Calcitriol
Encyclopedia
Calcitriol (US; UK), also called 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3, is the hormonally active form of vitamin D
with three hydroxyl groups (abbreviated 1,25-(OH)2D3 or simply 1,25(OH)2D). It increases the level of calcium
(Ca2+) in the blood
by (1) increasing the uptake of calcium from the gut
into the blood, (2) decreasing the transfer of calcium from blood to the urine
by the kidney
, and (3) increasing the release of calcium into the blood from bone
.
(when specified).
Because cholecalciferol
already has one alcohol group, only two are further specified in the nomenclature.
) and Decostriol (Mibe, Jesalis).
and increasing renal tubular reabsorption of calcium thus reducing the loss of calcium in the urine. Calcitriol also stimulates release of calcium from bone by its action on the specific type of bone cells referred to as osteoblasts, causing them to release RANKL
, which in turn activates osteoclasts.
Calcitriol acts in concert with parathyroid hormone
(PTH) in all three of these roles. For instance, PTH also stimulates osteoclasts. However, the main effect of PTH is to increase the rate at which the kidneys excrete inorganic phosphate (Pi), the counterion
of Ca2+. The resulting decrease in serum phosphate causes Ca5(PO4)3OH to dissolve out of bone thus increasing serum calcium. PTH also stimulates the production of calcitriol (see below).
Many of the effects of calcitriol are mediated by its interaction with the calcitriol receptor
, also called the vitamin D receptor or VDR. For instance, the unbound inactive form of the calcitriol receptor in intestinal epithelial cells resides in the cytoplasm
. When calcitriol binds to the receptor, the ligand
-receptor complex translocates to the cell nucleus
, where it acts as a transcription factor
promoting the expression of a gene encoding a calcium binding protein
. The levels of the calcium binding protein increase enabling the cells to actively transport more calcium (Ca2+) from the intestine across the intestinal mucosa into the blood.
The maintenance of electroneutrality requires that the transport of Ca2+ ions catalyzed by the intestinal epithelial cells be accompanied by counterion
s, primarily inorganic phosphate. Thus calcitriol also stimulates the intestinal absorption of phosphate.
The observation that calcitriol stimulates the release of calcium from bone seems contradictory, given that sufficient levels of serum calcitriol generally prevent overall loss of calcium from bone. It is believed that the increased levels of serum calcium resulting from calcitriol-stimulated intestinal uptake causes bone to take up more calcium than it loses by hormonal stimulation of osteoclasts. Only when there are conditions, such as dietary calcium deficiency or defects in intestinal transport, which result in a reduction of serum calcium does an overall loss of calcium from bone occur.
Calcitriol also inhibits the release of calcitonin
, a hormone which reduces blood calcium primarily by inhibiting calcium release from bone. (The effect of calcitonin on renal excretion is disputed.)
of the nephron
in the kidneys by the action of 25-hydroxyvitamin D3 1-alpha-hydroxylase
, a mitochondrial oxygenase
and an enzyme
which catalyzes the hydroxylation
of 25-hydroxycholecalciferol (calcifediol). The activity of the enzyme is stimulated by PTH. The reaction is an important control point in Ca2+ homeostasis
.
The production of calcitriol is also increased by prolactin
, a hormone which stimulates lactogenesis (the formation of breast milk), a process which requires large amounts of calcium. It is decreased by high levels of serum phosphate and by an increase in the production of the hormone FGF-23 by osteocyte cells in bone.
through the action of 24-hydroxylase
. Calcitroic acid is excreted in the urine.
Calcitriol is also sometimes used topically in the treatment of psoriasis
, however the evidence to support its efficacy is not well established. The vitamin D analogue calcipotriol
is more commonly used for psoriasis. Research on the noncalcemic actions of calcitriol and other VDR-ligand analogs and their possible therapeutic applications has been reviewed.
associated with calcitriol therapy is hypercalcaemia
– early symptoms include: nausea, vomiting, constipation, anorexia
, apathy
, headache, thirst, sweating, and/or polyuria
). Compared to other vitamin D compounds in clinical use (cholecalciferol
, ergocalciferol
), calcitriol has a higher risk of inducing hypercalcaemia. However, such episodes may be shorter and easier to treat due to its relatively short half-life.
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
with three hydroxyl groups (abbreviated 1,25-(OH)2D3 or simply 1,25(OH)2D). It increases the level of calcium
Calcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
(Ca2+) in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
by (1) increasing the uptake of calcium from the gut
Gut (zoology)
In zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...
into the blood, (2) decreasing the transfer of calcium from blood to the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
by the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
, and (3) increasing the release of calcium into the blood from bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
.
Nomenclature
Calcitriol usually refers specifically to 1,25-dihydroxycholecalciferol, but may also sometimes include 24,25-dihydroxycholecalciferol24,25-Dihydroxycholecalciferol
24,25-Dihydroxycholecalciferol, also known as 24,25-dihydroxyvitamin D3 and -hydroxycalcidiol , is a compound which is closely related to 1,25-dihydroxyvitamin D3, the active form of vitamin D3, but like vitamin D3 itself and 25-hydroxyvitamin D3 is inactive as a hormone both in vitro and in...
(when specified).
Because cholecalciferol
Cholecalciferol
Cholecalciferol is a form of vitamin D, also called vitamin D3 or calciol.It is structurally similar to steroids such as testosterone, cholesterol, and cortisol .-Forms:Vitamin D3 has several forms:...
already has one alcohol group, only two are further specified in the nomenclature.
Pharmaceutical trade names
Calcitriol is marketed under various trade names including Rocaltrol (Roche), Calcijex (AbbottAbbott Laboratories
Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr....
) and Decostriol (Mibe, Jesalis).
Function
Calcitriol increases blood calcium levels ( [Ca2+] ) by promoting absorption of dietary calcium from the gastrointestinal tractGastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
and increasing renal tubular reabsorption of calcium thus reducing the loss of calcium in the urine. Calcitriol also stimulates release of calcium from bone by its action on the specific type of bone cells referred to as osteoblasts, causing them to release RANKL
RANKL
Receptor activator of nuclear factor kappa-B ligand , also known as tumor necrosis factor ligand superfamily member 11 , TNF-related activation-induced cytokine , osteoprotegerin ligand , and osteoclast differentiation factor , is a protein that in humans is encoded by the TNFSF11 gene.RANKL is...
, which in turn activates osteoclasts.
Calcitriol acts in concert with parathyroid hormone
Parathyroid hormone
Parathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...
(PTH) in all three of these roles. For instance, PTH also stimulates osteoclasts. However, the main effect of PTH is to increase the rate at which the kidneys excrete inorganic phosphate (Pi), the counterion
Counterion
A counterion is the ion that accompanies an ionic species in order to maintain electric neutrality. In table salt the sodium cation is the counterion for the chlorine anion and vice versa.In a charged transition metal complex, a simple A counterion is the ion that accompanies an ionic species in...
of Ca2+. The resulting decrease in serum phosphate causes Ca5(PO4)3OH to dissolve out of bone thus increasing serum calcium. PTH also stimulates the production of calcitriol (see below).
Many of the effects of calcitriol are mediated by its interaction with the calcitriol receptor
Calcitriol receptor
The calcitriol receptor, also known as the vitamin D receptor and also known as NR1I1 , is a member of the nuclear receptor family of transcription factors...
, also called the vitamin D receptor or VDR. For instance, the unbound inactive form of the calcitriol receptor in intestinal epithelial cells resides in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
. When calcitriol binds to the receptor, the ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
-receptor complex translocates to the cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
, where it acts as a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
promoting the expression of a gene encoding a calcium binding protein
Vitamin D-dependent calcium-binding protein
Vitamin D-dependent calcium binding proteins were discovered in the cytosolic fractions of chicken intestine, and later in mammalian intestine and kidney, by workers including Robert Wasserman of Cornell University....
. The levels of the calcium binding protein increase enabling the cells to actively transport more calcium (Ca2+) from the intestine across the intestinal mucosa into the blood.
The maintenance of electroneutrality requires that the transport of Ca2+ ions catalyzed by the intestinal epithelial cells be accompanied by counterion
Counterion
A counterion is the ion that accompanies an ionic species in order to maintain electric neutrality. In table salt the sodium cation is the counterion for the chlorine anion and vice versa.In a charged transition metal complex, a simple A counterion is the ion that accompanies an ionic species in...
s, primarily inorganic phosphate. Thus calcitriol also stimulates the intestinal absorption of phosphate.
The observation that calcitriol stimulates the release of calcium from bone seems contradictory, given that sufficient levels of serum calcitriol generally prevent overall loss of calcium from bone. It is believed that the increased levels of serum calcium resulting from calcitriol-stimulated intestinal uptake causes bone to take up more calcium than it loses by hormonal stimulation of osteoclasts. Only when there are conditions, such as dietary calcium deficiency or defects in intestinal transport, which result in a reduction of serum calcium does an overall loss of calcium from bone occur.
Calcitriol also inhibits the release of calcitonin
Calcitonin
Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...
, a hormone which reduces blood calcium primarily by inhibiting calcium release from bone. (The effect of calcitonin on renal excretion is disputed.)
Biosynthesis and its regulation
Calcitriol is produced in the cells of the proximal tubuleProximal tubule
The proximal tubule is the portion of the duct system of the nephron of the kidney which leads from Bowman's capsule to the loop of Henle.-Structure and appearance:...
of the nephron
Nephron
The renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus. After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron....
in the kidneys by the action of 25-hydroxyvitamin D3 1-alpha-hydroxylase
25-Hydroxyvitamin D3 1-alpha-hydroxylase
25-Hydroxyvitamin D3 1-alpha-hydroxylase also known as cytochrome p450 27B1 is a cytochrome P450 enzyme that in humans is encoded by the CYP27B1 gene....
, a mitochondrial oxygenase
Oxygenase
An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14....
and an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
which catalyzes the hydroxylation
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
of 25-hydroxycholecalciferol (calcifediol). The activity of the enzyme is stimulated by PTH. The reaction is an important control point in Ca2+ homeostasis
Calcium metabolism
Calcium metabolism or calcium homeostasis is the mechanism by which the body maintains adequate calcium levels. Derangements of this mechanism lead to hypercalcemia or hypocalcemia, both of which can have important consequences for health....
.
The production of calcitriol is also increased by prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
, a hormone which stimulates lactogenesis (the formation of breast milk), a process which requires large amounts of calcium. It is decreased by high levels of serum phosphate and by an increase in the production of the hormone FGF-23 by osteocyte cells in bone.
Metabolism
Calcitriol becomes calcitroic acidCalcitroic acid
Calcitroic acid is a metabolite of 1α,25-dihydroxyvitamin D3 . Its formation is catalyzed by the enzyme calcitriol 24-hydroxylase. Calcitroic acid is soluble in water and excreted in urine....
through the action of 24-hydroxylase
CYP24A1
1,25-dihydroxyvitamin D3 24-hydroxylase, mitochondrial is an enzyme that in humans is encoded by the CYP24A1 gene.This gene encodes a member of the cytochrome P450 superfamily of enzymes...
. Calcitroic acid is excreted in the urine.
Medical use
Calcitriol is prescribed for:- Treatment of hypocalcaemiaHypocalcaemiaIn medicine, hypocalcaemia is the presence of low serum calcium levels in the blood, usually taken as less than 2.1 mmol/L or 9 mg/dl or an ionized calcium level of less than 1.1 mmol/L or 4.5 mg/dL. It is a type of electrolyte disturbance...
– hypoparathyroidismHypoparathyroidismHypoparathyroidism is decreased function of the parathyroid glands with under production of parathyroid hormone. This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany , and several other symptoms...
, osteomalaciaOsteomalaciaOsteomalacia is the softening of the bones caused by defective bone mineralization secondary to inadequate amounts of available phosphorus and calcium, or because of overactive resorption of calcium from the bone as a result of hyperparathyroidism...
(adults), ricketsRicketsRickets is a softening of bones in children due to deficiency or impaired metabolism of vitamin D, magnesium , phosphorus or calcium, potentially leading to fractures and deformity. Rickets is among the most frequent childhood diseases in many developing countries...
(infants, children), renal osteodystrophyRenal osteodystrophyRenal osteodystrophy or chronic kidney disease-mineral and bone disorder is a bone pathology, characterized by bone mineralization deficiency, that is a direct result of the electrolyte and endocrine derangements that accompany chronic kidney disease...
, chronic renal dialysis - Treatment of osteoporosisOsteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
- Prevention of corticosteroidCorticosteroidCorticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
-induced osteoporosis
Calcitriol is also sometimes used topically in the treatment of psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, however the evidence to support its efficacy is not well established. The vitamin D analogue calcipotriol
Calcipotriol
Calcipotriol or calcipotriene is a synthetic derivative of calcitriol or vitamin D. It is used in the treatment of psoriasis, marketed under the trade name Dovonex or Daivonex.-Mechanism:...
is more commonly used for psoriasis. Research on the noncalcemic actions of calcitriol and other VDR-ligand analogs and their possible therapeutic applications has been reviewed.
Adverse effects
The main adverse drug reactionAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
associated with calcitriol therapy is hypercalcaemia
Hypercalcaemia
Hypercalcaemia is an elevated calcium level in the blood. . It can be an asymptomatic laboratory finding, but because an elevated calcium level is often indicative of other diseases, a workup should be undertaken if it persists...
– early symptoms include: nausea, vomiting, constipation, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, apathy
Apathy
Apathy is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion. An apathetic individual has an absence of interest in or concern about emotional, social, spiritual, philosophical or physical life.They may lack a sense of purpose or meaning in...
, headache, thirst, sweating, and/or polyuria
Polyuria
Polyuria is a condition usually defined as excessive or abnormally large production or passage of urine . Frequent urination is sometimes included by definition, but is nonetheless usually an accompanying symptom...
). Compared to other vitamin D compounds in clinical use (cholecalciferol
Cholecalciferol
Cholecalciferol is a form of vitamin D, also called vitamin D3 or calciol.It is structurally similar to steroids such as testosterone, cholesterol, and cortisol .-Forms:Vitamin D3 has several forms:...
, ergocalciferol
Ergocalciferol
Ergocalciferol is a form of vitamin D, also called vitamin D2. It is marketed under various names including Deltalin , Drisdol and Calcidol...
), calcitriol has a higher risk of inducing hypercalcaemia. However, such episodes may be shorter and easier to treat due to its relatively short half-life.