Chemotherapy Vitamin D And Its Molecular Actions

Published Date: 02 Nov 2017

Ever since the beginning of its research, vitamin D is regarded as an important regulator of calcium homeostasis and bone mineralization (8 mas tb posso adicionar outros). However, in the late 1970s Vitamin D was found in tissues not previously considered targets of vitamin D action, which came to disclose that this hormone may carry out several unknown functions until date (2). Furthermore in the last decade, the scientific community has been showing an increasing interest in Vitamin D’s other metabolic actions (6 na pasta vitD review).

It is now firmly established that vitamin D, beyond its vital role in calcium homeostasis and bone mineralization, is also a major regulator in cell growth and differentiation in cancer cells (9, mas posso por vários, todos q no titulo tem cancer!!!)).

In humans’ bloodstream, Vitamin D can be found in two forms: D2 or ergocalciferol, and D3 or cholecalciferol. The first one is from dietary source and can be found in several kinds of food such as salmon and cereals. In contrast the latter is produced in the epidermis from the action of sunlight and represents 95% of total blood’s Vitamin D (3). As it is shown in figure X, these two forms present chemical differences in their side chains in that D2 has an extra a methyl group at C24 and an extra double bond between C22 and C23. These structural changes are reflected in their affinity for the carrier protein vitamin D binding protein (DBP). Despite the fact that Vitamin D3 has a higher affinity for DBP, generally the biologic activity of their metabolites is equivalent (13 e (3 do novo)).

Vitamin D binding protein (DBP) plays a key role in the bioavailability of calcitriol, since it is responsible for its carrying into the human body (12 e 3). When vitamin D values reach the saturation point of DBP, the free vitamin molecules accumulate in the tissue, causing hypervitaminosis. That’s why the Dietary Reference Intake should not exceed 250 mcg/day. Otherwise these doses could become toxic (3).

During exposure to sunlight, the UV radiation breaks the B ring of 7-dehydrocholesterol, the precursor, to form previtamin D3. Pre-D3 is rapidly isomerized by the body temperature to Vitamin D3 (cholecalciferol), or with continued UV irradiation to tachysterol and lumisterol (12 review, 8, 13 mas posso por mais). Once formed, cholecalciferol is translocated from the plasma membrane into the blood-stream where it bounds to the vitamin D-binding protein (DBP). (artigo 8) However Vitamin D doesn’t remain for a long time in circulation because it is almost instantly stored in adipose tissue or taken up by the liver for metabolism (2).

Metabolism

Activation

As Vitamin D is inert and must be metabolized in the liver and the kidney to be converted to its active for, it will undergo two hydroxylation processes, a hepatic 25-hydroxylation followed by a renal 1a-hydroxylation. These two steps produce the subsequent active form of vitamin D3, the calcitrol hormone or 1α,25-dihydroxyvitamin D3 [1,25-(OH)2D3] (Vários). Thus the first step of this activation occurs in the liver where cholecalciferol is modified by insertion of a hydroxyl (OH) group in C25, thereby creating 25-hydroxyvitamin D3 (25-OH-D3) . This step of 25-hydroxilation is mediated by a 25-hydroxylase enzyme (CYP2R1) and is followed by a 1-hidroxilation in the kidney. 25-hydroxyvitamin D3 1 α -hydroxylase (CYP27B1) enzyme is responsible for the insertion one more OH group into the C1 of the A ring, converting it into the hormone in its activated form, 1α25 -dihydroxycholcalciferol or calcitriol. In figure X it’s schematized the overall process of Vitamin D activation (Vários como 12 por exemplo, 13 tem im,agem, 2).

Inactivation and elimination

High levels of calcitriol can lead to uncontrolled levels of 1,25-(OH)2D3 in blood-stream, which subsequently result in some hypercalcemia (12 e 2). The danger to hypercalcemia is calcification of soft tissues especially kidney, heart, aorta, and intestine, causing organ failure and death (2). As a result, the human body has a control mechanism that allows the inactivation of calcitriol. As this process of inactivation intends the prevention of hypercalcemia therefore is up regulated by the administration of Vitamin D, high levels of 1,25-(OH)2D3 itself and high levels of serum Calcium(2). 24-hydroxylase enzyme (CYP24) inactivates calcitriol by hydroxylation. This hydroxylation may occur in the liver or in any other target tissue, such as bone or intestine. The obtained inactive form, 1,24,25-(OH)3D3, is metabolized and excreted as calcitroic acid. As, the product is 10 times less biologically active than calcitriol, it has low affinity for vitamin D receptor (VDR).As a consequence it is easily eliminated, representing the principal biliary excretory of Vitamin D3 (12 e 2).

The 24-hydroxylation reaction is critical for the inactivation of 1,25-(OH)2D3 since it is the first step of target cell C-24 oxidation pathway. 24 C-oxidation pathway is a process that comprises five successive enzymatic hydroxylation/oxidation reactions at C23 and C24, followed by cleavage of the molecule at C23-C24 bond and subsequent oxidation of the cleaved product to calcitroic acid. (2 e http://books.google.pt/books?id=rOwyIM8DAm0C&pg=PA166&lpg=PA166&dq=C-24+oxidation+pathway&source=bl&ots=dPRvrkwkAq&sig=T462jPBZ-Q6m1q1-2a8F7kVo7ds&hl=pt&sa=X&ei=CahHUbKQFIPXPcCqgYAL&ved=0CDcQ6AEwAjgK#v=onepage&q=C-24%20oxidation%20pathway&f=false).

The Nuclear VDR: Biological and Molecular Regulatory Properties of Vitamin D

The recent findings that it is the metabolites of vitamin D that are important in its biological activity led to an deep focus on the molecular events surrounding the mechanism of action of calcitriol, which resulted in the disclosure of the vitamin D receptor (VDR) and its interaction with the transcriptional machinery of target cells (2 4 novos). Calcitriol exerts its effects through the vitamin D receptor (VDR) which is a transcription factor that regulates gene expression that mediate the hormone biologic activity. VDR is not restricted to classic target cells and tissues involved in calcium homeostasis, but also is widely distributed among other cells including malignant cells as has been proved (11 e 13).

With the increasing research, Vitamin D3 was found to be synthesized as a prohormone, its inactive form, i.e. Vitamin D3 is only a precursor to its active metabolite, 1α,25-dihydroxyvitamin D3 [1,25-(OH)2D3] (2, 12, mas mais).

vitamin D3 represents only a precursor to its functionally active form, 1a,25-dihydroxyvitamin D3 [1,25-(OH)2D3].

Ambas as formas sofrem o processo de activaç-ao, mas sendo que a forma D3 é mais fortemente activa, é esta que irá ser abordada ao longo deste trabalho.