| Objectives: To develop a new antilipemic and antioxidative drug for clinical application, we studied the regulation of flavone compound DH01 on lipid metabolism and its antioxidation in experimental hypercholesterolemia rats, and detected its adverse effect and toxicity.Methods: 70 Wistar rats were randomized into normal group, model group, silymarin group, atorvastatin group, and high dosage group(50mg/kg), middle dosage group (17mg/kg), small dosage group (5.67mg/kg) according to DH01 . (1)To establish the hypercholesterolemia rat model by intragastric administrating fat emulsion. (2)Two or four weeks later, the concentrations of TC, TG, LDL-c, HDL-c in serum were detected by enzyme methods. AI and CHD-R were calculated according to TC, LDL-c, HDL-c. (3) The livers were harvested to obtain the TI and the levels of hepatic TC, TG were detected by enzyme methods after the last treatment. (4) Using optical microscopes and macroscopic observations to monitor the morphologic change of liver. (5)Using immunohistochemistry assay to detect the expressed level of LDLR in liver. (6)The levels of serum ox-LDL were measured with ELISA. The activities of SOD were measured with enzyme assay, meanwhile the GSH-PX activities and MDA content were assessed with spectrophotometry. (7)Wistar rats were intragastric administed with DH01 at the dosage of 50 mg/kg and 150mg/kg for four weeks, the liver and kidney functions were determined at the end of treatment. (8)The acute toxicity reaction was observed by maximal tolerance dose test in mice (6g/kg) and rat (4g/kg). Results: (1)After a week of the modeling, the levels of serum TC, LDL-c in model group were increased significantly (p<0.01). After 3 weeks of the modeling, the levels of HDL-c were decreased (p<0.01), while the levels of TC and LDL-c continue increasing (p<0.01). (2)Two and four weeks later, compared with the model group, the levels of TC, LDL-c, AI, CHD-R in high dosage group(50mg/kg) and middle dosagegroup(17mg/kg) were decreased, while the levels of HDL-c were increased (p<0.05 or p<0.01). The levels of serum TG in high dosage group (50mg/kg) were lower than the silymarin group and the model group after four-week-treatment (p<0.01). (3)After the last treatment, compared with the normal group, the TI and the levels of hepatic TC, TG in the model group are higher (p<0.05). The hepatic TG in the high dosage group (50mg/kg) is lower than the model group (p<0.05). Compared with the model group, the levels of TI in medication administration groups were decreased (p<0.05 or p<0.01). (4)The pathology showed that, in the comparison group of the rats, the morphological structures of the livers were normal. Livers lobule was regular, no lipid drop was found, in the model group, many abnormal symptoms where visible: liver cells were swollen, lipid drop of various sizes where found on the liver, in the treatment group, liver had mild and less lipid drops. (5)It obviously increased the presence of LDLR in rats' liver of the high dosage group (50mg/kg), showed obvious difference from the model group and the silymarian group. (6)At the dosage of 50mg/kg, DH01 obviously increased the activities of SOD and GSH-PX, as well as decreased the levels of ox-LDL and MDA (p<0.01). (7)No side effects after administrating DH01 50 or 150mg/kg for four weeks were observed. DH01 did not change kidney functions, but improved liver function by reducing level of ALT, AST, GGT and TB(p<0.05 or p<0.01). (8)There was no death of mice or rats in 14 days and there was no pathologic change in major organs by pathological observation. The maximal tolerance dose of DH01 in mice was higher than 6g/kg, while in rats was higher than 4g/kg.Conclusions: (l)The experimental animal model of hypercholesterolemia in rats were successfully established for 3 weeks by intragastric administrating fat emulsion. (2)DH01 could decrease TC, LDL-c, AI, CHD-R and increase HDL-c in treating hypercholesterolemia as effective as silymarin and in dose, time-dependent manner. (3)The possible mechanism might be that DH01 can increase the presence of LDLR in liver. The increased quantity and activity of LDLR induced the increased elimination of serum LDL. (4)DH01 could decrease the hepatic TG, TI and improved liver function. (5)DH01 could reduce the levels of ox-LDL and MDA, increase the levels ofSOD and GSH-PX in serum, which could reduce the formation of lipoperoxide, therefore to achieve the effect of hyperlipidemia and AS prevention. The results also suggested that the impact of DHOl in anti-lipid peroxidation was better than silymarin at the same dose. (6)DH01 has small adverse effect and little acute toxicity reaction and is a new antilipemic and antioxidative compound for further study. |
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