Review of Medical Physiology - William F. Ganong 2002

Endocrine System, Metabolism, and Reproduction
Hormonal Regulation of Calcium Metabolism and Bone Physiology
Vitamin D and Hydroxycholecalciferols

Chemistry

Active Transport of Ca²⁺ and PO₄³ across the intestinal mucosa is enhanced by vitamin D metabolites. The term vitamin D refers to a group of closely related sterols produced by the action of ultraviolet light on certain provitamins (Fig. 21-7). Vitamin D₃, also known as cholecalciferol, is synthesized in mammalian Skin from 7-dehydrocholesterol under METABOLISM/18.html">The Influence of sunlight. The reaction involves the rapid formation of provitamin D₃, which subsequently converts more slowly into vitamin D₃ (cholecalciferol). Vitamin D₃ and its hydroxylated derivatives circulate in plasma bound to the vitamin D-binding protein (DBP), which is also known as G_c-protein and binds G-Actin (see Chapter 1). Additionally, DBP enhances the Complement-induced chemotactic activity of neutrophils. Its affinity for provitamin D₃ is low, whereas its affinity for vitamin D₃ is high, allowing DBP to transport vitamin D₃ from the skin into the bloodstream. Vitamin D₃ is also obtained from dietary sources.

Vitamin D₃ is metabolized by Enzymes belonging to the cytochrome P450 (CYP) superfamily (see Chapters 17 and 20). In the Liver, vitamin D₃ is converted into 25-hydroxycholecalciferol (calcidiol, 25-OHD₃), which is then converted in the Cells of the renal proximal tubules into the more active metabolite 1,25-dihydroxycholecalciferol, also referred to as calcitriol or 1,25-(OH)₂D₃. 1,25-Dihydroxycholecalciferol is also synthesized in the Placenta, skin keratinocytes, and macrophages. In patients with sarcoidosis, 1,25-dihydroxycholecalciferol is produced by pulmonary alveolar macrophages, presumably upon stimulation by y-interferon. The normal plasma concentration of 25-hydroxycholecalciferol is approximately 30 ng/mL, whereas that of 1,25-dihydroxycholecalciferol is 0.03 ng/mL (100 pmol/L). A less active metabolite, 24,25-dihydroxycholecalciferol, is also produced in the Kidneys (see Fig. 21-7).

Vitamin D₃ and its derivatives are secosteroids—that is, Steroids in which one ring, in this case the B-ring, is opened (see Fig. 21-7). Furthermore, 1,25-dihydroxycholecalciferol Functions as a hormone because it is synthesized endogenously, acts on target cells, and is transported via the Blood.

MECHANISM OF ACTION

Given that 1,25-dihydroxycholecalciferol is a steroid, it is not surprising that it acts through a receptor belonging to the nuclear receptor superfamily through which steroids, THYROID Hormones, and many Other Compounds mediate changes in Gene Expression (see Chapter 1). Binding of the steroid to the receptor affects the DNA-binding domain, resulting in the upregulation of Transcription for certain mRNAs and the downregulation of others.

Actions

The action of 1,25-dihydroxycholecalciferol induces the synthesis of mRNAs that control The production of the calbindin-D family of Proteins. These proteins belong to the troponin C superfamily of Ca²⁺-binding proteins, which also includes calmodulin (see Chapter 1). Calbindin-Ds are found in the human intestine, Brain, and Kidney, as well as in various Tissues of rats. In the intestinal epithelium and other tissues, two calbindins are induced: calbindin D_9K, which has a molecular mass of 9,000 and binds two Ca²⁺ ions, and calbindin D_28K, with a molecular mass of 28,000, which typically binds four Ca²⁺ ions despite possessing six Ca²⁺-binding sites. In the intestine, the elevation of calbindin D_9K and calbindin D_28K levels is dependent on Ca²⁺ transport; however, the precise mechanism by which they facilitate Ca²⁺ passage across the intestinal epithelium remains unclear. There is also evidence that 1,25-dihydroxycholecalciferol increases the number of Ca²⁺-H⁺-ATPase molecules in intestinal cells, which are required for the extrusion of Ca²⁺ into the interstitial space.

Class="center">

Fig. 21-7. Biosynthesis and hydroxylation of vitamin D₃; 25-hydroxylation occurs in the liver, whereas other hydroxylations take place primarily in the kidneys. The chemical structures of 7-dehydrocholesterol, vitamin D₃, and 1,25-dihydroxycholecalciferol are also shown.

In addition to increasing intestinal Ca²⁺ absorption, 1,25-dihydroxycholecalciferol promotes renal Ca²⁺ reabsorption. It acts on bone, where it mobilizes Ca²⁺ and PO₄^3- by increasing the number of mature osteoclasts, and it also stimulates osteoblasts, though the net physiological outcome is bone resorption and Ca²⁺ mobilization.

Receptors for 1,25-dihydroxycholecalciferol have been identified in numerous tissues beyond the intestine, kidney, and bone, including the skin, lymphocytes, monocytes, skeletal and cardiac Muscle, mammary gland, and anterior pituitary. Accumulating evidence indicates that 1,25-dihydroxycholecalciferol stimulates the differentiation of immune system cells and cutaneous keratinocytes. Consistent with this, Vitamin D deficiency is associated with an increased incidence of infections. Furthermore, 1,25-dihydroxycholecalciferol has been implicated in the Regulation of Cell growth and the production of growth factors; however, its precise physiological role in these processes requires further investigation.

Regulation of Synthesis

The synthesis of 25-hydroxycholecalciferol does not appear to be tightly regulated. In contrast, The formation of 1,25-dihydroxycholecalciferol in the kidneys, catalyzed by 1a-hydroxylase, is feedback-regulated by plasma levels of Ca²⁺ and PO₄^3- (Fig. 21-8). Its production is stimulated by parathyroid hormone (PTH); when plasma Ca²⁺ levels are low, PTH secretion increases. Conversely, when plasma Ca²⁺ levels are high, little 1,25-dihydroxycholecalciferol is produced, and the kidneys instead generate the relatively inactive metabolite 24,25-dihydroxycholecalciferol. This effect of Ca²⁺ on 1,25-dihydroxycholecalciferol synthesis provides a mechanism for adapting intestinal Ca²⁺ absorption (see above). The formation of 1,25-dihydroxycholecalciferol is also stimulated by low plasma PO₄^3- levels and inhibited by high levels through a direct action of PO₄^3- on 1a-hydroxylase. Additional control over 1,25-dihydroxycholecalciferol synthesis is exerted via direct negative feedback of the metabolite on 1a-hydroxylase, positive feedback on the formation of 24,25-dihydroxycholecalciferol, and a direct inhibitory effect on parathyroid gland synthesis of PTH mRNA. Prolactin enhances 1a-hydroxylase activity, leading to elevated circulating levels of 1,25-dihydroxycholecalciferol during Lactation. Estrogens increase total circulating 1,25-dihydroxycholecalciferol, although this effect is likely mediated by an increase in the synthesis of its binding protein without significant changes in free 1,25-dihydroxycholecalciferol. Hyperthyroidism is associated with decreased circulating 1,25-dihydroxycholecalciferol and an increased prevalence of Osteoporosis. The synthesis of 1,25-dihydroxycholecalciferol is inhibited by metabolic acidosis. Growth Hormone, prolactin, and Calcitonin also stimulate 1,25-dihydroxycholecalciferol production.

Fig. 21-8. Feedback regulation of 1,25-dihydroxycholecalciferol (1,25-[OH]₂D₃) synthesis from 25-hydroxycholecalciferol (25-OHD₃) in the kidneys. Solid arrows indicate stimulation, and dashed lines indicate inhibition.

Rickets and Osteomalacia

Vitamin D deficiency impairs the mineralization of the bone matrix, resulting in rickets in children and osteomalacia in adults. In severe cases, childhood rickets causes weakness and bowing of weight-bearing bones, dental defects, and hypocalcemia. In adults, the condition is subtler and has historically been linked to inadequate sunlight exposure in smoggy urban environments, though today it predominantly stems from insufficient Dietary intake of provitamins subject to cutaneous photoactivation. In such cases, vitamin D supplementation is required. These disorders can also be caused by inactivating Mutations in the gene encoding renal 1a-hydroxylase, a condition characterized by a lack of response to vitamin D coupled with a normal response to 1,25-dihydroxycholecalciferol (type I vitamin D-resistant rickets). Rarely, the disease may arise from inactivating mutations in the 1,25-dihydroxycholecalciferol receptor gene (type II vitamin D-resistant rickets), which presents with unresponsiveness to both vitamin D and 1,25-dihydroxycholecalciferol.