Decreased turnovers of glutathione and ascorbic acid in watanabe heritable hyperlipidemic rabbits

Oxidative stress has been postulated to play important roles in the pathogenesis of various diseases such as atherosclerosis in hyperlipidemic subjects. Although the possible role of oxidation of low-density lipoprotein (LDL) in the etiology of atherosclerosis has been studied extensively, the turnover of endogenous antioxidants, which is an important protection system against oxidative stress, remains to be elucidated. The aim of our study was to determine the change of the turnover of endogenous antioxidants such as glutathione and ascorbic acid in case of hyperlipidemia, using Japanese white rabbits (JW) and Watanabe heritable hyperlipidemic rabbits (WHHL). The levels of total glutathione and low molecular weight thiols in the liver, kidney, and other organs in both strains of rabbits were similar. However, a kinetic analysis using L-buthionine-(S,R)-sulfoximine revealed that the rate of glutathione turnover in the liver and kidney of WHHL was about 50%) lower than that of JW. Furthermore, intravenously administered ascorbic acid disappeared more slowly in WHHL than in JW. These results indicate that the turnovers of both glutathione and ascorbic acid in WHHL are depressed in comparison with that in JW. These changes would be closely related to the increased oxidizability of lipids in the circulation of hyperlipidemic subjects.