Vitamin D and its Function/Role(s) as a Steroid Hormone in Mammals and Reptiles.
Vitamin D has been known for years as the “sunshine hormone” and its importance in mammalian systems is well documented. Vitamin D has been known as cholecalciferol, ergocalciferol, vitamin D3, calcitriol, solitriol and many other names. The active form has several specific functions. The most well known of it’s actions is in bone mineralization (9) and regulation of calcium homeostasis. Other functions include: regulation of circadian rhythms possibly through melatonin metabolism (3), expression of tyrosine hydroxylase, increasing cerebral dopamine and serotonin levels, increasing choline actyltransferase activity, expression of nerve growth factor and neurotrophins (4), production of vitamin D dependant calcium binding protein (19), influencing memory and learning (2), proper muscle functioning (8), changes in second messenger production and protein kinase C (PKC) activity in myotubes (5), regulation of the CYP19 gene encoding P450 aromatase, full gonadal functioning in both sexes (12), immunoregulation and numerous other functions under investigation. Most of the research is performed on mammals, but vitamin D is essential in numerous other classes of animal as well. Vitamin D has been discovered in members of all vertebrate phyla (4) and is vitally important in several species of reptile. The goal of this research paper is to accumulate and review as much literature as possible to find how vitamin D affects mammals as well as reptiles.
Vitamin D3 is actually a misnomer, because it is not really a vitamin, but rather a precursor to a steroid hormone. The body produces this hormone in the skin from 7-dehydrocholesterol under the influence of ultraviolet radiation (UV-B, wavelength 290-315 nm for humans (8) and 290-305 nm in reptiles (1, 7)). A similar UV-B irradiation-dependant process has been found in plants and invertebrates (4), converting ergosterol to vitamin D2, but its physiological functions are not known. The vitamin D3 (cholecalciferol) is still inactive and must undergo two more conversions. The first one is mainly in the liver with 25-hydroxlase converting D3 to 25-hydroxyvitamin D3 and this major circulating metabolite of vitamin D3 undergoes the second hydroxylation in the kidney. In the kidney, a mitochondrial 1 -hydroxylase converts 25-OH-D3 to the active hormonal form 1,25-(OH)2D3 (vitamin D)(9). Like other hormones, vitamin D must be carried from the site of synthesis to the site of action. As a testament to vitamin D’s importance, no mammal has ever been found that lacks a vitamin D binding protein (10). Also, after being transported, the hormone must have a nuclear receptor in order to elicit a response (12). It is logical that if the precursors are not available in sufficient quantity, through improper diet or UV exposure, the products can not be fully produced. This was studied by Need, et al., who noted that elderly women had low serum levels of 25-OH-D3, high serum PTH and a higher risk of hip fracture. They confirmed that concentrations of 25-OH-D3 are related to average daily hours of sunlight, skinfold thickness, BMI, and age, with hours of sunlight being the most important factor (17).
1,25-(OH)2D3 synthesis is strongly correlated with serum calcium (Ca2+) levels and therefore to PTH (parathyroid hormone) and CT (calcitonin). Vitamin D is produced under hypocalcemic conditions if PTH is present. Hypocalcemia stimulates PTH, and PTH stimulates renal cortical 1 -hydroxylase to synthesize 1,25-(OH)2D3. The PTH and 1,25-(OH)2D3 both increase serum calcium levels, which decrease the parathyroid PTH production through calcium receptors. There is evidence that vitamin D directly inhibits PTH production through an interaction with the gene for perproparathyroid hormone (2, 9). PTH also stimulates the renal excretion of phosphate. The resulting hypophosphatemia is directly stimulatory to 1,25-(OH)2D3 production. Calcitonin indirectly stimulates vitamin D by lowering plasma calcium levels.
The effects of vitamin D are vast and diverse, affecting all vital systems (9). Starting with perhaps the most important role, vitamin D is of extreme importance in calcium homeostasis and bone mineralization. Vitamin D raises the plasma calcium levels (and also the PO4-3 levels) by increasing the Ca2+ and PO absorption across the gut epithelium, increasing bone demineralization, and increasing reabsorption of Ca2+ and PO4-3 from the kidney. Even though it causes bone demineralization, vitamin D is necessary for bone growth and renewal. It may promote the synthesis of new osteoblasts to mineralize some of the surplus calcium, but initially vitamin D and PTH suppress osteoblast activity while stimulating the osteoclast cells to dissolve more bone for Ca2+. With calcium levels on the rise, PTH levels decrease and vitamin D can work on its own with much longer lasting effects. Vitamin D stimulates osteoblasts to produce alkaline phosphatase and stimulates osteocytes to secrete matrix proteins including collagen and osteocalcin to which the hydroxyapatite binds. Also under times of hypercalcemia (low PTH), calcitonin can do its role in bone mineralization by inhibiting the osteoclasts lysosomal enzymes, reducing their ruffled borders and actually reducing their lifespan (9). The other functions listed in the introduction may be of just slightly less importance, and can be researched in the appropriate literature.
What happens when there is a deficiency in vitamin D? In mammals, a deficiency can cause bone problems such as rickets (osteomalacia), skeletal deformities, metabolic bone disease (6), osteoporosis, accelerated bone turnover rate (22), swollen wrists or ankles, and other problems such as muscle weakness (8), improper gonadal function (12), hypocalcemic seizures, decreased memory and learning, and possibly the winter blues. With my only two grandmothers suffering from Alzheimer’s, I found it especially interesting to learn that hippocampal levels of mRNA’s for both vitamin D receptor and calcium binding protein are reduced in these patients. In reptiles, the symptoms are very similar. The problem rarely occurs in the wild, but in today’s age, as people keep other animals in captivity (out of want or necessity), problems occur. Besides being extremely hard to artificially duplicate natural conditions, a human confining other animals often does not allow the confined animal to decide which food to eat or when to bask or hide. Besides hypocalcemia from poor diet leading to nutritional secondary hyperparathyroidism (NSHP), many reptiles (and other captive animals as well) are vitamin D3 deficient. The main cause is lack of exposure to sunlight or other ultraviolet light source. Sunlight filtered through glass is not adequate because the UV rays needed to convert 7-dehydrocholesterol to vitamin D3 are reflected (13). Vitamin D3 deficient reptiles have thin, weak bones that are surrounded with fibrous connective tissue (cartilage overgrowth) for stability, giving them a swollen appearance. Lower jawbones are often rubbery and misshapen (23). If not treated (mainly by proper housing and diet), these animals may undergo fine muscular twitching, spasms, paralysis and even death (6). Other more drastic treatments include injection of calcium (Neocalgucon®), vitamin D3 and calcitonin-salmon (used to treat Paget’s disease and osteoporosis) to jumpstart the recovery process by stimulating osteoblasts (23). There is also a synthetic form of vitamin D and D3, but many animals cannot use the synthetic kind, and over abundance of these secosteroids can lead to calcification of tissues besides bone (heart, lung, G.I. tract, bladder, skin, spinal chord and brain tissue) (6). There have been several studies to establish the effects of vitamin D3 and/or vitamin D. These studies show an overall increase in serum calcium and phosphorus levels (11, 19, 20, and 21). These studies often show a gradual decrease in the elevated calcium levels after about a week. This may be because the high calcium levels have suppressed PTH and therefore vitamin D. There is also some degeneration of the parathyroid cells (18).
Other areas of interest involving vitamin D are in the binding proteins. Some shocking discoveries were made in the early 1990’s while studying what was thought to be a reptilian thyroxine binding protein (TBP). It was unrelated to the mammalian thyroxine-binding globulin (TBG), but very similar to mammalian vitamin D binding protein (DBP) (13, 14), especially at the NH2 terminus (16). This raises some important evolutionary questions. In a most species of turtle including the ancient Chelydra serpentina (snapping turtle), the DBP cannot carry thyroxine like the binding protein of the Family Emydidae , even though the protein sequences only differ in three residues (9). In most other turtle species, thyroxine has no binding protein and is carried by albumin. By carrying both vitamin D and thyroxine on the same protein (“TDBP”), the emydid turtles separate themselves from other turtles as well as higher species that typically have two binding proteins from two unrelated gene families. Results show that this dual binding protein probably evolved from the “primitive” DBP in stem reptiles (15). The role of vitamin D on animal functions is far greater than most people realize and its actions should not be overlooked or disregarded.
Vitamin D and its Function/Role(s) as a Steroid Hormone in Mammals and Reptiles.
November 28, 2000