Vitamin D Biochemistry and Functions

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Questions and Answers

What is the main biological active form of Vitamin D synthesized in the kidneys?

Calcitriol (correct)

Vitamin D3

Calcidiol

25-OH-D3

Which enzyme is responsible for hydroxylation of 25-OH-D3 to form calcitriol in the kidneys?

25-hydroxylase

Cytochrome P450

Vitamin D binding protein

1-alpha-hydroxylase (correct)

Which factor stimulates the synthesis of calcitriol?

Increased calcitonin levels

High plasma calcium levels

Parathyroid hormone (PTH) (correct)

Increased serum phosphate levels

What is the role of 24, 25(OH)2D3 in bone metabolism?

It aids in the deposition of hydroxyapatite in bone. Signup and view all the answers

What role does 25-OH-D3 play in the body?

It serves as a major storage form of Vitamin D. Signup and view all the answers

What is the effect of high levels of calcitriol in the body?

Inhibits 1-alpha-hydroxylase activity Signup and view all the answers

What is the Daily Recommended Allowance (DRA) of vitamin D for men above the age of 70?

20 mcg / 800 IU per day Signup and view all the answers

Which blood level range is considered sufficient for vitamin D?

20 ng/ml to 30 ng/ml Signup and view all the answers

Which coenzymes are required for the hydroxylation of Vitamin D in the liver?

Mg++, Molecular O2 Signup and view all the answers

What is affected by the feedback inhibition of 25-OH-D3 levels in the liver?

25-hydroxylase activity Signup and view all the answers

What is the primary cause of rickets in growing children?

Decreased calcium and phosphate due to vitamin D deficiency Signup and view all the answers

Which of the following symptoms is NOT typically associated with rickets?

Thickened ankle joints Signup and view all the answers

Which of the following factors does NOT promote calcitriol formation?

High plasma calcium levels Signup and view all the answers

What condition describes adult rickets, particularly affecting women with repeated cycles of pregnancy?

Osteomalacia Signup and view all the answers

Which test is useful in the diagnosis of rickets due to its association with bone metabolism?

Serum Alkaline Phosphatase test Signup and view all the answers

Why is early diagnosis of rickets critical?

Once bone develops, reversibility is difficult. Signup and view all the answers

What is the primary function of Alkaline Phosphatase (ALP) in bone mineralization?

It facilitates the deposition of inorganic phosphate into bone. Signup and view all the answers

How does calcitriol primarily affect calcium absorption in the intestine?

By facilitating the synthesis of calcium binding proteins. Signup and view all the answers

Which of the following statements about calcitriol is NOT true?

It decreases overall plasma calcium levels. Signup and view all the answers

What effect does calcitriol have on parathyroid hormone (PTH) activity when vitamin D levels are adequate?

It induces an anti-proliferative effect on PTH activity. Signup and view all the answers

What is a consequence of hypocalcemia on PTH activity?

It stimulates hyperparathyroidism. Signup and view all the answers

What role does calcitriol play in the mobilization of calcium from bones?

It stimulates both bone forming and mobilizing osteoclast activity. Signup and view all the answers

What is the impact of 1,25 (OH)2D3 on bone mineralization?

It promotes the synthesis of calcium binding proteins. Signup and view all the answers

Which type of alkaline phosphatase is primarily responsible for bone mineralization?

Bone ALP Signup and view all the answers

Study Notes

Vitamin D

Vitamin D is a group of fat-soluble secosteroids.
Vitamin D has hormone-like action.
Vitamin D can be made in the body when exposed to sunlight, also called "Sunshine vitamin".
It occurs naturally in food.
Vitamin D increases intestinal absorption of calcium, magnesium, and phosphate.
Vitamin D has many other biological effects.
Two major forms: Vitamin D2 (ergocalciferol) and Vitamin D3 (cholecalciferol). These are collectively known as calciferol.

Chemistry and Types of Vitamin D

Provitamin D2: Ergosterol, found in plants.
Provitamin D3: 7-dehydrocholesterol, found in the skin and animal sources.
Structural characteristics:
- OH group at C3.
- Two conjugated double bonds (between C5-C6 and C7-C8).
- A hydrocarbon chain at C17

Vitamin D2 (Ergocalciferol)

Synthesized by plants, mainly through irradiation of ergosterol.
Isolated from a seaweed plant called ergosterol, hence it is of vegetable origin.
Not produced by the human body.

Vitamin D3 (Cholecalciferol)

Produced in large quantities in the skin when exposed to sunlight.
Ingested from animal sources.
In humans and animals, cholesterol in the epidermis converts into provitamin D3 (7-dehydrocholesterol) with the help of UV radiation.
Ergosterol and 7-dehydrocholesterol are preliminary forms of vitamin D.

Occurrence

Vitamin D3 is less widespread than Vitamin A.
Fish liver oil and egg yolks are good sources.
Milk and livers of mammals are poor, their content dependent on diet and light exposure of the animals.
Plant and vegetable sources are poor sources of Vitamin D.
Foods containing cholesterol can form cholecalciferol through UV rays.

Sources

Vitamin D2 (ergocalciferol):
- Specially labeled "High Vitamin D" mushrooms (exposed to UV light).
- Foods made with "High Vitamin D" mushrooms.
- Dietary supplements.
Vitamin D3 (cholecalciferol):
- Oily fish and fish oil.
- Egg yolks.
- Select types of liver.
- Dietary supplements.

Main Reason of Deficiency

Excessive melanin in the skin blocks UV radiation, limiting D3 production (clothing and sunscreens also have this effect).
Poor exposure to sunlight.
Thick skin.
Incidence of deficiency higher in some rich women (based on a text source.)

Absorption, Storage and Excretion

Bile salts are needed for absorption, which occurs in chylomicrons.
Stored in fat tissues.
Transported in plasma after binding with D-binding protein.
Primarily eliminated by bile; some part deactivated in the liver by enzymes.

Metabolism of Vitamin D

7-dehydrocholesterol in skin becomes Vitamin D3 (cholecalciferol) through UV light.
Ergosterol in plants becomes Vitamin D2 (ergocalciferol) through UV light.
Both forms travel to the liver and kidneys, where they are hydroxylated to become active.
Inactive forms (D2 and D3) become 25-hydroxy vitamin D in the liver
Then 1-hydroxylase in the kidneys converts 25-hydroxy vitamin D to 1,25-dihydroxyvitamin D, the active form of vitamin D.
24-hydroxylase converts 25-hydroxy vitamin D to 24, 25-dihydroxy vitamin D; an inactive form (for storage).

Formation of Calcitriol

Transported by vitamin D-binding protein (DBP - 85-88%) and albumin (12-15%).
Transported to liver from skin.
Production of 25(OH)D3 (calcidiol) in the liver. This involves hydroxylation at the 25 position by the 25-hydroxylase enzyme. This takes place in the endoplasmic reticulum of liver mitochondria .

Continuation (Vitamin D Metabolism)

Cofactors required: Mg++, NADPH, molecular O2, cytochrome P450 reductase and cytochrome P450
25-OH-D3 (calcidiol) is a major storage form in liver.
25-OH-D3 exerts a feedback inhibition on the 25-hydroxylase enzyme.
Renal production of 1,25-OH-D3 (calcitriol):
- 25-OH-D3 bound to vitamin D-binding protein, carried to kidneys.
- Hydroxylation at the 1-position by 1-alpha-hydroxylase in the endoplasmic reticulum of the kidney mitochondria.

Factors Regulating Calcitriol

Its own concentration (feedback inhibition of 1α-hydroxylase).
Stimulated by Parathyroid hormone (PTH), estrogen, prolactin, progesterone, and growth hormone (GH).
Serum phosphate level.
Hypocalcemia leads to increased 1α-hydroxylase activity.
Calcitriol regulates its own concentration by inhibiting 1α-hydroxylase and stimulating the formation of 24,25-dihydroxy-D3 (a storage form)

Factors regulating active D3

Calcitonin increases 1,25-dihydroxy vitamin D formation (in response to hypocalcemia).
Suppressed by high intake of D, high plasma Ca+2 and Pi, and 1,25-dihydroxy D (negative feedback).

Bone Physiology

Bone is a connective tissue made rigid by mineral deposition
Main protein in bone is ossein
Bones are continuously destroyed and renewed.
- Water = 25%.
- Inorganic matter (Ca and Pi) = 45%.
- Organic (protein and mucopolysaccharides) = 30% (osse in 95%).
Bone's end cartilage is degenerated and replaced by osteoblasts.
Osteoblasts produce organic matter.
Bone cell contains Alkaline phosphatase, an enzyme that helps in bone mineralisation.
ALP is a major regulator of bone mineralization .
ALP provides inorganic phosphate from pyrophosphate and organic phosphate for the synthesis of bone crystals (CaOH, Ca(PO4). Different types of ALP are present.
Bones become dense through crystal growth and displacement of water.

Action of Calcitriol

Increases calcium binding protein (calbindin) formation in the intestine, which increases Ca absorption.
Increases Ca and Pi reabsorption in renal tubules.
Increases mobilization of Ca and Pi from old bone (stimulates bone forming and bone mobilizing osteoclast activity).
Raises plasma Ca and Pi levels.

Main MOA of Calcitriol

Induces gene for osteoblast forming proteins.
Induces gene for Ca binding protein (9K and 28K).
Decreases PTH formation.

Functions of Vitamin D

Acts on target organs to regulate calcium and phosphate metabolisms (bones, kidneys, and intestinal mucosa).
Promotes calcium absorption
Expressed genes for calcium-binding proteins and ATPase in intestinal cells to increase calcium absorption.
Promotes bone mineralization, promoting the synthesis of calcium binding proteins, like osteocalcin ad alkaline phosphatase.
Promotes the deposition of hydroxyapatite (mineral) in bone.
Promotes bone resorption and calcium mobilization to raise Ca and P blood levels (associated with PTH).

Dietary Recommendations for Vitamin D

Depends on age, sex, clothing, season and exposure to sunlight.
Women (1-70 years) 15 mcg/ 600 IU per day, above 70: 20mcg/ 800 IU per day.
Men (1-70 years) 15 mcg/ 600 IU per day, above 70: 20mcg / 800 IU per day.
Breastfed infants should receive 400 IU of vitamin D per day up to age 12 months

Blood Levels of Vitamin D

Blood levels above 20 ng/mL or 30 ng/mL are considered sufficient.
Vitamin D is considered deficient if below 20ng/ml.
5000IU of vitamin D is required to reach 30ng/ml in case of deficiency in adults.
800-2000 IU raised blood levels to above 20 ng/mL in postmenopausal women.

Deficiency of Vitamin D (Hypovitaminosis D)

Rickets (children):
- Low calcium and phosphorus stimulate PTH.
- Undeveloped bones with less inorganic matter contents, and increase in AlkPhosphatase levels.
- Signs and Symptoms: Bone pain, tender bones, slow growing bones, bowed or curved legs, muscle weakness, soft bones that break easily, large forehead or abdomen, unusual rib and breastbone shapes, wide joints, dental cavities and irregularities.
Osteomalacia (adults):
- Repeated cycles of pregnancy and lactation affect women.
- Mineralization process incomplete, soft collagen remains.
- Signs and Symptoms: Pain in the knees, thighs and legs, weak and stiff muscles, difficulty walking, pseudofractures (fractures that appear as cracks in the bones).

Diagnosis in Rickets

Initially, low plasma calcium levels, but later increase due to PTH.
Increased serum alkaline phosphatase levels.
Defective enamel production.
Poor muscle development (pot belly).
Difficult to reverse once bones are developed.
Defective conversion (metabolism) of Vitamin D.

Other Clinical Aspects

Vitamin D deficiency might be indicative of future heart attacks
Diabetes type-1 (IDDM-1) more common in areas with less sunlight.
Can slow breast cancer cell growth.
May protect against peripheral artery disease (PAD)

Causes of Vitamin D Deficiency

Poor intake (breastfed infants, older adults).
Decreased cutaneous synthesis (dark skin, less sun exposure, use of sunscreen, clothing).
Malabsorption: Crohn's disease, celiac disease, obesity.
Lack of fat in diet: needed for absorption.
Some surgeries: gastric bypass, severe liver or kidney disease.
Some medications: cholestyramine, anti-seizure drugs, glucocorticoids, antifungals and HIV/AIDS meds.
Some diseases: hyperparathyroidism, sarcoidosis, tuberculosis, histoplasmosis.
Some cancers.

Prevention and Treatment

Aim for adequate Vitamin D levels.
Taking good sources of food may not be enough (especially when not exposed to UV light), Supplements may be needed.

Hypervitaminosis

Rare but serious.
Main cause: buildup of calcium in the blood (hypercalcemia).
High levels of supplements (over 60,000IU/day for extended period).
Immediate effects: Anorexia, thirst, lassitude, constipation, polyuria, nausea, vomiting, diarrhea.
Delayed effects: Persistent hypercalcemia and hyperphosphatemia may result in: urinary calculi, Metastatic calcification of multiple organs and systems (kidneys, bronchi, pulmonary alveoli, muscles, arteries and gastric mucosa), renal failure, and death.

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Description

Explore the intricate details of Vitamin D metabolism, including its synthesis, active forms, and role in bone health. This quiz covers key enzymes, factors promoting calcitriol formation, and the effects of Vitamin D deficiency. Perfect for students studying biochemistry or human physiology.