Vitamin prohormone

Vitamin A (retinol), present in carnivorous diets, and the provitamin (P-carotene), found in plants, form retinaldehyde, utilized in vision, and retinoic acid, which acts in the control of gene expression. Vitamin D is a steroid prohormone yielding the active hormone derivative calcitriol, which regulates calcium and phosphate metaboUsm. Vitamin D deficiency leads to rickets and osteomalacia. 

The primary supply of vitamin in humans is not obtained from the diet but rather is derived from the ultraviolet photoconversion of 7-dehydrocholesterol to vitamin Ds in skin. Thus, vitamin Dj synthesis varies with the seasons. D3 is a prohormone and requires further metabolic conversion to exert biological activity in its target organs (Fig. 66.2). The liver and the kidney are the major sites of metabolic activation of this endogenous sterol hormone. The initial transformation of D3 occurs in the liver and is catalyzed by the enzyme 25-OH-D3-hydroxylase... 

Three hormones serve as the principal regulators of calcium and phosphate homeostasis parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and the steroid vitamin D (Figure 42-2). Vitamin D is a prohormone rather than a true hormone, because it must be further metabolized to gain biologic activity. PTH stimulates the production of the active metabolite of vitamin D, l,25(OH)2D. l,25(OH)2D, on the other hand, suppresses the production of PTH. l,25(OH)2D stimulates the intestinal absorption of calcium and phosphate. l,25(OH)2D and PTH promote both bone formation and resorption in part by stimulating the proliferation and differentiation of osteoblasts and osteoclasts. Both... 

Vitamin D is a prohormone that serves as precursor to a number of biologically active metabolites (Figure 42-3). Vitamin D is first hydroxylated in the liver to form 25-hydroxyvitamin D (25[OH]D). This metabolite is further converted in the kidney to a number of other forms, the best studied of which are 1,25-dihydroxyvitamin D (l,25[OH]2D) and 24,25-dihydroxyvitamin D (24,25[OH]2D). Of the natural metabolites, only vitamin D and l,25(OH)2D (as calcitriol) are available for clinical use (Table 42-1). Moreover, a number of analogs of l,25(OH)2D are being synthesized to extend the... 

Retinoid Hormones Retinoids are potent hormones that regulate the growth, survival, and differentiation of cells via nuclear retinoid receptors. The prohormone retinol is synthesized from vitamin A, primarily in liver (see Fig. 10-21), and many tissues convert retinol to the hormone retinoic acid (RA). 

In the absence of inadequate endogenous synthesis, vitamin D must be obtained from dietary sources or from supplements. Few foods contain vitamin D except for the flesh of fatty fish (salmon, mackerel, sardines), fish liver oils, and eggs from hens fed feed enriched with vitamin D. In the United States, all commercially produced milk is fortified with vitamin D2 at a level of 400 IU/L (1 IU = 0.025 fig of vitamin D3). Therefore, in the United States (and other economically advanced countries) most dietary vitamin D is obtained from milk and other vitamin D2-fortified foods. Both vitamin D2 and vitamin D3 are converted at the same rate to 25-hydroxyvitamin D by a hydroxylase in the liver and are equally active as a prohormone. Because dietary uptake of vitamin D is dependent on normal fat absorption, conditions in which fat malabsorption is present can result in vitamin D deficiency. Because breast milk contains little vitamin D, vitamin D deficiency can occur in infants who are solely breastfed, are not exposed to adequate sunlight, and are not receiving vitamin D supplements. The adequate intake of vitamin D for children is 5 pg/day (200 IU/day) (Table 30-2). 

The discovery that vitamin D3 (1), also called calciol [I], is actually a pro-hormone and not a vitamin as previously assumed has induced intense worldwide research activities within the last 20 years. Nowadays, it is known that the prohormone is transformed in liver and kidney into physiologically much more active metabolites by hydroxylation. In particular, the la,25-dihy-droxylated derivative, calcitriol (3), performs a key function in the regulation of different physiological events [2]. Some hydroxylated vitamin D derivatives and structural analogs are currently being clinically tested as drugs for the treatment of a range of human diseases such as cancer, psoriasis or immune defects. 

The unique interactions of vitamin D with the VDRs have been a focus of research and have led to the development of vitamin D analogs, which vary in their affinity for this receptor and thus may result in less hypercalcemia, while retaining the positive physiologic actions on bone and parathyroid tissue. Paricalcitol and doxercal-ciferol are D2 compounds which effectively lower PTH in dialysis patients. Paricalcitol differs from calcitriol by the absence of the exocyclic carbon 19 and the fact that it is a vitamin D2 derivative. Currently this analog is available only for IV administration however, an oral formulation is in development. Doxercalciferol, in contrast to calcitriol and paricalcitol, is a prohormone that needs to be hydrox-ylated in the liver to its active 1,25-dihydroxyvitamin D2 product. Doxercalciferol is available for both IV and oral administration. 

Derived from cholesterol, vitamin D is biosynthesized from its prohormone cholecalciferol (Ds), the product of solar ultraviolet irradiation of 7-dehydrocholesterol in the skin (2). In 1966, it was first recognized that vitamin D must undergo activation via two oxidative metabolic steps (Fig. 35.2). The first oxidation to 25-hydroxycholecalciferol (25(OH)D3 calcifediol Calderol) occurs in the endoplasmic reticulum of the liver and is catalyzed by vitamin D 25-hydroxylase. This activation step is not... 

Barreto, A.M., Schwartz, G.G., Woodruff, R., Cramer, S.D. 2000. 25-Hydroxyvitamin Dj, the prohormone of 1,25-dihydroxy vitamin D3, inhibits the proliferation of primary prostatic epithelial cells. Cancer Epidemiol. Biomarkers Prev. 9 265-70. 

Dihydroxycholecalciferol is able to act on a number of tissues with columnar epithelial cells, including intestinal mucosa, kidney tubules, the shell gland of birds and probably also various types of bone cell where it may assist the synthesis of osteocalcin (page 161). Its mode of action is very similar to that of steroid hormones (Figure 30.1). In this respect its precursor, vitamin Dj, may be considered to function as a prohormone rather than a vitamin. The ability of 1,25-DHCC and other metabolites of vitamin D3 to act on bone and kidney cells, as well as those of the intestine, means that vitamin D plays a key role in calcium and phosphorus metabolism (Hgure 30.2). 

Vitamin D2 and D3 are hydroxylated first in the liver to the prohormone 25-hydroxycholecalciferol (calcidiol) and subsequently in the kidney to the vitamin D hormone la,25-dihy-droxycholecalciferol (calcitriol). Calcitriol acts as an inductor of proteins in various organs. It promotes calcium resorption in the intestine and... 

Vitamin D can be viewed as a prohormone which arises by the action of ultraviolet light in the two-step process pictured in Fig. 20. Irradiation of 7-dehydrocholesterol in the skin can provide adequate amounts of vitamin D3 (cholecalciferol or calciol). The closely related vitamin D2 (ergocalciferol) arises from irradiation of the plant sterol ergosterol. This form of the vitamin has been widely used in fortification of milk. However, the natural vitamin D3 is more active in preventing rickets. The term vitamin Di was dropped when it was found to be a mixture of D2 and D3. The principal function of vitamin D is in the control of calcium metabolism. This control is exerted by polar, hydroxylated compounds of which the most important is la, 12-dihydroxy vitamin D3 (calcitriol). This hormone is distributed to all parts of the body. In cells of the intestinal lining it promotes uptake of calcium ions. It promotes reabsorption of both calcium and phosphate ions in the kidney tubules and increases blood calcium and depositon of calcium ions in bone. 

FIGURE 20 Creation of the prohormone vitamin D by the action of iight on 7-dehydrochoiesteroi in human skin or on the piant compound ergosteroi. 

---