Effects of chronic administration of N-(4-hydroxyphenyl)retinamide (4-HPR) in rats on vitamin A metabolism in the eye

The retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) effectively inhibits cancer in a variety of tissues. In contrast to many other retinoids, the toxicity problems associated with administration of 4-HPR have been found to be minimal or absent. However, the effects of 4-HPR upon normal metabolism of native physiological forms of vitamin A in vivo have not been adequately investigated. To understand better the interaction between 4-HPR and the native physiological forms of vitamin A, the present study examines the effects of long-term administration of 4-HPR upon normal vitamin A metabolism in the eyes. Male Sprague-Dawley rats were fed either a control diet sufficient in vitamin A (CON group; 0.8 retinol equivalents [RE]/g diet; n = 28) or a CON diet supplemented with 4-HPR (CON + 4-HPR group; 1173 mu g 4-HPR/g diet; n = 28). Following an i.v. dose of physiologically radiolabelled retinol, associated with its normal plasma transport complex, the vitamin A content and radioactivity of the plasma and eyes were examined at different times over a 41 day period. Mean plasma retinol levels measured during the study period were significantly reduced in the CON + 4-HPR group as compared with the CON group (23.5 +/- 7.0 and 50.3 +/- 5.3 [mean +/- S.D.]mu g/dl, respectively). From approximately 7 days post-dosing, vitamin A levels in the eyes of the 4-HPR-treated group steadily decreased such that by the end of the study, they were only approximately one-fifth those of the CON group (0.098 +/- 0.075 and 0.50 +/- 0.053 RE, respectively). Kinetic analysis of vitamin A turnover in the eyes indicated that there was no apparent down-regulation of the fraction of vitamin A leaving this tissue on a daily basis; these values were found to be similar in both groups, averaging 0.104 +/- 0.0393 and 0.113 +/- 0.0373 per day (mean +/- fractional standard deviation [F.S.D.]) for the CON and CON + 4-HPR groups, respectively. At the same time, the flow of vitamin A through the eyes was significantly decreased in the CON + 4-HPR group eyes (0.0162 +/- 0.101 mu g/day) as compared with the CON group (0.0604 +/- 0.0672 mu g/day). Our results suggest that compensatory mechanisms that would normally function to conserve depleting ocular vitamin A stores may be blocked in the 4-HPR-treated animals and further, that the 4-HPR itself appears to be interfering with the normal uptake and/or metabolism of vitamin A in the eye. These findings may help to provide at least a partial explanation for the visual impairment problems that have been reported in human trials that include long-term administration of 4-HPR.