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Europ. Journal of Drug Metabolism and Pharmacokinetics 2007, Vol. 32, No. 1, pp.1-6
EDITORIAL
The main role of vitamin D: seasonal regulation of vital functions.
High-resolution target recognition leads to a new paradigm and advanced drug
development
Running Title: The main role of vitamin D: seasonal regulation of vital functions
Keywords: Imaging, Receptor Microautoradiography, drug localization, autoradiography
Walter E. Stumpf
University of North Carolina and International Institute of
Drug Distribution, Cytopharmacology and Cytotoxicology/
Chapel Hill, NC/ USA
Evidence provided over twenty years ago and subsequently
consolidated and expanded points to vitamin D’s main
biological role for seasonal adaptation of vital functions, as
opposed to the long-dominating and widely accepted
calcium concept. Calcium regulation of bone growth and
repair is but one of vitamin D’s many important functions.
The large number of non-classical target tissues - most of
them discovered with the sensitive method of receptor
microscopic autoradiography [1-3] – has provided new
research incentives and insights. Acceptance of the new
paradigm is slow in overcoming the persistent and narrow
emphasis on calcium. Methodology and concept bias are
major causes for delayed progress in fully understanding
and appreciating the role of vitamin D. Holistic
consideration of non-classical targets of this polyfunctional
sunshine hormone points to a high potential for a multitude
of new therapies.
A few “classical” versus many “non-classical” targets
During the 1980s over fifty target tissues for 1,25(OH)2
vitamin D3 (vitamin D) were discovered and characterized
as primarily not associated primarily with systemic calcium
regulation. This is opposed to the ‘classical organ’ concept
that involves intestine, kidney, bone, parathyroid and liver
(1, 2). The new findings with the high resolution autoradiographic method (3) were
surprising and at first largely ignored or even rejected with remarks like: “These are a
few cells, it does not matter”.
Based on the detailed histochemical information from receptor microscopic
autoradiography, a holistic view of vitamin D has become possible and is increasingly
supported by results from biochemical, functional and clinical follow-up studies. New
therapeutic applications have evolved (4, 5, 6).
More hormone than “vitamin”, the biological role of vitamin D is in concert with the
roles of gonadal and adrenal steroids. Actions of these three classes of steroid hormones
appear to be closely interrelated. Their genomic effects appear to be aimed at optimal
survival and procreation under the variable conditions of life, such as season and
environment; growth, reproduction and age; and the struggle for food, territory and
partner.
Figure 4
Understanding the vitamin D target system requires information on target kinetics and
function. To arrive at a meaningful concept of the whole, including hierarchical actions
and interactions, detailed information on all individual target systems is prerequisite. For
that data from appropriate high resolution in vivo methods are necessary
A comparison with estradiol is instructive:
In contrast to estradiol, the elucidation of vitamin D’s comprehensive actions has been
much delayed and is still a work in progress. One reason may be the comparatively late
availability of high resolution vitamin D target information. Estradiol non-classical
targets were identified through the early use of microscopic autoradiography during the
1960s and early 1970s in collaboration with biochemists. Unlike vitamin D, these results
were widely accepted and prompted stimulating and mutually guiding rapid advancement
of experimentation (8, 9).
Estradiol, once perceived as hormone acting solely on female reproductive organs, has
been recognized to act on other organs and in the male as well, including elements of the
skin, atrial cardiomyocytes, thymus reticular cells, Leydig cells in the testis, epithelium of
the epididymis, prostate, and distinct regions throughout the brain and spinal cord (9). On
that basis, estradiol was soon understood to perform important functions in a wide range
of target tissues, significantly affecting drug development and therapeutic applications.
The reasons for the slow progress in vitamin D research and understanding are worth
pondering (10). As the comparison with estradiol suggests, major obstacles involve the
chosen methodologies, the limited diagnostic focus, and bias. In the case of vitamin D,
the emphasis on calcium was fostered by the relative ease of assessing bone conditions
and measuring plasma calcium levels, the pronounced visibility of rachitic changes of
growing bone and the impressive cures enabled by ultraviolet light or oral vitamin D.
Biochemical measurements of organs or chunks of tissue, however, such as brain or
stomach, did not reveal specific receptor binding. Based on biochemical data alone, a
blood-brain barrier for vitamin D was postulated, even though, at the same time, receptor
autoradiography provided maps of target neuron populations and related circuits
throughout the brain and spinal cord.
Lack of follow-up on vitamin D target discoveries
With high resolution data from receptor autoradiography, nuclear receptor occupation in
the stomach was identified in pyloric muscle, in entero-endocrine cells, and in mucous
neck cells of gastric glands. These sites were not observed in biochemical assays. Since
stomach was reported negative with radioassays, ergo, even to-date, stomach target sites
have not been followed up. Other ‘non-classical’ vitamin D target tissues missed by
biochemical studies but discovered with the microscopic receptor autoradiography
approach include skin, anterior and posterior pituitary, adrenal medulla, prostate, thymus
reticular cells, epithelial cells of ductuli efferentes, epididymis, and deferent duct, kidney
podocytes and macula densa, atrial cardiomyocytes, ovarian germinal epithelium,
esophageal epithelium, pulp cells in teeth, and many others (2).
Many of the ‘non-classical’ vitamin D targets tissues, identified with the
histopharmacological approach, have not yet been fully explored. Funding for such
studies was not favored at a time when these findings did not excite the calcium mentality
of anonymous peer expert reviewers. Much remains to be evaluated and considered for
therapeutic use, such as target cell populations in the stomach-intestinal system, in male
and female reproductive organs, in the brain and spinal cord, in endocrine and exocrine
glands, in cardio-vascular tissues, and in the blood and immune systems, apparently at
dose levels without elevated systemic blood calcium.
Vitamin D effects on most of these tissues are not associated with calcium homeostasis.
Instead, these ‘non-classical’ core-target tissues appear to be primarily involved in
regulating specific cell proliferation and differentiation and exo- and endocrine secretion.
If receptor occupancy is quantitatively related to action, as is generally accepted, nuclear
uptake and retention of vitamin D, measured in the brain in neurons of the stria
terminalis-central amygdala continuum, motor neurons of cranial nerves and spinal cord
lamina IX, thyrotropes of the anterior pituitary, and keratinocytes of the skin, corresponds
to that in classical vitamin D target tissues, such as, osteoblasts, kidney tubular
epithelium, and intestinal absorptive epithelium. Vitamin D effects on non-classical target
cell populations can be measured at physiologic plasma calcium levels, that is, these
actions are not linked to hypercalcemia which is frequently a consequence of overdosing
(11).
Vitamin D’s therapeutic potential – not primarily linked to systemic calcium regulation
Therapeutic potentials of the polyfunctional vitamin D and its analogs appear
considerable, especially for conditions in which multiple systems need to be addressed, as
during pregnancy and development, states of stress and exhaustion, postoperative fatigue,
and deficiency syndromes of old age. As part of a steroid hormone triangle, capturing all
of the ebb and flow of life, a holistic view of hormonal interactions, along with
comprehensive and specific understandings of vitamin D roles and effects should be
viewed as an exciting, pivotal and promising field of study.
It is important to note: During vitamin D treatment of rickets, osteoporosis, tumor, or any
other condition, all of the vitamin target system may be activated, depending on blood
and target bioavailability and the (response)hierarchy of receptor binding (2,11). Such
systems approach is initiated in the vitamin D drug-receptor homunculus (11) and applies
to estradiol and other compounds as well. The roles and actions of compounds can be
fully understood only if all of their sites and modes of action are considered.
Various target tissues function together as a mutually dependent system according to the
state and changes of the body. To view the individual systems in isolation most likely
will be misleading. Disturbance of one part affects the total, the equilibrium, the harmony,
and may results in disease.
Figure 5
→ → For the reproduction of Figures please see www.unc.edu/~stumpfwe/letter
Legends:
Figures 1-3: Examples of autoradiograms, showing 3H-1,25(OH)2 vitamin D3
concentration in nuclei of motor neuron of spinal cord (Figure 1; – This binding is not
recognized and reported as negative with radioassays and whole body
macroautoradiography). Pituitary thyrotropes (Figure 2; - with colocalization of
antibodies to TSH), and heart atrial myocytes (Figure 3; - without [left] and with
colocalization of antibodies to ANF-atrial natriuretic factor). Vitamin D treatment has
strong neurotrophic effects on skeletal.muscle and elevates blood levels of TSH and ANF.
Figure 4: This diagram indicates a close relationship of genomic actions of the sunshine
steroid vitamin D (Soltriol) with those of sex steroids and adrenal steroids. Also, there are
numerous overlapping targets and actions among these steroid hormones (2).
Figure5: Holistic view of targets for different wavelengths of sunlight, indicating
generalized temperature-related effects, visible light-related eye-pineal effects and
ultraviolet-related polyfunctional genomic vitamin D effects.
(Figures 1-5 reproduced from 1 and 12)
References:
1) Stumpf WE: Vitamin D-Soltriol. The heliogenic steroid hormone: Somatotrophic
activator and modulator. Discoveries from histochemical studies lead to new concepts.
Histochem (1988) 89:209-219
2) Stumpf WE: Vitamin D sites and mechanisms of action: a histochemical perspective.
Reflections on the utility of autoradiography and cytopharmacology for drug targeting.
Histochem Cell Biol (1995)104:417-427
3) Stumpf WE: Drug localization and targeting with receptor microscopic
autoradiography. J. Pharmacol. Toxicol. Meth (2005) 51:25-40.
4) Kumar R: 1Alpha,25-dihydroxyvitamin D(3) - not just a calciotropic hormone.
Nephron (2002) 91:576-81
5) Holick MF: Vitamin D: Important for prevention of osteoporosis, cardiovascular heart
disease, type 1 diabetes, autoimmune diseases, and some cancers. South Med J (2005)
98:1024-1027
6) Dusso AS, Brown AJ, Slatopolsky E: Vitamin D: Am J Physiol Renal Physiol (2005)
289:F8-28
7) Christakos S, Dhawan P, Shen Q, Peng X, Benn B, Zhong Y: New insights into the
mechanisms involved in the pleiotropic actions of 1,25dihydroxyvitamin D3. Ann N Y
Acad Sci (2006)1068:194-203
8) Jensen EV, DeSombre ER, Jungblut PW, Stumpf WE, Roth LJ: Biochemical and
autoradiographic studies of 3H-estradiol localization. In: Roth LJ, Stumpf WE (eds):
Autoradiography of diffusible substances. Academic Press, New York, pp 81-97, 1969
9) Stumpf WE, Sar M: Autoradiographic localization of estrogen, androgen, progestin
and glucocorticosteroid in "target tissues" and "non-target tissues". In: J. Pasqualini (Ed.),
Receptors and Mechanism of Action of Steroid Hormones. Modern
Pharmacology-Toxicology, Vol.8, pp.41-84, New York: Marcel Dekker, 1976
10) Kuhn, TS:The structure of scientific revolutions. University of Chicago Press,
Chicago, 2nd edition, 1970
11) Stumpf WE: The dose makes the medicine. Drug Discov Today (2006) 11:550-555
12) Stumpf:WE: Drug Localization in Tissues and Cells, IDDC Press, 2003