VITAMIN-D SITES AND MECHANISMS OF ACTION - A HISTOCHEMICAL PERSPECTIVE - REFLECTIONS ON THE UTILITY OF AUTORADIOGRAPHY AND CYTOPHARMACOLOGYFOR DRUG TARGETING

Knowledge about sites and mechanisms of action of vitamin D and its an alogs has been greatly advanced by histochemical approaches. High reso lution and high sensitivity, combined with the integrative potential o f relatively intact histochemical tissue preparations, contributed inf ormation that is difficult or impossible to obtain otherwise. In in vi vo distribution studies with conventional biochemical assays, target c ell populations associated with non-target tissues frequently remain u nrecognized without the resolution achieved by cellular autoradiograph y. Autoradiography, alone or combined with immunohistochemistry when a pplied to in vivo drug targeting and target characterization, has prov ided information on cellular-subcellular receptor distribution in over 50 tissues. These discoveries, importantly, contribute to a new under standing of the biological role of vitamin D and challenge the concept of ''the calcium homeostatic steroid hormone'' as being too narrow. W hile some of the outstanding effects of vitamin D deficiency and toxic ity relate to calcium homeostasis, the vast majority of the target tis sues appear not to be primarily related to calcium metabolism, but rat her to the activation and regulation of exo- and endocrine secretory a nd somatotrophic processes such as cell differentiation and proliferat ion. Also, several highly calcium-dependent tissues such as striated a nd smooth muscles are not genomic targets for vitamin D. The reviewed data on the diverse and extensive presence of target tissues forecast a high therapeutic potential for vitamin D and especially its low-calc emic analogs, far beyond that which is presently utilized. The evidenc e provided for vitamin D also testifies to the utility and need to inc lude in vivo cytopharmacology in any target evaluation of bioactive co mpounds to further the understanding of their mechanisms of action, an d to identify preferential targets and their differential therapeutic and toxic potentials.