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Retinoid Metabolism in the Prostate

Effects of Administration of the Synthetic Retinoid N-(4-Hydroxyphenyl)retinamide

Basic Research Laboratory, Division of Basic Sciences [K. C. L.] and Intramural Research Support Program, Science Applications International Corporation-Frederick [J. F. H.], National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201

We have carried out a series of complementary in vivo and in vitro studies to better understand the metabolism of vitamin A by the prostate gland. Male Sprague-Dawley rats were fed either a control diet sufficient in vitamin A [CON group; 0.8 µg retinol equivalents (RE)/g diet] or a CON diet supplemented with the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR; CON+4HPR group; 1173 µg of 4-HPR/g diet). After an i.v. injection of a physiological radiolabeled dose of retinol, the vitamin A content and radioactivity of plasma and a number of tissues, including the prostate glands, were monitored for time periods ranging between 30 min and 41 days. On the basis of the results of these vitamin A turnover studies, we developed tissue subsystem models to describe vitamin A dynamics in the prostates of both the CON and CON+4HPR groups. There was a gradual decrease in the vitamin A content of the prostates of the 4-HPR-treated group as compared with the control, such that by the end of the study period, the CON+4HPR group averaged 0.166 ± 0.0827 (mean ± SD) REs, whereas the CON group was 0.732 ± 0.190 REs. The fraction of vitamin A exiting the prostate each day was not significantly different in the CON as compared with the CON+4HPR group [0.149 ± 0.103 versus 0.155 ± 0.191 h^-1 (mean ± FSD), respectively]; however, the average amount of vitamin A turning over from the CON+4HPR group prostates (0.0885 µg/day) was nearly three times less than that of the CON group (0.243 µg/day). To obtain more detailed information on the mechanisms that might be involved in the changes in vitamin A kinetics observed in our in vivo studies, we used both a normal human prostate cell line (PrEC) and a human prostate adenocarcinoma cell line (LNCaP) to monitor in vitro retinol and 4-HPR dynamics. Cells were treated with 4-HPR for different time periods up to 48 h (PrEC) or 96 h (LNCaP). Retinol in the media was taken up readily by both PrEC and LNCaP cells, and there was conversion of retinol to the major storage esters of vitamin A, retinyl palmitate and retinyl stearate, as well as several minor retinyl esters, in a pattern indicative of normal retinoid esterification activity. Although 4-HPR was taken up readily and over time accumulated in both cell lines, conversion of 4-HPR to its major metabolite, N-[4-methoxyphenyl]retinamide, as well as several other metabolites of 4-HPR was apparent only in the LNCaP cells. Our findings would suggest that a study design that includes appropriately designed complementary in vivo and in vitro experimental systems represents a useful approach to better understanding possible mechanisms involved in basic retinoid functioning and interactions in the prostate as well as in other organs and related tissue culture systems.

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