The clinical usefulness of retinoids is not likely to be fully realized until basic aspects of their metabolism are better understood. Accordingly, the general focus in our laboratory in regard to our work with retinoids has been twofold: 1) to investigate the various mechanisms involved in the normal physiological metabolism of vitamin A at the molecular, tissue, and whole body level and 2) to examine how the administration of certain retinoids shown to be clinically useful in regard to cancer treatment or prevention affect normal vitamin A metabolism. Several studies have been completed, including two long-term experiments involving the administration of either N-[4-hydroxyphenyl] retinamide (4- HPR) or all-trans retinoic acid (RA). Tracer kinetic studies were carried out in these experiments, and various kinetic parameters were determined using the SAAM/CONSAM computer modelling programs. Analysis of data indicated that these compounds significantly perturbed normal vitamin A metabolism. Both retinoids reduced normal plasma vitamin A levels and altered plasma kinetics of the vitamin. Additionally, these compounds had variable effects on individual tissue levels and kinetics of the vitamin A. For example, as compared to the control, the fraction of the plasma retinol being catabolized per day was nearly twice as high in the CON + 4-HPR treated group, whereas it was nearly the same in the retinoic acid-treated group. Before being lost from the system, a retinol molecule, on average, recycled through the plasma of the 4-HPR treated group only about half the number of times as it did in the control group; however, in contrast, the RA-treated group recycled a molecule of the vitamin nearly twice as many times as compared to the control. The possible consequences of these and other such alterations of vitamin A metabolism remain to be clarified. We are investigating potential mechanisms by which 4-HPR and RA alters retinol metabolism. Thus, we have developed molecular probes to determine whether an altered expression of certain retinoid binding proteins might be involved. Our initial findings indicate that in the tissues examined thus far (liver and kidney), the expression of retinol-binding protein or the cellular binding proteins for retinol or retinoic acid does not appear to be affected. We are presently developing compartmental models that will more fully describe vitamin A metabolism in individual organs as well as whole body metabolism of the vitamin. Additionally, we have expanded our studies at the molecular level and have initiated a number of tissue culture studies in relevant tumor cell lines. Whether or not the 4-HPR and RA associated alterations in vitamin A metabolism we have observed in an animal model might also occur in humans with possible untoward clinical consequences deserves careful evaluation.
