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1. Vitamin D hormone--the "calciferols".

Vitamin D basically directs the make-up of connective tissue and the hardening of

bone from new growth. It is derived from the diet, but a person must be exposed to

ultraviolet light to convert to its "active sterol", containing compounds needed by the immune

system and to stop bone overgrowth due to misplacement of calcium. 25-hydroxyvitamin D

is the active form of vitamin D measured in the blood. It has been found that levels above

80nmol/L are needed to maximize absorption of calcium, and the production of an enzyme

which helps break down vitamin D3 (the form most vitamin pills provide).

A lack of sunlight can cause serious consequences on levels of vitamin D in the blood.

Broad results from studies of cord blood from newborns showed those born in the summer had 99%

higher serum vitamin D levels than those born in winter months (1). 5-10 minutes of exposure to

most of body, 2-3 times a week is a reasonable amount of light without increasing the risk of

skin cancer (2). If the level of 25-hydroxyvitamin D is below 80 nmol/L, vitamin D

supplementation is recommended to avoid bone loss and secondary overproduction of bone

to replace it (3).

Vitamin D compounds have a potential to be used as anticancer drugs because they

control cell proliferation and differentiation (4), besides regulating the development of bone

mass. The receptors for vitamin D are in the steroid/thyroid family, and new synthetic

vitamin D analogs appear to act on them to control development of new blood vessels, and

blood lipid proteins (5).

 

2. Different compounds and what they do.

Vitamin D3 is added to calcium pills, milk and other foods.  It must be converted first by

liver enzymes of the P450 detoxification pathway, then by kidney enzymes to create the active

form of vitamin D. D3 is also known as "cholecalciferol", and chemically as 1,25-hydroxyvitamin

D3. The vitamin occurs naturally in oils, especially fish oils. Vitamin D3 prevents photo damage

 from the sun, including wrinkles, but tends to increase calcium metabolism (6). And while the

 supplementation of vitamin D is recommended for bone maintenance and immune system factors

 such as cytokine IL-10 regulation (1), there are studies which show that it is not well assimilated in

 older adults unless it is coupled with sunshine (7). Also, many people with cystic fibrosis, liver or

kidney disease, or malabsorption syndromes cannot readily metabolize this form of the vitamin (8).

Vitamin D2, known as ergocalciferol, is an alternate metabolite of vitamin D, which

has shown even more promise as a bone mass stabilizer in those with disease causing vitamin

D deficiency. Zemplar, a form of paricalcitol (vitamin D2) made in the lab, has been found

to inhibit parathyroid hormone (9), is an antiproliferative agent (inhibits cancerous growth) in

the prostate and inhibits HL60 leukemia (10). Laboratory created analogs, doxercalciferol

and 19-nor-paracalcitol control secondary hyperparathyroidism in those with kidney disease

with minimal changes in calcium or phosphorus levels (11).

Attempts to create the active vitamin D compound 1 alpha,24(S)-dihydroxyvitamin D

(2) will override the need for the liver and kidneys to produce enzymes. Rat studies have

shown that doses at 30 times normal were needed for vitamin D2 to produce the intestinal

calcium absorption equal to D3. In these studies both D2 and D3 produced bone

overgrowth when injected, rather than when eaten and digested (12).

 

3. Producing active vitamin D hormone.

In studies with cats, a definite affinity (liver enzymes) to deal with cholecalciferol was

seen--130 times over that of ergocalciferol, or vitamin D2 (13). In rats with ovaries removed

(menopause model), supplementation with vitamin D2 caused much less reabsorption of

bone, and over mineralization of bone in the marrow cavities, than in the D3 treated rats

(14). Experiments with chickens, where the goal was to produce vitamin D fortified eggs for

the European population in winter, showed vitamin D3 passed through the hens to their eggs

more effeciently than did vitamin D2. And even large amounts of D3 did not cause any

calcium accumulation in bones, kidneys, liver or heart (15). D3 is good for chickens and

cats; D2 is better for humans.

In humans, certain liver enzymes known as hydroxylates are required for vitamin D

metabolism. The most abundant liver P450 enzyme, CYP3A4, showed the highest activity

with 1-alpha-hydroxyvitamin D2, than with 1-alpha-hydroxyvitamin D3 (the man-made

analogs), and even less with vitamin D2. There was no liver enzyme action on the vitamin D3

substrate at all. CYP3A4 is the liver enzyme required (as a first step), to convert vitamin D2 to an

active form of vitamin D in the blood (16).

In a study of 307 elderly women, 21% saw a significant increase in serum vitamin D

levels when supplemented with vitamin D2 in the winter. Overall, when comparing the

vitamin D2 with the vitamin D3 supplemented, the wintertime serum vitamin D levels were

consistently higher in the vitamin D2 group (17). Vitamin D2 has been found to suppress

inflammatory IL-6 reactions to radiation, and it is suggested that putting it on the skin may

become a way to suppress sun damage (6). There are vitamin D receptor positive breast

cancer cells which can be turned off by taking vitamin D2 (18), and the synergistic effects

when taken with chemotherapy drugs make D2 a valued therapy (4).

Humans need sunlight to satisfy their vitamin D requirements. The UVB rays are

absorbed by 7-dehydrocholesterol in the skin, and converted to pre-vitamin D3 (2) and 7-

dehydropregnenolone through steroid cleaving enzymes. These reactions occur outside the

regular (liver enzyme) pathway, the sun's rays causing vitamin D3-like molecules and

hormones to be produced (19). This pathway is more a function of adrenal gland hormones,

and is a novel way of metabolizing active vitamin D in an enzyme deficient person.

The sun also increases the concentration of vitamin D in wild mushrooms, which are

already vitamin D rich and the ergocalciferol easily absorbed (20). The ergosterol in

mushrooms is converted to vitamin D2 when irradiated. Lentinus edodes (shiitake

mushroom extracts) were fed to two groups of rats--group 1 with irradiated feed, and group 2 with

non-irradiated feed as controls. After four weeks the mean serum vitamin D level in group 1

was 129.42 nmol/liter, whereas the control group mean was 6.06 nmol/liter--the data

showing irradiated mushrooms had more than 20 times the vitamin D potency than regular

mushrooms! Calcium concentrations among both groups were also significantly higher, with

increased bone mineralization in group 1 (21). (These mushrooms are also known for their

potent antiviral properties and the ability to "heal" the liver!)

 

4. Causes of vitamin D deficiency and treatments.

Vitamin D-resistant rickets. A familial condition which may skip generations, the

symptoms usually include sweating on the head, muscle pain with nodules on ends and sides of

bones. A person will be resistant to unusually large doses of vitamin D due to a renal tube

defect, and lack of reabsorption of phosphorus. This is also known as "Type II vitamin D-dependent

rickets".

While rickets is usually thought of as a childhood disease, it is present at any age

when there is inadequate calcium to form cartilage and new bone. Symptoms may include a

slight fever at night, diffuse achiness, slight diarrhea, liver and spleen enlargement, badly

formed teeth, a joining or arching of bones, etc. It is primarily a vitamin D deficiency

syndrome, which secondarily affects absorption of calcium and phosphorus in the intestines,

resulting in a lack of reabsorption of phosphorus by the kidney tubules and finally the alteration of

bone cell formation. This is also known as secondary hyperparathyroidism, and is characterized by

low blood calcium. A vitamin D deficiency may be prevented by exposure to ultraviolet light

and supplementation of 400 IU vitamin D.  The Johns Hopkins University School of Medicine

acknowledges continuing reports of subclinical vitamin D-deficiency rickets in dark skinned,

breast-fed, unsupplemented infants, which is only identified by blood levels and is not evident

upon physical examination (22).

"Renal rickets" is caused by kidney disease and results in dwarfism and gonadal failure.

Persistent acidosis is common, and it is associated with damage to the pituitary. It is present

at birth and is immediately a severe condition, due to the absence of kidney enzymes which

produce active vitamin D. Male rat studies have confirmed that pituitary removal significantly

impacts the liver, and the production of liver enzymes necessary for hydroxylation of vitamin D

into an active form (23).

In cases of chronic kidney disease, reduced production of kidney enzyme results in

reduced vitamin D production, inadequate phosphate clearance and calcium imbalance,

bone disease and higher incidence of cardiovascular disease. Paricalcitol (vitamin D2

analog) has been a better treatment option than calcitriol (vitamin D3 analog), the survival

benefit seems to be from improvement in cardiovascular functioning, which leads to

questions worth investigating regarding vitamin D interaction with this system ( 24, 25).

Other factors which impair the absorption and metabolism of vitamin D include the

intake of retinyl acetate, or vitamin A. Rats who were fed retinyl acetate, or an all-trans-retinoic

acid (broad spectrum vitamin A) along with different metabolites of vitamin D

including ergocalciferol and cholecalciferol, resulted in lowered calcium/raised phosphorus

levels in blood. The broad spectrum vitamin A caused even further imbalance (26).

Magnesium is also a bone mass modulator. It has been shown in animal studies that

magnesium deficiency results in impaired bone growth, and bone fragility. A study using

albino rats showed that after 4 months of low magnesium diet, parathyroid hormone, vitamin

D levels, and the percent of potassium found in bone fell progressively. Serum calcium

increases caused bone resorption and abnormal growth on bone surfaces, while bone mass

significantly decreased (27).

Liver disorders are also a cause of vitamin D deficiency where the liver cannot

produce the enzyme required to metabolize the vitamin. Any disorder of the liver has far

reaching effects, as most hormones and endocrine organs depend upon its output. In the case

of vitamin D metabolism, the kidney is affected down-line when the liver cannot add its -OH

to the compound. In response, the kidneys may become overrun with calcium salts. A

natural compound, sodium alginate (prepared seaweed), can help eliminate calcium

compounds and is a crystal inhibiting agent, protecting the kidneys. Other natural

compounds can be used to balance calcium, magnesium, zinc and copper

in the kidney by retaining the calcium salts (28). There are many natural compounds which

have not been recognized by the American medical community as "medicine", and many

more to yet be researched.

Vitamin D analogs are currently being investigated as treatments for secondary

hyper-parathyroidism and osteoporosis, and also for autoimmune diseases, psoriasis and

cellular proliferation disorders such as different cancers (29). Although these analogs are

thought to be mostly non-calcemic, a new class of drug called the calci-mimetic will allow for

more control over calcium-phosphorus imbalances seen in chronic kidney diseases and

secondary parathyroid action (30).

 

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Some more current research on vitamin D:

 

 Tufts University's Jean Mayer USDA Human Nutrition Research Center on Aging

 

The Harvard University website

 

New research reported by Fox