The interactions among retinoids and other nutrients as well as certain hormones and chemopreventive and/or chemotherapeutic agents remain to be clarified. The relationship between these interactions and various carcinogenic processes are even less well characterized. We have carried out a number of complementary in vivo and in vitro studies to examine the mechanisms involved in retinoid-nutrient-drug interactions and their role in cancer. Based on our in vivo studies, we have developed physiologically based, mathematical/compartmental models to describe the metabolism of retinoids and various retinoid interactions in a number of tissues. For example, our previous work has indicated that the synthetic retinoid 4HPR appears to interfere with normal uptake and/or metabolism of vitamin A in the eyes and prostate as well as a number of other tissues examined. Our findings in the eyes have provided a possible explanation for the visual disturbances often observed in human trials using 4HPR. In contrast, administration of all-trans retinoic acid was not associated with similar types of perturbations in retinoid kinetics. To test the hypotheses derived from our in vivo models and to study the mechanisms involved in greater detail, we have screened and subsequently developed a number of in vitro systems specifically designed to simulate as closely as possible, the physiological responses we have observed in vivo. Thus far, we have carried out studies in a novel tissue culture system for human retinal pigment epithelium and a modified human prostate carcinoma cell line. Using HPLC and photodiode array analytical methods developed in our laboratory, we have studied the dynamics of a number of native and administered retinoids and drugs in these systems. Among other findings, we have demonstrated the presence of retinoid esterification activity in these systems as well as uptake and metabolism of different retinoids. We are presently characterizing how this activity as well related molecular events, such as expression of retinoid-binding proteins and nuclear retinoid receptors, are altered by various retinoid, nutrient, drug and hormonal treatments. For a collaborative project, we have developed methodology to simultaneously monitor native and administered retinoids in human plasma samples to be collected in a clinical study trial using 4HPR as a chemopreventive agent. In another collaborative project we are comparing the effects of several different retinoid treatments including 4HPR and several new variants of this retinoid, on metabolism of native retinoids and related molecular events, in a number of tissues including the eyes, prostate, liver, kidneys, and colon. For an additional collaborative study, we have developed methodology to isolate and monitor a number of carotenoid, retinoid, and tocopherol species in plasma and tissues. We are presently using this methodology to investigate how beta-carotene and alpha-tocopherol supplementation in a p-53 deficient transgenic mouse model affect retinoid metabolism in a number of selected tissues. - chemotherapy, nutrition, Pharmacology, regulation, retinoids,
