EFFECTS OF N-(4-HYDROXYPHENYL)RETINAMIDE SUPPLEMENTATION ON VITAMIN-AMETABOLISM

The efficacy of the retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) has been demonstrated in the inhibition of cancers in a variety of tissue s. Moreover, toxicity effects following administration of 4-HPR have b een found to be reduced or absent when compared to other retinoids. Ph armacokinetic studies in both animals and humans have focused on the m etabolism of 4-HPR and its metabolites, and relatively little informat ion has been published detailing the effects of long-term administrati on of 4-HPR upon normal endogenous vitamin A metabolism. Thus, the pre sent study was carried out to examine the effects of long-term adminis tration of 4-HPR upon plasma and tissue vitamin A kinetics. Male Sprag ue-Dawley rats were fed either a control diet sufficient in vitamin A [CON group; 1.0 retinol (ROH) equivalents/g diet] or a CON diet supple mented with 4-HPR (CON+4HPR group; 1173 mu g 4-HPR/g diet). Following i.v. injection of a physiologically radiolabeled dose of ROH, ROH trac er and tracee kinetics were monitored in plasma and tissues over a 41- day period. Kinetic parameters were determined using the SAAM/CONSAM c omputer modeling programs to carry out graphical analysis of the trace r concentration curves. Mean plasma ROH levels measured for the CON+4H PR group were reduced to one-third of those of the CON group. Most of the kinetic parameters calculated were found to be significantly alter ed by the inclusion of 4-HPR in the diet. The fraction of the plasma R OH being catabolized per day (fractional catabolic rate) was nearly tw ice as high in the CON+4HPR treated group (3.61 +/- 0.49 day(-1); mean +/- SD) as compared to the CON group (2.00 +/- 0.68 day(-1)). The amo unt of time that vitamin A molecules spent in the body before being lo st irreversibly from the system (system residence time) was decreased by half in the CON+4HPR group (19.20 +/- 7.13 days) versus the CON gro up (38.63 +/- 9.62 days). Despite the increased catabolic rates and de creased system residence times measured for the CON+4HPR group, the es timated vitamin A use in these animals (11.01 +/- 3.10 mu g/day) was 3 3% less than that used by the CON group (16.31 +/- 2.47 mu g/day). Stu dies investigating the mechanisms by which 4-HPR alters vitamin A kine tics are presently under way in our laboratory. Nevertheless, these re sults suggest that long-term administration of 4-HPR markedly perturbs normal vitamin A metabolism in rats. Whether 4-HPR similarly alters h uman vitamin A metabolism with untoward clinical consequences deserves careful evaluation.