Vitamins b6, folate and b12

Mathew Rogers
Muyinda
BSc. (Hons) Human Nutrition
Makerere University
1
11/4/2018© Mathew R. Muyinda

 Vitamin B6 is a group
of 3 related
compounds: pyridoxine
(PN), pyridoxal (PL)
pyridoxamine (PM).
 The principal one in the
body and in food, is
pyridoxal 5’ –
phosphate (PLP).
Structure of Vitamin B6
2

Food sources
 Major food sources:
o Meats & organ meats;
o Fish;
o Poultry;
o whole grain products;
o starchy vegetables
and nuts;
o enriched RTE cereals
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3
© Mathew R. Muyinda

Figure 1 Common food sources of vitamin B6. The RDA for vitamin B6 is 1.3 mg/day for men and
women aged 19 to 50 years. (Data from: U.S Department of Agriculture, Agricultural Research Service.
USDA Nutrient Database for Standard Reference, Release 21. Available online at
www.ars.usda.gov/Services/docs.htm?docid=8964.)
4

Table 1 RDA values for vitamin B6
5
Infants mg/day Females mg/day
0 – 0.5 0.1 9 – 13 1.0
0.5 – 1 0.3 14 – 18 1.2
Children 19 – 30 1.3
1 -3 0.5 31 – 50 1.3
4 – 8 0.6 51 – 70 1.5
> 70 1.5
Males Pregnancy
9 – 13 1.0 ≤ 18 1.9
14 – 18 1.3 19 – 30 1.9
19 – 30 1.3 31 – 50 1.9
31 – 50 1.3 Lactation
51 – 70 1.7 ≤ 18 2.0
> 70 1.7 19 – 30 2.0
31 – 50 2.0
Source: Whitney & Rofles, 2011

Stability
 Vitamin B6 is stable under acidic conditions
 Pyridoxine is the most stable of three vitamers.
 Vitamin B6 is fairly stable with cooking.
 During cooking and thermal processing, plant-
derived foods lose little, if any, of the vitamin.
 Animal products lose substantial amounts.
6

Bioavailability
 About 70 – 80 % of dietary vitamin B6 is available.
 Bioavailability of vitamin B6 is influenced by:
1. Presence of pyridoxine glycosides.
2. Peptide adducts.
3. Extent and type of processing
4. Storage.
7

Functions
 Amino acid
metabolism
 Formation of
neurotransmitters e.g.
GABA
 Synthesis of heme in
hemoglobin
 Synthesis of
sphingomyelin and
lecithin;
 Synthesis of taurine;
 Cofactor for glycogen
phosphorylase;
 Modulation of steroid
hormone receptors;
 Cofactor for the
condensing enzyme
functioning in fatty
acid synthesis
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Non-nutritional uses
 Vitamin B6 has been used to:
 overcome the side-effects of oral contraceptives
 alleviate the symptoms of premenstrual syndrome
 treating nausea due to its antiemetic effect;
 treat hyperhomocysteinemia, carpal tunnel
syndrome, morning sickness, depression, and
muscular fatigue.
9

Absorption, Transport & Metabolism
 PLP, PNP & PMP are dephosphorylated by alkaline
phosphatase in the intestinal mucosa.
 PL, PN & PM are all rapidly absorbed passively.
 In the enterocyte, the different forms of the vitamin
are rapidly converted to PL by PLP oxidase.
 PL are released directly into the portal blood and
most of it is taken up passively by the hepatocytes.
 In the hepatocytes, PL is phosphorylated by
pyridoxal kinase.
10

 PLP and some PL are exported from the liver
bound to albumin and hemoglobin.
 Free PL remaining in the liver is rapidly
oxidised to 4-pyridoxic acid, which is the main
excretory product.
 Extrahepatic tissues take up both PLP and PL
from the plasma.
11

Metabolism of Vitamin B6 in the liver (Gropper & Smith, 2012)
12

Catabolism & Excretion
 PLP is dephosphorylated and oxidised primarily in
the liver to yield 4-pyridoxic acid.
 The pyridoxic acid is excreted mainly in urine and
little in feces.
 About 3 mg of pyridoxic acid is excreted in urine
daily.
 PL and PM are excreted in urine in small amounts of
0.5 – 0.7 mg/day.
13

Storage
 Total body content of vitamin B6 is 40 – 185 mg in
adults.
 About 75 - 80% is in the form of PLP in muscle,
mostly associated with glycogen phosphorylase .
 The liver stores about 5 – 10% of the vitamin.
 Other tissues with significant amounts of the vitamin
are kidneys, brain and spleen, typically bound to
enzymes.
15

Deficiency
 Deficiency signs and
symptoms include:
 Seborrheic dermatitis;
 Weakness and fatigue;
 Cheilosis;
 Glossitis;
 Angular stomatitis;
 Hypochromic, macrocytic
anemia;
 Hyperhomocysteinemia;
 Impaired niacin synthesis
from tryptophan;
 Neurological problems
 Increased sensitivity of
target tissues to steroid
hormones
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Seborrheic dermatitis
17
Cheilosis, glossitis & angular
stomatitis

People at risk of deficiency
18
 Elderly;
 Alcoholics;
 People of a variety of drug therapies.

Toxicity
 The tolerable UI for
adults is 100 mg/day.
Megadoses cause:
 sensory and
peripheral neuropathy,
 dermatological lesions,
 Loss of myelination,
 Paresthesia in the feet
and hands,
 Ataxia
 Degeneration of
neurons in the spinal
cord and peripheral
nerves
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 Vitamin B12 is a generic
term for a group of
compounds called
corrinoids.
 Vitamin B12 is a red
compound made up of a
corrinoid ring containing a
cobalt atom.
 Vitamin B12 is the largest
molecule of vitamins Structure of cyanocobalamin
20

Sources
 Vitamin B12 is found only in foods of animal
origin.
 There are no plant sources.
 The best sources of Vitamin B12
are meat and meat products, fish,
shellfish, and eggs.
 Fortified plant-derived foods,
such as RTE cereals and
soymilk are also good sources.
21

22

Table 2 RDA values for vitamin B12
23
Infants 𝜇g/day Females 𝜇g/day
0 – 0.5 0.4 9 – 13 1.8
0.5 – 1 0.5 14 – 18 2.4
Children 19 – 30 2.4
1 -3 0.9 31 – 50 2.4
4 – 8 1.2 51 – 70 2.4
> 70 2.4
Males Pregnancy
9 – 13 1.8 ≤ 18 2.6
14 – 18 2.4 19 – 30 2.6
19 – 30 2.4 31 – 50 2.6
31 – 50 2.4 Lactation
51 – 70 2.4 ≤ 18 2.8
> 70 2.4 19 – 30 2.8
31 – 50 2.8

Digestion, Absorption and Transport
24
 The digestion and absorption of Vitamin B12 is
summarized in the figure on next slide.
 Within the enterocytes, vitamin B12 is released into
the cytosol.
 The vitamin is released and transported to the
hepatocytes bound to transcobalamin II (TC II),
 TCI (haptocorrin) transports about 80% of vitamin
B12 (as methylcobalamin) in blood.
 TCII carries (10 – 25%) cobalamin from peripheral
tissues back to the liver.

Absorption of vitamin B12
25

Tissue uptake
 All tissues have receptors for TCII and TCI-B12
complex.
 The TCII-cobalamin complex binds to TCII cell
receptors, which triggers internalization by
endocytosis.
 Within the cells, the complex is hydrolysed by
lysosomal enzymes to release free cobalamin within
the cytosol.
 Free cobalamin is converted to methylcobalamin.
26

Storage
 Vitamin B12 can be stored and retained in the body
for long periods.
 About 2 to 4 mg of the vitamin is stored in the
body, mainly (about 50%) in the liver.
 Small amounts are also found in the muscle, bone,
kidneys, heart, brain and spleen and circulating
blood as transcobalamins (TC).
27

Excretion
 Vitamin B12 is lost from the system in the urine and
the bile at a daily rate of about 0.1 – 0.2% of the
total body reserves.
 Vitamin B12 (0.5 – 5 𝜇g/day) is excreted in bile;
however, most of it (65 - 75%) can bind to IF in the
small intestines and be reabsorbed in the ileum.
 This enterohepatic recirculation provides about 3 to
8 𝜇g of vitamin B12 per day.
28

Metabolism
 Vitamin B12 is only active as methylcobalamin or
adenosylcobalamin.
 Two enzymes are involved in the conversion to these
coenzyme forms:
1. Generation of methylcobalamin. This is catalysed
by a cytosolic enzyme 5-methyl-FH4:
homocysteine methyltransferase.
2. Generation of adenosylcobalamin. This occurs in the
mitochondria under the catalysis of vitamin B12
coenzyme synthetase.
29

Functions
1. Vitamin B12 acts as a coenzyme for two enzymes:
methylmalonyl-CoA mutase and methionine synthetase.
2. Involved in DNA synthesis, which is necessary for the
proper formation of RBCs
3. It is essential for healthy functioning of the nervous
system because it helps maintain the myelin sheath.
30

Deficiency
 Vitamin B12 deficiency can be produced in several
situations, such as with:
1. Inadequate intake.
2. Impaired pancreatic function.
3. Impaired gastric function.
4. Impaired intestinal function.
5. Competition with parasites and bacteria.
6. Chemical factors such as alcohol, oral
contraceptives, NO.
31

Stages of Vitamin B12 Deficiency
 Stage I. A decline in the blood level of cobalamin
attached to its transport protein.
 Stage II. Levels of cobalamin attached to its
transport protein continue to decline.
 Stage III. The ability to synthesize new RBCs is
inhibited.
 Stage IV. Macrocytic anemia develops.
32

Table 3 Signs and Symptoms of vitamin B12 deficiency
33
Organ Signs
General
Growth Decreased
Vital
organs
Hepatic, cardiac and renal steatosis
Fetus Hemorrhage, myopathy and death
Circulatory
Anemia; low blood cell counts; skin pallor; fatigue;
shortness of breath; and palpitations
Nervous Peripheral neuropathy (Numbness in extremities);
increased loss of coordination; loss of propioception;
demyelination; irritability; memory loss;
disorientation; psychosis and dementia

34

 Folate is a generic
descriptor for folic acid
and related compounds.
 Folic acid is the oxidised
form of the vitamin found
in fortified foods and in
supplements.
 Folate is the reduced
form of the vitamin found
naturally in foods and in
biological tissues.
35

Sources of Folate
Good food sources are:
 Mushrooms & leafy
dark green vegetables .
Additional good food
sources:
 Peanuts, legumes, lentils,
Some fruits, liver.
 Fortified whole grain
products.
11/4/2018
36

37

Table 4 RDA values for folate
38
Infants 𝜇g/day Females 𝜇g/day
0 – 0.5 65 9 – 13 300
0.5 – 1 80 14 – 18 400
Children 19 – 30 400
1 -3 150 31 – 50 400
4 – 8 200 51 – 70 400
> 70 400
Males Pregnancy
9 – 13 300 ≤ 18 600
14 – 18 400 19 – 30 600
19 – 30 400 31 – 50 600
31 – 50 400 Lactation
51 – 70 400 ≤ 18 500
> 70 400 19 – 30 500
31 – 50 500

Destruction of Folate in Foods
 Folate is destroyed by:
i. Heat
ii. Oxidation
iii. Exposure to UV light
 Folate is also reduced
by food processing and
preparation.
 Folate can be preserved
in the ways outlined in
the next slide.
39
© Mathew R. Muyinda 2017

 Using little water when
cooking, and letting it boil
before adding vegetables;
 Steaming of vegetables;
 Consuming folate-rich foods
raw whenever possible;
 Covering the pan, cooking
vegetables until bright in
color and crisp tender;
 Saving any cooking liquid
for later use in soups &
stews;
 Storing fresh vegetables in
a cool dark place;
 Heating canned vegetables
quickly in their own liquid.
 Vitamin C in foods prevents
loss of folate during
cooking.
11/4/2018
40

Bioavailability
Factors affecting folate bioavailability:
 Source of folate.
 Antifolates in diet.
 Inherent characteristics of various folates.
 Nutritional status of the host.
 Variation in intestinal pH.
41

Table 5 Biologic availability to humans of folates in food
42

Digestion of Folate
 Folate conjugates (polyglutamates) are hydrolyzed
in the small intestine by a Zn-dependent conjugase.
 Folate is then taken up into enterocytes by the
proton-coupled folate transporter (PCFT).
 Within the enterocyte, folate and folic acid are
reduced to dihydrofolate (DHF),
 DHF is reduced to generate THF by DHF reductase.
43

Metabolism & Transport
 Folate is actively transported across the basolateral
membrane into blood.
 Folate is transported to the liver as folate and 5-
methyl THF.
 THF is converted to 5-methyl THF in the hepatocytes.
 5-methyl THF is converted to either 5- or 10-formyl
THF by folylpolyglutamate synthetase.
 Polyglutamates are then hydrolyzed to majorly 5-
methyl THF before release into systemic circulation.
44

Metabolism continued…
 5-methyl THF (2/3) circulates bound to albumin and
is available for uptake by extrahepatic tissues.
 Folate is taken up by the liver and other tissues via
a carrier-mediated mechanism.
 It is trapped by formation of polyglutamates, which
do not cross the cell membrane.
45

Storage of folate
 Total body folate levels range from 11 to 28 mg,
with about one-half stored in the liver.
 The main storage forms of folate are the
polyglutamate forms of THF and 5-methyl THF.
 Storage occurs in association with intracellular
folate-binding proteins (FBP).
 Folate is found in the cytosol and mitochondria of
cells.
46

Excretion of folate
 Folate is excreted from the body in both the urine
and the feces.
 However, urinary losses are minimal (5 – 10
nmol/day) because:
a. it is bound to plasma proteins thus protecting it
from glomerular filtration;
b. the renal brush border has a high concentration of
FBP, which acts to reabsorb any filtered in the
urine.
47

Functions of folate
 Involved in amino acid Metabolism for example
regeneration of methionine from homocysteine.
 Involved in purine and pyrimidine synthesis which
are essential for DNA synthesis and cell division.
 Prevention of neural tube defects.
48

Figure 11 Role of vitamin B12 and folate in DNA synthesis
Role of folate in DNA synthesis
11/4/2018
49

To prevent NTDs, women of child bearing age (15 to 45 yr) should:
 Eat folate-rich foods
 Eat folate-enriched foods
 Take a multivitamin daily (most provide 400 𝜇g folate)
Folate helps to protect against spina bifida, a neural tube defect which is
characterized by the incomplete closure of the spinal cord and its bony
encasement.
50

Folate deficiency
 The signs & symptoms
associated with folate
deficiency are
summarized in Table 6.
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51

Table 6 Signs and symptoms of folate deficiency
52 Organ system Signs
General
Appetite Decrease
Growth Decrease
Dermatologic Alopecia; achromotrichia; dermatitis
Muscular Weakness
Gastrointestinal Inflammation; shortening of the villi’s height;
thinning GIT layers; bright red tongue
Circulatory Macrocytic anemia; fatigue
shortness of breath; heart palpitations;
increased homocysteine
Nervous Depression; headaches; neuropathy;
paralysis; irritability; difficulty concentrating
Fetus Neural tube defects (NTDs)

53
Folate deficiency signs

Table 7 Contributing factors to folate deficiency
54

Toxicity of folate
 A tolerable Upper Intake Level for adults is 1 mg.
 Intake of 15 mg have been associated with:
 insomnia,
 malaise,
 irritability, and
 gastrointestinal distress.
 Increase cancer risk and cancer mortality
 It masks vitamin B12-deficiceny symptoms.
55

56
 If you are on a diet high in unenriched processed
foods, you’re missing out on these essential B
vitamins.
 Feeding on diet high in processed foods produces
poor vitamin status in just 11 weeks!

Does your diet or anyone you know resemble this one?
57
 Breakfast: white rolls, margarine,
cheese, jam, ‘chapati’, samosa
 Lunch: white rolls, potato chips,
cheese, Beef, white posho
 Dinner: ‘Rolex’, white rice, carrots,
green peas, beans, beef, cream,
peaches
 Snacks: soft drinks, honey cake,
cookies, tea, coffee, sugar, margarine

If YES…
58
 To obtain B vitamins in adequate amounts, try out a
diet that is:
1. High in whole grain
2. High in fruits
3. High in vegetables
4. Low in sugar and fat
5. Snack on enriched cereals

In conclusion…
59
 Vitamin B6 , B12 and folate work together in energy
metabolism and other body processes.
 A deficiency of one vitamin creates multiple problems.
 Thus, diets should ensure an adequate supply of all the
B vitamins.
 Deficiencies of the vitamins may be caused by
inadequate dietary intake, and other conditions.
 Vitamin supplements may be used to address
deficiencies but their use MUST be controlled because
excessive use may cause toxicities.

References
60
 Bender, D. (2004). Introduction to Nutrition and Metabolism (Third Edit). Taylor &
Francis Inc.
 Chatterjea, M., & Shinde, R. (2012). Medical Biochemistry. (R. Saxena, Ed.) (Eighth).
New Delhi: Jitendar P Vij.
 Combs, G. F. (2008). The Vitamins (Third). California: Elsevier Academic Press.
 Gibney, M. J. (2009). Introduction to Human Nutrition. (M. J. Gibney, S. A. Lanham-
New, A. Cassidy, & H. H. Vorster, Eds.) (Second Edi). Wiley Blackwell.
 Gropper, S. S., & Smith, J. L. (2012). Advanced Nutrition and Human Metabolism
(Sixth Edit). Belmont: Wadsworth Cengage Learning.
 Mann, J., & Truswell, A. S. (2002). Essentials of Human Nutrition. (J. Mann & A. S.
Truswell, Eds.) (Second Edi). Oxford University Press.
 Thompson, J. L., Manore, M. M., & Vaughan, L. A. (2011). The Science of Nutrition.
(K. Balayti, Ed.) (Second Edi). Pearson Benjamin Cummings.
 Vasudevan, D., S, S., & Vaidyanathan, K. (2013). Textbook of Biochemistry for
Medical Students (Seventh). New Delhi: Jaypee Brothers Medical Publoshers (P) Ltd.
 Whitney, E., & Rofles, S. R. (2011). Understanding Nutrition. (P. Williams, N. Rose, E.
Feldman, & L. Tarson, Eds.) (12TH Ed). Cengage Learning.

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