Vitamin D sites and mechanisms of action: a histochemical perspective. Reflections on the utility of autoradiography and cytopharmacology for drug targeting.
Knowledge about sites and mechanisms of action of vitamin D and its analogs has been greatly advanced by histochemical approaches. High resolution and high sensitivity, combined with the integrative potential of relatively intact histochemical tissue preparations, contributed information that is difficult or impossible to obtain otherwise. In in vivo distribution studies with conventional biochemical assays, target cell populations associated with non-target tissues frequently remain unrecognized without the resolution achieved by cellular autoradiography. Autoradiography, alone or combined with immunohistochemistry when applied to in vivo drug targeting and target characterization, has provided information on cellular-subcellular receptor distribution in over 50 tissues. These discoveries, importantly, contribute to a new understanding of the biological role of vitamin D and challenge the concept of "the calcium homeostatic steroid hormone" as being too narrow. While some of the outstanding effects of vitamin D deficiency and toxicity relate to calcium homeostasis, the vast majority of the target tissues appear not to be primarily related to calcium metabolism, but rather to the activation and regulation of exo- and endocrine secretory and somatotrophic processes such as cell differentiation and proliferation. Also, several highly calcium-dependent tissues such as striated and 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-calcemic analogs, far beyond that which is presently utilized. The evidence provided for vitamin D also testifies to the utility and need to include in vivo cytopharmacology in any target evaluation of bioactive compounds to further the understanding of their mechanisms of action, and to identify preferential targets and their differential therapeutic and toxic potentials.
Stumpf
W E
WE
International Institute of Drug Distribution, Chapel Hill, NC 27516, USA.
D000818:Animals; D001345:Autoradiography; D002118:Calcium / Q000378:metabolism; D004702:Endocrine Glands / Q000502:physiology; D005088:Exocrine Glands / Q000502:physiology; D006651:Histocytochemistry; D051381:Rats; D018167:Receptors, Calcitriol / Q000096:biosynthesis / Q000235:genetics; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D014018:Tissue Distribution; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology
D018167:Receptors, Calcitriol; D064030:S100 Calcium Binding Protein G; D014807:Vitamin D; D002118:Calcium