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Vitamin C Transport in Oxidized Form across the Rat Blood–Retinal Barrier

¹From the Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama, Japan; ²Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corp., Japan; the ³Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, and the ⁴New Industry Creation Hatchery Center, Tohoku University, Sendai, Japan.

PURPOSE. To elucidate the mechanisms of vitamin C transport across the blood–retinal barrier (BRB) in vivo and in vitro.

METHODS. [¹⁴C]Dehydroascorbic acid (DHA) and [¹⁴C]ascorbic acid (AA) transport in the retina across the BRB were examined using in vivo integration plot analysis in rats, and the transport mechanism was characterized using a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2) as an in vitro model of the inner BRB.

RESULTS. The apparent influx permeability clearance (K_in) per gram of retina of [¹⁴C]DHA and [¹⁴C]AA was found to be 2.44 x 10³ µL/(min · g retina) and 65.4 µL/(min · g retina), respectively. In the retina and brain, the K_in of [¹⁴C]DHA was approximately 38 times greater than that of [¹⁴C]AA, whereas there was no major difference in the heart. The K_in of [¹⁴C]DHA in the retina was eight times greater than that in the brain. HPLC analysis revealed that most of the vitamin C accumulated in AA form in the retina. These results suggest that vitamin C is mainly transported in DHA form across the BRB and accumulates in AA form in the rat retina. In an in vitro uptake study in TR-iBRB2 cells, the initial uptake rate of [¹⁴C]DHA was 37 times greater than that of [¹⁴C]AA, which is in agreement with the results of the in vivo study. [¹⁴C]DHA uptake by TR-iBRB2 cells took place in an Na⁺-independent and concentration-dependent manner with a K_m of 93.4 µM. This process was inhibited by substrates and inhibitors of glucose transporters. [¹⁴C]DHA uptake was inhibited by D-glucose in a concentration-dependent manner with a 50% inhibition concentration of 5.56 mM. Quantitative real-time PCR and immunostaining analyses revealed that expression of GLUT1 and -3 was greater than that of the Na⁺-dependent L-ascorbic acid transporter (SVCT)-2 in TR-iBRB2 cells.

CONCLUSIONS. Vitamin C is mainly transported across the BRB as DHA mediated through facilitative glucose transporters and accumulates as AA in the rat retina.

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