To better understand the relationships and interactions between retinoids and various carcinogenic processes, we have been carrying out a series of complementary in vivo and in vitro studies to examine the mechanisms involved in retinoid-drug-nutrient interactions and their role in cancer. Our approach has involved carrying out a number of turnover studies of the normal physiological transport form of vitamin A in the circulation and subsequently developing physiologically based compartmental models to describe the metabolism of retinoids in various tissues. We then design further experiments to test in vivo and in vitro the hypotheses derived from these models. For example, we have developed a model of in vivo retinoid metabolism in the prostate which is compatible with the known physiology of this tissue as well as its apparent resistance to a number of drug therapies. We found administration of N-[4-hydroxyphenyl retinamide] (4-HPR) but not retinoic acid (RA) to be associated with depletion of prostate vitamin A stores over time as well as an alteration of vitamin A kinetics in this tissue. A number of kinetic parameters were estimated from the model and these indicated that the fraction of vitamin A leaving the RA group prostates was similar as was the amount of time that vitamin A spent in the tissue before exiting the tissue. In contrast, administration of 4-HPR was associated with an increased fraction of vitamin A leaving the prostate, a decreased flow of the vitamin through the tissue, and an increased turnover of the vitamin from both prostate compartments. Several of the findings in the prostate are similar to those we observed for the eyes. Our previous work has suggested that 4-HPR may interfere with normal uptake and/or metabolism of vitamin A in the eye. The vitamin A content of both the prostates and eyes of 4-HPR treated animals decreased over time despite sufficient dietary vitamin A. Moreover, compensatory mechanisms that would normally function to conserve a diminishing supply of the vitamin did not appear to be operating in these tissues. Our findings may provide a partial explanation for the visual impairment problems observed in human trials with 4-HPR. Using in vitro cell culture systems for prostate and ocular tissue (as well as ovarian and mammary tissue), we are presently investigating at the molecular level possible mechanisms that may be involved in the altered retinoid metabolism we have observed in vivo. Of particular interest is whether the apparent perturbation of normal metabolism of native retinoid forms by synthetic retinoids might be associated with altered expression of specific nuclear retinoid receptor isoforms (the so-called RAR's and RXR's) and/or specific retinoid binding proteins (RBP, CRBP, CRABP, CRALBP, and IRBP).
