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)

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, p.o., 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, p.o., 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.

Effects of Biphenyldimethyl-dicarboxylate Administration Alone or Combined with Silymarin in the CCL4Model of Liver Fibrosis in Rats

“…In the present work, treatment of rats with DDB or silymarin along with CCl 4 resulted in diminution of cirrhosis and fibrosis. Other researchers reported that dimethylnitrosamine (DMN)-induced liver fibrogenesis, however, was not reduced by DDB [28]. In rats treated with CCl 4 , Favari and Perez-Alvarez [46] reported a 55% reduction in liver collagen by silymarin.…”

“…It is worth to note that both DDB and silymarin possess important anti-inflammatory properties, which are likely to be of relevance to their hepatoprotective and antifibrotic effects. Kang et al [28] suggested that DDB decreases liver cell injury and inflammation through inhibition of nuclear factor-kB. In an immune-mediated liver injury caused by concanavalin A in mice, the elevation of serum TNF-alpha and liver TNF-alpha mRNA expression 2 h after Con A injection was decreased by the prior administration of DDB [38].…”

“…Biphenyldimethyldicarboxylate and silymarin were dissolved in saline to obtain the necessary doses. The doses of DDB and silymarin used in the study were chosen based on other studies in which the drugs produced beneficial effects in models of hepatic injury [14,15,28,29].…”

Comparative Analysis of the Antioxidative and Hepatoprotective Activities of Dimethyl Diphenyl Bicarboxylate in Four Animal Models of Hepatic Injury

“…Thus, DDB is a promising approach as compared to Schisandra chinensis and its active compounds for clinical application. In addition, DDB effectively ameliorated serum aminotransferase, oxidative stress-associated parameters, and liver fibrosis in previous studies [18][19][20]. Owing to its quick effects, low price and easy synthesis by using gallic acid, DDB has widely been applied as a hepatoprotective and antiviral therapeutic agent to cure various liver disorders in Asian countries, such as south Korea, China, and Indonesia [21][22][23][24].…”

Pharmacokinetic interaction between oltipraz and dimethyl-4,4‘-dimethoxy-5,6,5′,6’-dimethylene dioxybiphenyl-2,2′-dicarboxylate (DDB) after single intravenous and oral administration to rats

“…Oltipraz (oltipraz powder was suspended in 40% PEG 400, 50 mg kg ¡1 , nˆ7), DDB (DDB powder was also suspended in 40% PEG 400, 10 mg kg ¡1 , nˆ7) and oltipraz (50 mg kg ¡1 ) plus DDB (10 mg kg ¡1 ) (nˆ9) were administered via the jugular vein over 1 min (total injection volume was approximately 0.6 mL). It has been reported from our laboratories (Kang et al 2002b) that an improved liver antifibrotic effect was observed when oltipraz (25 mg kg ¡1 ) plus DDB (5 mg kg ¡1 ) was administered orally to rats. Because of the assay sensitivity of DDB, the dose of DDB and oltipraz was increased twice in the present study.…”