Data from human and animal trials have revealed contradictory results regarding the influence of selenium (Se) status on homocysteine (HCys) metabolism. It was hypothesised that sufficient Se reduces the flux of HCys through the transsulphuration pathway by decreasing the expression of glutathione (GSH) synthesising enzymes. Glucoraphanin (GRA) is a potent inducer of genes regulated via an antioxidant response element (ARE), including those of GSH biosynthesis. We tested the hypothesis that GRA supplementation to rat diets lowers plasma HCys levels by increasing GSH synthesis. Therefore 96 weaned albino rats were assigned to 8 groups of 12 and fed diets containing four different Se levels (15, 50, 150 and 450 μg kg(diet)−1), either without GRA (groups: C15, C50, C150 and C450) or in combination with 700 μmol GRA kg(diet)−1 (groups G15, G50, G150 and G450). Rats fed the low Se diets C15 and G15 showed an impressive decrease of plasma HCys. Se supplementation increased plasma HCys and lowered GSH significantly by reducing the expression of GSH biosynthesis enzymes. As new molecular targets explaining these results, we found a significant down-regulation of the hepatic GSH exporter MRP4 and an up-regulation of the HCys exporter Slco1a4. In contrast to our hypothesis, GRA feeding did not reduce plasma HCys levels in Se supplemented rats (G50, G150 and 450) through inducing GSH biosynthesis enzymes and MRP4, but reduced their mRNA in some cases to a higher extent than Se alone. We conclude: 1. That the long-term supplementation of moderate GRA doses reduces ARE-driven gene expression in the liver by increasing the intestinal barrier against oxidative stress. 2. That the up-regulation of ARE-regulated genes in the liver largely depends on GRA cleavage to free sulforaphane and glucose by plant-derived myrosinase or bacterial β-glucosidases. As a consequence, higher dietary GRA concentrations should be used in future experiments to test if GRA or sulforaphane can be established as HCys lowering compounds.
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