Biochemistry and Physiology of the Vitamin D Endocrine System

A detailed study of the biochemical mode of action of the fat-soluble vitamin D was not possible until the availability in the 1960s of preparations of high specific activity radioactive vitamin D. As a consequence of efforts in several laboratories a new model emerged to describe the biological mechanisms of action of vitamin D₃. This model is based on the concept that, in terms of its structure and mode of action, vitamin D is similar to the classic steroid hormones, e.g. aldosterone, testosterone, estradiol, progesterone, cortisol, and ecdysterone.

As summarized in the figure on the left, the concept of the existence of the vitamin D endocrine system is now firmly established.

The elements of the vitamin D endocrine system include the following:

(a) In the skin, photoconversion of 7-dehydrocholesterol to vitamin D3 or dietary intake of vitamin D3.

(b) Metabolism of vitamin D3 by the liver to 25(OH)D3, which is the major form of vitamin D circulating in the blood compartment.

(c) Conversion by the kidney of 25(OH)D3 [functioning as an endocrine gland] to produce the two principal dihydroxylated metabolites, namely 1a,25(OH)2D3 and 24R,25(OH)2D3.

(d) Systemic transport of the dihydroxylated metabolites 1a,25(OH)2D3 and 24R,25(OH)2D3 to distal target organs.

(e) Binding of the dihydroxylated metabolites, particularly 1a,25(OH)2D3, to a nuclear receptor at the target organs followed by the subsequent generation of appropriate biological responses.

An additional key component in the operation of the vitamin D endocrine system is the plasma vitamin D binding protein (DBP) that carries vitamin D₃ and all of its metabolites to their various target organs.

Over the past 25 years, research efforts have largely focused upon understanding how 1a,25(OH)₂D₃ generates biological responses; an enormous scientific literature of over 5,000 scientific papers exists on this subject. By comparison, the biological actions of 24R,25(OH)₂D₃ have been relatively less studied. However, evidence has been presented to support the view that the combined presence of both 1a,25(OH)₂D₃ and 24R,25(OH)₂D₃ are required to generate the complete spectrum of biological responses attributable to the parent vitamin D.

Metabolism of Vitamin D₃

Thus, vitamin D₃ is, in reality, a prohormone and is not known to have any intrinsic biological activity itself. It is only after vitamin D₃ is metabolized, first into 25(OH)D₃ in the liver, and then into 1a,25(OH)₂D₃ and 24R,25(OH)₂D₃ by the kidney, that biologically active molecules are produced. In toto some 37 vitamin D₃ metabolites have been isolated and chemically characterized.

The key kidney enzymes, the 25(OH)D₃-1-hydroxylase and the 25(OH)D₃-24-hydroxylase, as well as the liver vitamin D₃-25-hydroxylase, are all known to be cytochrome P-450 mixed-function oxidases. Both of the renal enzymes are localized in mitochondria of the proximal tubules of the kidney. Mixed-function oxidases use molecular oxygen as the oxygen source instead of water. Mitochondrial mixed-function oxidases are composed of three proteins that are integral components of the mitochondrial membrane; they are renal ferredoxin reductase, renal ferredoxin, and cytochrome P-450.

The most important point of regulation of the vitamin D endocrine system occurs through the stringent control of the activity of the renal 1-hydroxylase. In this way the production of the hormone 1a,25(OH)₂D₃ can be modulated according to the calcium and other endocrine needs of the organism. The chief regulatory factors are 1a,25(OH)₂D₃ itself, parathyroid hormone (PTH), and the serum concentrations of calcium and phosphate. Probably the most important determinant of the 1-hydroxylase is the vitamin D status of the animal. When circulating concentrations of 1a,25(OH)₂D₃ are low, production of 1a,25(OH)₂D₃ by the kidney is high, and when circulating concentrations of 1a,25(OH)₂D₃ are high, the output of 1a,25(OH)₂D₃ by the kidney is sharply reduced.

The regulation of gene transcription by 1a,25(OH)₂D₃ is known to be mediated by interaction of this ligand with a nuclear receptor protein, termed the VDR. The tissue distribution of the VDR is known to occur in over 30 different cell types. In addition 1a,25(OH)₂D₃ and the VDR are known to regulate the independent transcription of numerous proteins. A number of excellent articles have appeared describing our current understanding of how the VDR regulates gene transcription.

References:

References for lay persons:

Norman, A.W. Vitamin D. In: Encyclopedia of Human Biology, edited by Dulbecco, R., Orlando, FL, Academic Press, pp. 749-762 (1997).

Comprehensive references to review articles covering all aspects of vitamin D with particular emphasis on 1a,25(OH)₂D₃:

Vitamin D, edited by Feldman, D., Glorieux, F.H. and Pike, J.W. San Diego, Academic Press, pp. 1-1285 (1998).

Figure 1: Summary of the vitamin D endocrine system. In addition, to production of 1a,25(OH)₂D₃ and 24R,25(OH)₂D₃ by the endocrine gland function of the kidney, small amounts of 1a,25(OH)₂D₃ are also produced in a paracrine fashion and by the placenta during pregnancy. Target organs and cells for 1a,25(OH)₂D₃ by definition contain nuclear receptors for 1a,25(OH)₂D₃ (VDR_nuc). Also, 1a,25(OH)₂D₃ generates biological effects involving rapid signal transduction pathways utilizing a putative membrane receptor. The precise biological roles of 24,25(OH)₂D₃ are not yet defined although it is believed to function in bone and cartilage.