Comparison of hepatoprotective effects of clofibrate and its novel siliconized analogue in isolated rat hepatocyts

Annals of Biological Research 04/2012; 3(4):1895-1903.


Background and the purpose of the study: Peroxisome proliferator ligands have been found to have a
hepatoprotective effect against induced injuries in hepatotoxicants. FeIII:8HQ induces oxidative stress in freshly isolated cells. The hepatoprotective effects of clofibrate and its novel siliconized analog (silafibrate) against the FeIII:8HQ complex are compared here for the first time. Methods: A siliconized analog of clofibrate synthesized by replacement of the chlorine atom in the phenoxy ring with trimethylsilyland ethyl2-methyl-2-(4- (trimethylsilyl)phenoxy)propionate was prepared. Hepatocytes were obtained from male rats by a two-step collagenase perfusion. The viability of isolated hepatocytes was evaluated by Trypan blue exclusion method. Levels of reactive oxygen species (ROS) were measured with the fluorescent probes2′,7′-dichlorofluorescein diacetate (DCFHDA). Mitochondrial membrane potential was measured by using Rhodamine 123 fluorescence. Results: Incubation of hepatocytes with low to moderately toxic doses of silafibrate (200, 250, 400, and 500 μM) for 3 hours did not evoke a notable toxic response in three time-repeated experiments. However, higher doses (1, 2mM) have significant toxicity in Trypan blue exclusion cell viability experiments. Mitochondrial membrane potential decrease was prevented by pretreatment of hepatocytes with clofibrate and/or silafibrate, 20 minutes before adding FeIII:8HQ complexes (I, II). 100 μM clofibrate protected hepatocytes against FeIII: 8HQ induced ROS production, whereas silafibrate with 100, 200, and 400 μM strongly inhibited ROS production. Conclusion: These results demonstrate that fibrates have an in vitro hepatoprotective effect against oxidative stress. Silafibrate, the novel analog, has a better effect in protection against oxidative stress in comparison with clofibrate.

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    • "Second, some experiments have shown that the treatment with fibrates reduce the susceptibility of plasma proteins, especially LDLs, to oxidation (22, 23). Third, our previous studies (11, 24) and several other studies have demonstrated that fibrates possesspotent anti-inflammatory effects and antioxidant effects. Inflammatory cells are an important source of ROS generated by phagocytes› plasma membrane (25). "
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    ABSTRACT: Silicon is the element very similar to carbon, and bioactive siliconized compounds have therefore received much attention. Siliconization of a compound enhances its biological activities. In the present study the hypolipidemic effect and toxicity of clofibrate and its siliconized analog, silafibrate, were compared. The experiments were performed in hypercholesterolemicWistar rats. Animals received high fat diet with 62.75% normal chow, 2% cholesterol, 0.25% cholic acid, 15% lard oil, 10% wheat flour and 10% sucrose.Silafibrate(40 mg/kg/day) produced a predominant reduction in the serum levels of total cholesterol (28.4%, p < 0.001), triglycerides (62%, p < 0.0001) and low-density lipoproteins (27%, p < 0.001) being more effective than the reference drug clofibrate (20%, 40%, 14.5%; p < 0.05). Similarly, it increased the total antioxidant levels in serum by 40% (p < 0.05). Simultaneously, treatment with silafibrate also reduced the malondialdehyde(MDA) concentration by 41% (p < 0.05). LD50 of silafibrate, given orally,was greater than 2000 mg/kg body weight inalbino mice while LD50 for clofibrate was calculated to be 1220 mg/kg. Thirty-day subacute toxicity was also evaluated with oral daily dose at 25, 50 and 100 mg/kg body weight in Wistarrats. No significant changes in body weight, food intake, behavior, mortality, hematology, blood biochemistry, vital organ weight were detected. The results of this study indicate that the effectiveness and safety of thehypolipidemic drug, clofibrate, were enhanced remarkably by replacing chlorine atom in its phenoxy ring with trimethylsilyl.
    Full-text · Article · Mar 2013 · Iranian journal of pharmaceutical research (IJPR)