Dynamic aspects of ascorbic acid metabolism in the circulation: analysis by ascorbate oxidase with a prolonged in vivo half-life

Abstract

Because AA (L-ascorbic acid) scavenges various types of free radicals to form MDAA (monodehydroascorbic acid) and DAA (dehydroascorbic acid), its regeneration from the oxidized metabolites is critically important for humans and other animals that lack the ability to synthesize this antioxidant. To study the dynamic aspects of AA metabolism in the circulation, a long acting AOase (ascorbate oxidase) derivative was synthesized by covalently linking PEG [poly(ethylene glycol)] to the enzyme. Fairly low concentrations of the modified enzyme (PEG-AOase) rapidly decreased AA levels in isolated fresh plasma and blood samples with a concomitant increase in their levels of MDAA and DAA. In contrast, relatively high doses of PEG-AOase were required to decrease the circulating plasma AA levels of both normal rats and ODS (osteogenic disorder Shionogi) rats that lack the ability to synthesize AA. Administration of 50 units of PEG-AOase/kg of body weight rapidly decreased AA levels in plasma and the kidney without affecting the levels in other tissues, such as the liver, brain, lung, adrenal grand and skeletal muscles. PEG-AOase slightly, but significantly, decreased glutathione (GSH) levels in the liver without affecting those in other tissues. Suppression of hepatic synthesis of GSH by administration of BSO [L-buthionin-(S,R)-sulfoximine] enhanced the PEG-AOase-induced decrease in plasma AA levels. These and other results suggest that the circulating AA is reductively regenerated from MDAA extremely rapidly and that hepatic GSH plays important roles in the regeneration of this antioxidant.

Modulation of osteogenic differentiation in hMSCs cells by submicron topographically-patterned ridges and grooves

“…Expression of the BGLAP and normalized calcium deposition on topography with 400 nm pitch were consistently higher than that on planar controls. These results showed the advantage of employing topographically modified implants over traditional osteoinductive agents as topographic cues last longer than osteoinductive agents that have mean residence time of less than 8 days [42, 43]. …”

The Impact of Senile Cataract Maturity on Blood Oxidative Stress Markers and Glutathione-Dependent Antioxidants: Relations with Lens Variables

“…As the key enzyme of the GSH-redox cycle, GR controls many aspects of antioxidant defense including the plasma vitamin C redox state (16). Hence, our findings of decreased plasma ascorbate and GSH, with virtually unchanged total vitamin C levels, argue for inadequate recycling of oxidized vitamin C, rather than the nutritive deficiency.…”

“…GR is also involved in the main tenance of vitamin C in its reduced state as ascorbic acid (ascorbate), which is the principal nonenzymatic antioxidant of the blood plasma. Incompletely oxidized vitamin C is uptaken in cells and reduced back to ascorbate by GSH, which acts either directly or as a cofactor of glutaredoxin and erythrocyte membrane cytochrome b561 (16). This prevents the formation of irreversible, completely oxidized diketogulonic acid and its loss from the body.…”

Prospects for studying the pharmacokinetics, pharmacodynamics and pharmacogenetics of vitamin C in patients with neurological diseases and mental disorders

“…When transported to cells, DHA is enzymatically converted to ascorbate by glutathione (GSH), thioredoxin, or nicotinamide adenine dinucleotide phosphate (NADP) [97].…”