The protective effect of glutathione administration on adriamycin-induced acute cardiac toxicity in rats.

Adriamycin (ADR) is a potent antitumor antibiotic drug known to cause severe cardiac toxicity. Although ADR generates free radicals, the role of these radicals in the development of cardiac toxicity is still not well understood. In the present study, we evaluated the effect of glutathione (GSH) supplementation or depletion on ADR-induced cardiotoxicity in male Wistar rats. Cardiac toxicity was induced by a single intraperitoneal injection of ADR (20 mg kg(-1)) and manifested by an increase in heart rate, blood pressure elevation, and increased serum creatine kinase (CK) and lactate dehydrogenase (LDH). The extent of lipoprotein oxidation, lipid peroxide measured as malondialdhye (MDA), total homocysteine (tHcy), lipid profile, and atherogenic index were markedly elevated, whereas cardiac GSH content was dramatically decreased in ADR rats. Pre- and co-treatment of ADR rats with GSH (5 mm kg(-1)) (ADR +GSH) markedly reduced the levels of CK, LDH, lipoprotein oxidation susceptibility, cardiac MDA, tHcy and atherogenic index, and elevated GSH levels in cardiac tissues. In contrast, GSH depletion through administration of l-buthionine-(S,R)-sulfoximine (BSO) (15 mm kg(-1)) before and after ADR injection (ADR +BSO) greatly exacerbated ADR cardiotoxicity compared to the control and ADR groups. Finally, there were also severe cardiac histopathological changes in ADR and ADR +BSO groups, which were nearly restored by GSH treatment. These results suggest that GSH inhibits ADR cardiotoxicity and might serve as a novel combination with ADR to limit free radical-mediated organ injury.

The effect of vitamin E, probucol, and lovastatin on oxidative status and aortic fatty lesions in hyperlipidemic-diabetic hamsters.

Diabetes mellitus is associated with an increased risk of premature atherosclerosis, which may be due in part to an increased rate of low density lipoprotein (LDL) oxidation. Previous studies have shown that vitamin E, probucol, and lovastatin can reduce the oxidative susceptibility of LDL in normoglycemic animal models; however, few studies have investigated this in conjunction with aortic fatty streak lesion formation in diabetic hyperlipidemic models. Forty-eight Syrian hamsters were made diabetic by intraperitoneal injection of low dose streptozotocin. Diabetic animals (12 animals/groups) received a high saturated fat and cholesterol diet for 12.5 weeks. At 2.5 week of dietary treatments, the diet was supplemented with either: (1) 500 IU/day vitamin E (D+E); (2) 1% probucol w/w of the diet (D+P); (3) 25 mg/kg lovastatin (D+L); or (4) diabetic control (D). An age-matched group of hamsters (n=6) receiving the same diet but not made diabetic (ND) was used as control. At the end of the study, aortic arch foam cell-rich fatty streak lesion, plasma glucose, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), phospholipids, alpha-tocopherol, plasma lipid peroxide and the susceptibility of LDL to copper-catalyzed oxidation were determined. Diabetes increased plasma glucose, and when combined with an atherogenic diet resulted in a further increase of plasma lipids. Vitamin E, probucol, and lovastatin significantly reduced plasma TG in the diabetic hamsters fed the atherogenic diet. Vitamin E treatment increased TC, probucol reduced HDL-C without affecting TC; whereas lovastatin reduced TC and selectively decreased non-HDL-C, and significantly reduced fatty streak lesion formation in the aortic arch. While vitamin E and probucol were effective in reducing several indices of oxidative stress including plasma lipid peroxides, cholesterol oxidation products and in vitro LDL oxidation, they had no effect on fatty streak lesion formation. Our results indicate that the LDL in diabetic animals is more susceptible to oxidation than in non-diabetic hamsters and that not only vitamin E and probucol but also lovastatin provide antioxidant protection. It appears that in this combined model of diabetes and hypercholesterolemia, progression of fatty streak lesion formation is mainly associated with changes in TC and non-HDL-C as affected by lovastatin, and is less dependent on the extent of LDL oxidation, changes in plasma TG level and oxidative stress status.