Folate Depletion and Elevated Plasma Homocysteine Promote Oxidative Stress in Rat Livers

Abstract

This study was designed to determine whether nutritional folate depletion exerts hepatic oxidative stress in relation to elevated plasma homocysteine. To mimic various extents of folate depletion status in vivo, male Wistar rats 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 each decrement of dietary folate. Folate depletion did not significantly affect two major liver antioxidants: reduced glutathione and alpha-tocopherol. Conversely, folate depletion decreased Cu-Zn superoxide dismutase and glutathione peroxidase activities, but had no effect on catalase activity in liver homogenates. Lipid peroxidation products, as measured by thiobarbituric acid-reactive substances, were significantly higher in livers of folate-depleted rats than in those of the controls. This occurrence of hepatic oxidative stress in folate-depleted rats was confirmed by demonstrating an increased susceptibility of livers of folate-depleted rats to lipid peroxidation induced by additional H2O2 or Fe(2+) treatments compared with the controls. Decreasing dietary folate intake resulted in graded increases in plasma homocysteine concentrations of folate-depleted rats. Elevated plasma homocysteine and decreased plasma and hepatic folate concentrations in folate-depleted rats were all strongly and significantly correlated with increased liver lipid peroxidation (/r/ > or = 0.58, P < 0.0003). These data demonstrate that folate depletion and elevated plasma homocysteine promote oxidative stress in rat livers.

Deficiency of Glutathione Peroxidase-1 Sensitizes Hyperhomocysteinemic Mice to Endothelial Dysfunction

“…Therefore, it is perhaps more likely that indirect mechanisms are responsible for the oxidative stress of hyperhomocysteinemia ( Figure 6). Indirect oxidative effects of hyperhomocysteinemia may include generation of superoxide from xanthine oxidase 44 or uncoupled eNOS, 45 downregulation of antioxidant enzymes, 8,11,46 and depletion of intracellular glutathione. 23 Another potential source of superoxide is vascular NAD(P)H oxidase, which appears to contribute to endothelial dysfunction in hypertension and diabetes 47 but may be less important in hyperhomocysteinemia.…”

Folic acid and vitamin B12 in reproducing sows: New concepts

“…This is supported by the importance of this intermediary amino acid for (1) trophoblast integrity (DiSimone et al 2004), (2) its role in prostaglandin metabolism through intracellular depletion of arachidonic acid (stimulation of extracellular release (Signorello et al 2002)) and, finally, (3) its role in stimulating the ubiquitous transcription factor NF-κB, a key regulator of proinflammatory cytokines such as IL-2 (Huang et al 2001;Wang et al 2000).…”

Suplementação De Creatina, Homocisteína E Estresse Oxidativo

“…Huang et al 27 mostraram que ratos submetidos à baixa ingestão de folato apresentaram HHcy e maior susceptibilidade à danos causados pela peroxidação lipídica no fígado, além de comprometer a ação das enzimas antioxidantes de defesa hepática, sugerindo que elevados níveis de Hcy promovem peroxidação lipídica no fígado de ratos. Jacob et al 33 relatam que em humanos a baixa taxa de ingestão de folato resulta na elevação nos níveis de Hcy e de malonaldeído urinário (MDA).…”