Abstract
Purpose::
Vitamin A is frequently prescribed as a treatment for patients with retinitis pigmentosa (RP). A subset of RP is caused by mutations in the ABCA4 (ABCR) gene. Retinal degeneration mediated by ABCR is caused by the accumulation of toxic lipofuscin fluorophores, such as A2E, in the retinal pigment epithelium. Previously we showed that this accumulation can be blocked in abcr -/- mice treated with fenretinide, which inhibits delivery of vitamin A to the eye. This suggests that hyper-supplementation with vitamin A may promote A2E accumulation and possibly accelerate retinal degeneration in patients with ABCR mutations. To test this possibility, we administered vitamin A to abcr -/- mice and measured the effects on visual retinoids and A2E.
Methods::
A group of wild-type (WT) and abcr -/- knockout mice received vitamin A (0.05 - 56 mg/kg retinyl-acetate) by daily intraperitoneal (i.p.) injections for one month. A second group of WT and abcr -/- mice were started on dietary supplementation of vitamin A (120 IU/g) for six-months, while control WT and abcr -/- mice were fed a normal rodent diet containing 25 IU/g vitamin A. Serum retinol as well as retinoids and phospholipids extracted from mouse eyecups were analyzed by HPLC. Morphological and electrophysiological analyses were performed after one-month of i.p. vitamin A administration.
Results::
Serum retinol levels in WT and abcr -/- mice were unchanged after one-month of vitamin A supplementation. However, ocular levels of all-trans-retinyl esters (all-trans-RE’s) were increased in vitamin A-treated mice (1.5-fold in the 5.6 mg/kg group and three-fold in the 56 mg/kg group). Mice treated with 56 mg/kg showed a three-fold increase in ocular all-trans-ROL. Levels of A2E and A2E-precursors were similar in the treatment and control groups after one month. Light microscopic analysis showed no morphological changes in the retina after one-month of vitamin A supplementation. Similarly, electroretinographic (ERG) analysis of live mice showed normal retinal physiology with vitamin A supplementation for one month.
Conclusions::
One-month of vitamin A-treatment resulted in higher all-trans-RE’s in eyecups from WT and abcr -/- mice with no change in A2E levels. No evidence of retinal toxicity was seen by light microscopy or ERG. It remains to be seen if prolonged administration of vitamin A causes A2E accumulation or retinal toxicity.
Keywords: retinal degenerations: hereditary • retinoids/retinoid binding proteins • retinal pigment epithelium