Effect of antioxidants on acute (paracetamol hepatotoxicity) and chronic (atheroma) oxidising free radical-related diseases

Background. Oxygen free radicals have been reported to be involved in many diseases processes including paracetamol-induced hepatotoxicity and atherogenesis. Total flavonoids of Astragalus (TFA), is a mixture of flavonoids which was isolated from Astragalus mongholicus Bunge, and have been shown to have an antioxidant capacity such as scavenging hydroxyl and superoxide anion radicals directly and reducing cell and tissue damage caused by a variety of free radicals.;Objectives. To explore the effects of TFA and vitamins C and/or E on paracetamol-induced hepatotoxicity and atheroma formation in animal models.;Methods. The first of several experiments was to investigate the effects of TFA and vitamin C on paracetamol-induced hepatotoxicity in c57BL/6J mice, using serum enzymes and histopathological parameters as markers of liver damage. The possible mechanisms of the protective effect of TFA were explored by measuring urinary paracetamol metabolites using HPLC, and pentobarbital-induced sleeping time. The second experiment was designed to explore possible beneficial effects of TFA, vitamin E or vitamins E plus C on atheroma formation in a cholesterol-fed rabbit model. Male New Zealand white rabbits received normal chow or a 1% cholesterol diet with or without TFA (60 and 120mg/day) or vitamin E (20, 100, 400IU/day) or vitamin E (400IU/day) plus C (500mg/day) for 12 weeks. Changes in plasma lipid levels and antioxidant indices were monitored during the study. At 12 weeks, the rabbit aortas were examined and pathological changes evaluated. The cholesterol content of the aorta and liver was also analysed.;Results. (1) TFA (100mg/kg) or vitamin C (1000mg/kg) markedly reduced mortality induced by paracetamol (1000mg/kg) and significantly inhibited paracetamol-induced hepatotoxicity in a dose-dependent manner. It was also found that TFA could modulate the relative proportions of the paracetamol metabolites in urine with the concentration of the mercapturate conjugate decreasing and unchanged paracetamol increasing with increasing doses of TFA. TFA did not change pentobarbital metabolism, but paracetamol did significantly prolong pentobarbital-induced sleeping time. Both TFA and vitamin C significantly reversed paracetamol-induced prolongation of pentobarbital sleeping time. (2) The two doses of TFA and the combination of vitamin E plus C significantly reduced plasma levels of total and LDL-cholesterol. These antioxidants also markedly reduced the aortic content of total cholesterol, intima to media thickness ratio, and fatty streak area. The level of HDL-cholesterol was significantly increased by TFA. The plasma antioxidant activity parameters, such as FRAP were increased in the vitamin E and vitamin E plus C treated groups. There were non-significant relationships between the aortic fatty streak area and plasma antioxidant indices.;Conclusions. TFA and vitamin C reduced the severity of paracetamol-induced liver damage probably through their antioxidant capacity. Similarly, TFA and vitamin E alone or with vitamin C limited the development of atherosclerosis in the cholesterol-fed rabbits. These antioxidant studies support the involvement of oxygen free radicals in these disease processes.