Folate depletion and elevated plasma homocysteine promote oxidative stressin rat livers

This study was designed to determine whether nutritional folate depletion e xerts hepatic oxidative stress in relation to elevated plasma homocysteine. To mimic various extents of folate depletion status in vivo, male Wistar r ats were fed an amino acid-defined diet containing either 8 (control), 2, 0 .5, or 0 mg folic acid/kg diet. After a 4-wk feeding period, the plasma and hepatic Folate concentrations of the rats decreased significantly with eac h decrement of dietary folate. Folate depletion did not significantly affec t two major liver antioxidants: reduced glutathione and alpha -tocopherol. Conversely, folate depletion decreased Cu-Zn superoxide dismutase and gluta thione peroxidase activities, but had no effect on catalase activity in liv er homogenates. Lipid peroxidation products, as measured by thiobarbituric acid-reactive substances, were significantly higher in livers of folate-dep leted rats than in those of the controls. This occurrence of hepatic oxidat ive stress in folate-depleted rats was confirmed by demonstrating an increa sed susceptibility of livers of folate-depleted rats to lipid peroxidation induced by additional H2O2 or Fe2+ treatments compared with the controls. D ecreasing dietary folate intake resulted in graded increases in plasma homo cysteine concentrations of folate-depleted rats. Elevated plasma homocystei ne and decreased plasma and hepatic folate concentrations in folate-deplete d rats were all strongly and significantly correlated with increased liver lipid peroxidation (\r\ greater than or equal to 0.58, P < 0.0003). These d ata demonstrate that folate depletion and elevated plasma homocysteine prom ote oxidative stress in rat livers.