Protective effect of verapamil on multiple hepatotoxic factors-induced liver fibrosis in rats.
ABSTRACT The purpose of the present work was to investigate the effect of verapamil on liver fibrosis induced by multiple hepatotoxic factors in rats. Male Wistar rats were divided into a normal control group, a liver fibrosis model control group, and verapamil groups with different dosages. Multiple hepatotoxic factors including carbon tetrachloride (CCl(4)), ethanol and high cholesterol were used to make the animal model of liver fibrosis. The parameters of serum l-alanine aminotransferase (ALT), liver malondialdehyde and hydroxyproline contents were measured. Samples of the liver obtained by biopsy were subjected to histological and immunohistochemical studies for the expressions of alpha-smooth muscle actin (alpha-SMA) and transforming growth factor-beta(1) (TGF-beta(1)). Results showed that verapamil induced a dose-dependent decrease of serum ALT, liver malondialdehyde and hydroxyproline compared with liver fibrosis model control. Verapamil reduced hepatocyte degeneration and necrosis, and delayed the formation of liver fibrosis. The levels of expression of alpha-SMA and TGF-beta(1) in the hepatic tissue of three of the verapamil-treated groups were significantly less than those of the liver fibrosis model control group. The results showed that verapamil acts against the formation of liver fibrosis, the mechanism might be due to a protective effect for hepatocytes and through decreasing TGF-beta(1) to block the activation of hepatic stellate cells (HSCs) and collagen gene expression.
Article: Pathogenesis of liver cirrhosis[Show abstract] [Hide abstract]
ABSTRACT: Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.World Journal of Gastroenterology 06/2014; 20(23):7312-7324. DOI:10.3748/wjg.v20.i23.7312 · 2.43 Impact Factor
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ABSTRACT: Objective The objective of this study was to investigate the synergistic antifibrotic effect of verapamil and interferon-gamma (IFN-gamma) on rat liver fibrosis and its potential pharmacokinetic-based mechanism. Methods Rat liver fibrosis model was successfully established, and both the therapeutic effects and pharmacokinetic parameters of verapamil were evaluated after the administration of verapamil with or without IFN-gamma. The activities of cytochrome P450 3A (CYP3A) and the expression of multidrug resistance (Mdr) mRNA were measured in liver and small intestine. Results The results showed the synergistic antifibrotic effect of verapamil and IFN-gamma in rat liver fibrosis, in terms of decreased serum L-alanine aminotransferase activity and liver hydroxyproline content and improved liver histopathology, when compared with rats treated with verapamil or IFN-gamma alone. Meanwhile, the area under the curve of verapamil increased significantly after single administration of verapamil and IFN-gamma and the concentration of verapamil in plasma increased, but the metabolite : parent ratio of verapamil decreased after consecutive administrations of verapamil and IFN-gamma. Furthermore, the activities of CYP3A in both the liver and the small intestine and the expression of Mdr in small intestine decreased in rats treated with verapamil and IFN-gamma. Conclusion All these results indicated that the combination of verapamil and IFN-gamma exerts a synergistic antifibrotic effect on rat liver fibrosis. The mechanism was partially based on the enhanced oral bioavailability of verapamil by increasing the intestinal absorption as well as reducing the first-pass metabolism, through inhibition of CYP3A activity and P-glycoprotein expression by IFN-gamma. Eur J Gastroenterol Hepatol 22:466-473 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.European Journal of Gastroenterology & Hepatology 04/2010; 22(4):466-473. DOI:10.1097/MEG.0b013e32833226d5 · 2.15 Impact Factor
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ABSTRACT: Liver fibrosis progresses to cirrhosis in several settings, for example, severe acute alcoholic hepatitis, and hepatitis C virus (HCV) reinfection after liver transplantation. Cirrhosis produces hepatocellular dysfunction, which is also a risk factor for hepatocellular carcinoma. We studied verapamil as a prophylactic, therapeutic antifibrotic drug alone and in combination with silymarin in experimental rat's liver-induced fibrosis. Liver fibrosis was induced by intra-peritoneal injection of rats with pig serum 0.5ml twice weekly for 6 weeks, which resulted in score three fibrosis. Prophylactic verapamil alone and silymarin alone and a combination of both were administered at the same time of induction of liver fibrosis and continued for the duration of induction. Therapeutic verapamil was started on the last day of fibrosis induction and continued for 4 weeks. The extent of liver fibrosis was evaluated using Ishak's fibrosis score. Serum alanine aminotransferase (ALT) was measured for follow-up. Compared to fibrotic model rats, prophylactic verapamil, silymarin and combined verapamil plus silymarin significantly resulted in lower serum ALT levels. Prophylactic use of verapamil and silymarin each alone revealed score 2 fibrosis with positive α-SMA immunostaining; while prophylactic treatment with combined verapamil plus silymarin revealed no fibrosis supported by negative α-SMA immunostaining. Verapamil treated fibrotic rat's liver revealed significant regression in liver fibrosis scores with positive α-SMA immunostaining. Verapamil alone has a more significant prophylactic than therapeutic antifibrotic effect against induced liver fibrosis; it was more significant than silymarin. The combination of verapamil and silymarin, showed the best protection through their synergistic antifibrotic effect.Arab Journal of Gastroenterology 09/2011; 12(3):143-9. DOI:10.1016/j.ajg.2011.07.001