1560 (2001)   PUBMED
10 Pares, A., Caballeria, L., Rodes, J., Bruguera, M., Rodrigo, L., Garcia-Plaza, A, Berenguer, J., Rodriguez-Martinez, D., Mercader, J., and Velicia, R., Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. J. Hepatol., 32, 561-566 (2000)   DOI   ScienceOn
11 George, J. and Chandrakasan, G., Molecular characteristics of dimethylnitrosamine-induced fibrotic liver collagen. Biochim. Biophys. Acta., 1292, 215-222 (1996)   DOI   PUBMED   ScienceOn
12 Zhang, B. C., Zhu, Y. R., Wang, J. B., Wu, Y, Zhang, Q. N., Qian, G. S., Kuang, S. Y, Li, Y. F, Fang, X., Yu, L. Y, De Flora, S., Jacobson, L. P., Zarba, A, Egner, P. A, He, X., Wang, J. S., Chen, B., Enger, C. L., Davidson, N. E., Gordon, G. B., Gorman, M. B., Prochaska, H. J., Groopman, J. D., Munoz, A, and Kensler, T.W, Oltipraz chemoprevention trial in Qidong, Jiangsu Province, People's Republic of China. J. Cell Biochem. Suppl., 28-29, 166-173 (1997)   PUBMED
13 Ansher, S. S., Dolan, P, and Bueding, E., Chemoprotective effects of two dithiolthiones and of butylhydroxyanisole against carbon tetrachloride and acetaminophen toxicity. Hepatology, 3 ,932-935 (1983)   DOI   PUBMED
14 Clapper, M. L., Everley, L. C., Strobel, L. A, Townsend, A J., and Engstrom, P. F., Coordinate induction of glutathione Stransferase $\alpha$, $\mu$, and $\pi$ expression in murine liver after a single administration of oltipraz. Mol. Pharmacol., 45, 469-474 (1994)   PUBMED
15 Shear, N. H., Malkiewicz, I. M., Klein, D., Koren, G., Randor, S., and Neuman, M. G., Acetaminophen-induced toxicity to human epidermoid cell line A431 and hepatoblastoma cell line Hep G2, in vitro, is diminished by silymarin. Skin Pharmacol., 8, 279-291 (1995)   DOI   PUBMED
16 Bueding, E., Dolan, P., and Leroy, J.P, The antischistosomal activity of oltipraz. Res. Commun. Chem. Pathol. Pharmacol., 37, 293-303 (1982)   PUBMED
17 Moragas, A, Allende, H., and Sans, M., Characteristics of perisinusoidal collagenization in liver cirrhosis: computer-assisted quantitative analysis. Anal. Quant. Cytol. Histol., 20, 169-177 (1998)   PUBMED
18 Davidson, N. E., Patricia, A. E., and Kensler, T. W., Transcriptional control of glutathione S-transferase gene expression by the chemoprotective agent 5-(2-pyrazinyl)-1 ,2-dithione (oltipraz) in rat liver. Cancer Res., 50, 2251-2255 (1990)   PUBMED
19 Kim S. G., Nam, S. Y, and Kim, C. W., In vivo radioprotective effects of oltipraz in g-irradiated mice, Biochem. Pharmacol., 55. 1585-1590 (1998)   DOI   PUBMED   ScienceOn
20 Kim, S. G., Kim, H. J., Choi, S. H., and Ryu, J. Y., Inhibition of lipopolysaccharide-induced I-kappaB degradation and tumor necrosis factor-alpha expression by dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB): minor role in hepatic detoxifying enzyme expression. Liver, 20 319-329 (2000)   DOI   ScienceOn
21 Lee, -. S., Kim, Y. T., and Jung, H. C., Prospective randomized controlled trial with diphenyldimethyldicarboxylate in chronic active liver disease: the effect on lowering serum alanine arriotransferase levels. Korean J. Int. Med., 40, 173-178 (1991)
22 Kondo, A, Ishikawa, O., Okada, K., Miyachi, Y, Abe, S., and Kuboki, Y., Measurement of histidinohydroxylysinonorleucine and hydroxyproline in skin collagen by reversed-phase high-pertormance liquid chromatography after 9-fluorenylmethyl chloroformate labeling. Anal. Biochem., 252, 255-259 (1997)   DOI   ScienceOn
23 Kang, K. W, Choi, S. H., Ha, J. R., Kim, C. W., and Kim, S. G., Inhibition of dimethylnitrosamine-induced liver fibrosis by [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] (oltipraz) in rats: suppression of transforming growth factor-beta1 and tumor necrosis factor-alpha expression. Chem. Biol. Interact., 139, 61-77 (2002)   DOI   ScienceOn
24 Manna, S. K., Mukhopadhyay, A., Van, N. T, and Aggarwal, B.B, Silymarin Suppresses TNF-Induced Activation of NF-kappa B, c-Jun N-Terminal Kinase, and Apoptosis, J. lmmunol., 163, 6800-6809 (1999)
25 Bolton, M.G., Munoz, A, Jacobson, L. P, Groopman, J. D., Maxuitenko, Y. Y., and Roebuck, B. D., Transient intervention with oltipraz protects against aflatoxin-induced hepatic tumorigenesis. Cancer Res., 53, 3499-3504 (1993)   PUBMED
26 Kim, S. G., Nam, S. Y., Chung, H. C., Hong, S. Y, Jung, K. H., Enhanced effectiveness of dimethyl-4,4'-dimethoxy-5,6,5',6'-dirnethylene dioxybiphenyl-2,2'-dicarboxylate in combination with garlic oil against experimental hepatic injury in rats and mice. J. Pharm. Pharmacol., 47, 678-682 (1995)   DOI   PUBMED
27 Shimizu, I., Ma, Y. R., Mizobuchi, Y, Liu, F, Miura, T, Nakai, Y., Yasuda, M., Shiba, M., Horie, T, Amagaya, S., Kawada, N., Hori, H., and Ito, S., Effects of Sho-saiko-to, a Japanese herbal medicine, on hepatic fibrosis in rats. Hepatology, 29, 149-160 (1999)   DOI   ScienceOn
28 Igarashi, S., Hatahara, T., Nagai, Y., Hori, H., Sakakibara, K., Katoh, M., Sakai, A, and Sugimoto, T., Anti-fibrotic effect of malotilate on liver fibrosis induced by carbon tetrachloride in rats. Jpn. J. Exp. Med., 56, 235-45 (1986)   PUBMED
29 Tsukamoto, H., Matsuoka, M., and French, S. W., Experimental models of hepatic fibrosis: a review. Semin. Liv. Dis., 10, 56-63 (1990)   DOI   ScienceOn
30 Kim, J. H., Ahn, Y. K., and Ohsawa, M., Enhancing effects of diphenyl dimethyl dicarboxylate on serum antibody production in Balb/c mice. Biol. Pharm. Bull., 18, 24-27 (1995)   DOI   PUBMED   ScienceOn
31 Okuno, H., Murase, T, Nakanishi, S., Shiozaki, Y, and Sameshima, Y, Effect of malotilate (diisopropyl 1,3-dithiol-2-ylidenemalonate) on drug metabolizing activity in rat liver microsomes. Jpn. J. Pharmacol., 44, 303-310 (1987)   DOI   PUBMED
32 Kremer, J. M., Lee, R. G., and Tolman, K. G., Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. A prospective study with baseline and sequential biopsy samples. Arthritis Rheum., 32, 121-127 (1989)   DOI   ScienceOn