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Pharmacy School 2015-16 > PHAR 714 Vitamins > Flashcards

PHAR 714 Vitamins Flashcards

1
Q

The active principle for preventing scurvy?

A

Vitamin C

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2
Q

Vitamin C is also called _________________

A

Ascorbic Acid

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3
Q

Why can’t humans synthesize Vitamin C and instead depend on dietary sources?

A

Lack of gulonolactone oxidase enzyme (primates, fruit bats and guinea pigs also lack)

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4
Q

Common vitamin C containing foods

A

Citrus fruits, Brussels Sprouts, broccoli and kiwi fruit

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5
Q

Differences between Vitamin C from natural sources compared with supplements

A

Vitamin C from fruits and vegetables is identical to L-ascorbic acid in Vitamin C supplements (produced from D-glucose) and is therefore not superior

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6
Q

Describe ascorbic acid absorption

A

Absorbed in small intestine by sodium-dependent co-transporters (SVCT1 and SVCT2)

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7
Q

SVCT1 and SVCT2 differences

A

SVCT1 - found in most epithelial tissues

SVCT2 - found in lumenal membrane (brush border) and is widely distributed; not found in muscle and lung

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8
Q

Describe ascorbic acid transport

A

Oxidized form (dehydro-ascorbic acid) transported by sodium-independent glucose transporters (GLUTs - especially GLUT 1 and 3)

Transported in intestinal cells to plasma and lymph by facilitated diffusion through anion channels in basolateral membrane.

In plasma it is actually transported into cells by SVCTs.

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9
Q

Cellular and plasma concentrations of ascorbic acid

A

Cellular concentrations are 1-5mM (includes WBCs)

Plasma levels of dehydro-ascorbic acid are very low due to rapid uptake by GLUTs. Plasma levels of ascorbic acid are tightly regulated (about 50uM). IV administration required to achieve high levels of plasma ascorbic acid.

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10
Q

Gulonolacton oxidase catalyzes which transformation

A

L-gulonolactone oxidation to 2-keto-L-gulonolactone

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11
Q

Daily recommended intake of Vitamin C

A

90mg (kidney is very efficient)

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12
Q

Animals that can make Vitamin C make it from _____________. Describe the process.

A

alpha-D-glucose (oxidation to glucuronic acid –> glucuronic acid opens up to aldehyde form –>reduced to L-gulonic acid, an alcohol –> Carboxyl forms intramolecular ester with 5 membered ring, splitting water off and yielding L-gulonolactone –> oxidation via gulonolacton oxidase giving 2-keto-L-gulonoloactone –> keto-enol tautomerism to enol form, called L-ascorbic acid)

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13
Q

Does dehydro-ascorbic acid exist in solution?

A

No, reaction of tri-keto with water yields hemi-ketal hydrate (the typical oxidized form of Vitamin C)

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14
Q

What enzyme reduces the typical oxidized form of Vitamin C? Where does it get its electrons?

A

Dehydro-ascorbate reductase

From glutathione (2 GSH required for 1 dehydro-ascorbate)

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15
Q

GSSG reduced back to _____ by ____________

A

GSH; GSSG reductase

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16
Q

Purpose of NADPH in Vitamin C pathway

A

Recovers reduced glutathione from oxidized glutathione

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17
Q

What is the alternative way to recover reduced vitamin C from dehydro-ascorbate?

A

Dismutation (only yields 1 molecule of ascorbic acid from 2 of dehydro-ascorbate)

Recovers from dehydro-ascorbic acid radical!!

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18
Q

What is the main function of Vitamin C?

A

Functions as a co-factor in a number of hydroxylation reactions in which it maintains iron or copper ions in the metalloenzymes in the reduced state

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19
Q

Describe Vitamin C and collagen synthesis

A

Proline and lysine in collagen fibers undergo hydroxylation for cross-linking. The hydroxylase complex has an Fe2+ ascorbate cofactor in its active site. Oxygen is dissociated onto a proline and on to 2-ketoglutaric acid (forming succinc acid after decarboxylation). If Fe2+ is oxidized to 3+, ascorbate will convert it back to Fe2+

Summary: Proline-H + O2 + 2-ketoglutaric acid –> Proline-OH + CO2 + succinic acid

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20
Q

Describe Vitamin Cs role as a cofactor for prolyl 4-hydroxylase

A

Alpha-ketogluterate coordinates with enzyme bound Fe2+. Alpha-ketoglutaric acid is decarboxylated after O2 is activated, forming iron 4=O which hydroxylate proline residues. If no substrate, Fe4=O will oxidize ascorbic acid instead

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21
Q

How is Iron bound to prolyl 4-hydroxylase

A

Through interactions with His412, Asp414 and His483. Alpha-ketoglutaric acid binds in 2 sites which can be occupied by ascorbate when succinate leaves in uncoupled reaction.

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22
Q

What is the purpose of carnitine?

A

To transport long-chain fatty acids from the cell cytoplasm into the mitochondrial matrix where B-oxidation takes place.

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23
Q

What is the role of Vitamin C in carnitine synthesis?

A

Ascorbate-dependent hydroxylation occurs twice, allowing carnitine acylation with fatty acids.

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24
Q

Describe tyrosine catabolism and the role of Vitamin C

A

p-hydroxyphenylpyruvate is converted homogentisate (via p-hydroxyphenylpyruvate dioxygenase and a Cu1+ Asc2 complex)

Homogentisate is toxic and converted to maleylacetoacetate (via homogentisate dioxygenase and an Fe2+ Asc2 complex)

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25
Q

What happens if there is a defect in homogentisate dioxygenase?

A

A defect in this enzyme causes alkaptonuria, characterized by accumulation of homogentisate leading to painful joints. Excreted homogentisate in the urine will oxidize and turn the urine black.

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26
Q

Describe ascorbic acid-dependent hydroxylations for neurotransmitter synthesis (3)

A

Hydroxylation of dopamine by copper-dependent dopamine monooxygenase to give norepinephrine.

Hydroxylation of tryptophan (TRP monooxygenase) tot 5-OH-TRP (tetrahydrobiopterin-dependent) Ascorbate helps regenerate tetrahydrobiopterin (BH4) from BH3 radical. Decarboxylation of 5-OH-TRP gives 5-OH-tryptamine, or serotonin

Ascorbate maintains coppere in peptidylglycine a-amidating monooxygenase in the reduced state. Examples include gastrin-releasing peptide, calcitonin, corticotrophin-releasing factor, gastrin, oxytocin, and vasopressin.

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27
Q

Describe antioxidant activity of vitamin c

A

Hydroxyl radical (or O2 radical –> semi-dehydro-ascorbate radical + H2O (H2O2)

Hydrogen peroxide –> dehydroascorbate +2H2O

Hydrochlorous acid –> dehydroascorbate + HCl + H2O

Vitamin E radical –> Vitamin E + semi-dehydro-ascorbate radical

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28
Q

Vitamin C role in cardiovascular disease

A

Ascorbate decreases monocyte adhesion to endothelial cells of blood vessels by inhibiting expression of adhesion molecules

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29
Q

Vitamin C role in cataracts

A

Lens browning caused by oxidation and aggregation of crystalline proteins. Ascorbate functions as an antioxidant

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30
Q

Vitamin C role in cancer prevention

A

N/A

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31
Q

Vitamin C role in cancer therapy

A

Some success in animals. Mechanism believed to be the iron-mediated formation of H2O2 from ascorbate

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32
Q

Vitamin C role in colds

A

Believed to enhance immune cell function. Effect small and does not appear to be dose-dependent

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33
Q

Describe metabolism and excretion of ascorbic acid

A

Filtered in glomeular capsule and resorbed in tubular cells (highly efficient at low plasma levels, takes ~12 weeks without Vitamin C to become scorbutic). Ascorbic acid can compete with uric acid at transporters, risking kidney stone formation.

To an extent Vitamin C is oxidized and hydrolyzed to 2,3-diketoglulonic acid which breaks into oxalic acid and C4 and C5-hydroxy acids.

Ca2+ - Oxalate kidney stones can form with high Vitamin C intake.

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34
Q

Ascorbic acid interaction with iron

A

Enhances intestinal absorption of non-heme iron. Converts Fe3+ to 2+ and forms soluble complexes with iron ions. High vitamin C intake unsafe for those with iron metabolism disorders.

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35
Q

Ascorbic acid interaction with copper

A

Forms complexes with copper ions and causes copper dissociation from copper-containing proteins such as ceruloplasmin and metallothionin. Significance not clear.

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36
Q

Recommended Dietary Allowance Vitamin C

A

90mg (adult men)
75mg (adult women)

75 required for men, 60 for women.

120mg during pregnancy and lactation.

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37
Q

Describe Vitamin C deficiency

A

Scurvy (hemorrhage of gums, hyperkeratosis of hair follicles, hypochondriasis, hematologic abnormalities as a result of impaired iron absorption)

Scurvy seen in elderly, those with poor diets, diabetics and in some cancer patients.

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38
Q

Describe toxicity of Vitamin C

A

Over 2 g/day

GI problems such as abdominal pain and osmotic diarrhea. Increased kidney stone risk (calcium oxalate AND uric acid in urinary tract). Exacerbation of iron metabolism disorders (hemochromatosis, thalassemia, and sideroblastic anemia).

Excessive ascorbate in urine can interfere with some lab tests (glucose, false-negative for fecal occult blood)

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39
Q

Vitamin B1 also called __________

A

Thiamin

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40
Q

Thiamin general structure/forms

A

Thiazole ring and pyrimidine ring connected by a methylene bridge.

3 forms: free alcohol form and 2 phosphorylated derivatives

Thiaminpyrophosphokinase converts thiamin (T) and ATP into TDP and AMP; TDP-ATP phosphoryl transferase converts TDP and ATP into TTP and ADP

Thiamin monophosphate is NOT active

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41
Q

Dietary thiamin sources

A

Meat, beans, cereals and bread.

Thiamin hydrochloride and thiamin mononitrate found in supplements.

Thiamin exists in the alcohol form in plants. Animal products contain mainly the diphosphate.

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42
Q

Thiamin absorption

A

High absorption from plant or animal foods. Polyphenols in coffee, tea, and berries can inhibit absorption by complex formation or through oxidative degradation.

Primarily absorbed passively in jejunum and through sodium-dependent transport in lumenal membrane (ThTr1, ThTr2) - a defect in ThTr1 gene causes deficiency

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43
Q

Raw fish and thiamin?

A

Raw fish contains thiaminase that can degrade thiamin. Cooking the fish will destroy this enzyme.

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44
Q

Thiamin transport

A

Transport of thiamin-OH across basolateral membrane mediated by thiamin/H+ antiporter (inhibited by alcohol)

In blood, thiamin mostly bound to albumin or present in blood cells in diphosphate (TDP) form.

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45
Q

What happens to thiamin in the liver?

A

Thiamin-OH phosphorylated. TMP can be converted to T-OH by thiamin monophosphatase (TDP by diphosphatase)

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46
Q

Thiamin and pyruvate

A

Serves as a co-factor in conversion of pyruvate into acetly-CoA (pyruvate dehydrogenase complex)

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47
Q

Thiamin and a-ketogluterate

A

Serves as a co-factor in the a-ketogluterate dehydrogenase complex, converting a-ketogluterate to succinyl-CoA

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48
Q

Thiamin and a-ketoisovalerate

A

Serves as cofactor for branched chain a-keto acid dehydrogenase (BCAKAD) to convert a-ketoisovalerate into isobutyryl-CoA. A defect in BCAKAD causes maple syrup urine disease (MSUD)

Avoid accumulation of toxic a-keto acids by limiting leucine, isoleucine and valine intake.

Symptoms of MSUD include neurological decline and seizures.

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49
Q

Thiamin and transketolase

A

Serves as cofactor in transketloase reaction of pentose monophosphate. C2 unit transferred from donor carbohydrate to acceptor carbohydrate.

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50
Q

Metabolism and excretion of thiamin

A

Excess excreted in urine as TDP, TMP or metabolites. Cleavage into pyrimidine and thiazole moieties which are then further degraded (20+ metabolites)

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51
Q

How do you measure thiamin adequacy?

A

By measuring erythrocyte transketolase activity

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52
Q

Thiamin deficiency

A

Beriberi: symptoms include weakness, anorexia, cardiac hypertrophy, confusion, memory loss
>dry beriberi causing muscle weakness in extremities
>wet beriberi causing cardiomegaly and tachycardia
>acute beriberi, mostly in infants, causing acidosis

Deficiency often a result of alcohol abuse (W-K syndrome, characterized by ophthalmoplegia, nystagmus and ataxia)

Often seen in patients with congestive HF, presumably from urinary loss of thiamin from diuretics. Treatment = supplementation (100mg or more)

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53
Q

Thiamin toxicity

A

Over 500mg a day for 1 month

Headache, convulsions, cardiac arrhythmias and anaphylactic shock.

Large doses may be beneficial in one variant of MSUD and in thiamin-responsive lactic acidosis

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54
Q

Vitamin B2 also called ____________. It is part of ______

A

Riboflavin

FAD

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55
Q

Dietary B2 sources

A

Animal products such as milk, cheese, eggs and meat. Beans and spinach. Occurs in protein-bound form as FMD/FAD

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56
Q

Digestion of Riboflavin

A

Riboflavin released from FMN or FAD in the intestine by pyrophosphatases (FAD or FMD phosphatase)

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57
Q

Absorption of Riboflavin

A

Divalent metal ions chelate riboflavin and decrease absorption.

Free riboflavin is absorbed by an ATP-dependent transporter in the proximal small intestine. When large amounts are taken in, absorption can occur by diffusion.

Following absorption, riboflavin phosphorylated to form FMN by flavokinase (ATP is co-substrate, ADP is by-product). Dephosphorylation at basolateral surface, transported as free riboflavin to liver via the portal vein, and re-phosphorylated in the liver via flavokinase and FAD synthetase, converting FMN/ATP into FAD/PO4 3-

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58
Q

Riboflavin transport

A

In plasma, transported primarily bound to albumin. Enters tissues by carrier-mediated transport across cell membranes. Concentrations highest in liver, kidney and heart. Transported out of cells in free form.

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59
Q

How is FMN and FAD synthesis regulated?

A

Under hormones such as ACTH, aldosterone, and thyroid hormones.

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60
Q

Describe riboflavin and its involvement in Complex 2 of the electron transport chain

A

FAD reduced to FADH2 and then oxidized by 2 electron transfers through Fe-S clusters to reduce coenzyme Q to QH2.

Yield is 2 ATP

61
Q

What is the role of riboflavin in the pyruvate dehydrogenase and a-ketogluterate dehydrogenase.

A

FAD first oxidizes dihydrolipoamide. The resulting FADH2 is oxidized by NAD+

62
Q

Riboflavin role in fatty acid oxidation

A

Fatty acyl CoA dehydrogenase requires FAD

63
Q

Riboflavin role in Niacin synthesis

A

Synthesis from tryptophan requires FAD for the conversion of kynurenine into 3-hydroxykynurenine (via kynurenine monooxygenase)

64
Q

Riboflavin role in Neurotransmitters

A

Dopamine and other NTs required FAD-dependent monoamine oxidase metabolism

65
Q

Riboflavin and parkinsons

A

Anti-parkinsons agents of the N-N-dimethylpropargylamine type inhibit MAO by inactivating FAD (suicide inhibition)

66
Q

Riboflavin in Thioredoxin reductase (TR)

A

TR is a flavo (FAD) enzyme that has selenocysteine in its active site, transfering reducing equivalents from NADPH to FAD. Thioredoxin plays a role in DNA synthesis, regeneration of thioredoxin peroxidase and conversion of DHAsc into ascorbate

67
Q

Metabolism and excretion of Riboflavin

A

Riboflacin and metabolites excreted primarily in urine. Urine can change from yellow to brighter orange-yellow upon increased dietary intake.

68
Q

Deficiency of Riboflavin

A

Ariboflacinosis (lesions outside of lips and corners of mouth, inflammation of tongue, anemia, peripheral nerve dysfunction) - deficiency common in countries like India

FAD-dependent vitamin B3 and vitamin B6 synthesis may be impacted.

Increased risk of deficiency with alcohol abuse.

69
Q

Toxicity of riboflavin

A

Large amounts shown efficacy in treatment of migraine without side effects.

No known toxicity

70
Q

How to determine Riboflavin status

A

Determined by erythrocyte glutathione reductase activity (uses FAD as cofactor)

If FAD stimulates NADPH consumption, riboflavin may be low.

71
Q

Vitamin B3 also called ______________

A

Niacin

72
Q

Dietary Niacin sources

A

Fish and meat, whole grains, seeds, beans, coffee and tea.

In animals occurs mainly as NAD and NADP. Upon prcessing, hydrolysis yields free niacin as main source in meat.

Found in bound form in corn but only small amount available for absorption. Can covalently complex with carbs or small peptides.

73
Q

Describe Niacin synthesis in the body

A

Can be synthesized in the liver from tryptophan. Synthesis requires FAD, vit B6 and iron.

74
Q

Digestion of Niacin

A

NAD and NADP hydrolyzed in intestinal tract or enterocyte by glycohydrolase to form nicotinamide

75
Q

Niacin absorption

A

In small intestines, niacin absorbed by sodium-dependent, carrier mediated diffusion or by passive diffusion when in high concentrations

76
Q

Niacin transport and storage

A

In plasma, mainly present as nicotinamide. Transport into most cells occurs by diffusion. Organic Anion Transport System (OATS) used to transport nicotinic acid into renal tubules.

Predominant form in cells is NAD. In liver, excess niacin and tryptophan converted to NAD. NADP primarily found in cells in reduced form (NADPH)

77
Q

Functions and mechanisms of niacin

A

Many enzymes, primarily dehydrogenases, require NAD and NADP.

NADH - delivers electrons to electron transport chain

NADPH - acts as a reducing agent in many biosynthetic pathways (fatty acid, cholesterol, and steroid hormone synthesis) (also involved in synthesis of desoxyribonucleotides, and in generation of GSH, dehydroascorbic acid and thioredoxin)

NAD - participates in oxidative reactions (glycolysis, oxidative decarboxylation of pyruvate, oxidation of acetyl CoA in TCA cycle, b-oxidation of fatty acids, oxidation of alcohols and aldehydes)

78
Q

How is NADPH generated?

A

From NADP in conversion of glucose-6-phosphate into 6-phosphogluconolactone (via G-6-P dehydrogenase)

79
Q

Metabolism and excretion of niacin

A

NAD hydrolyzed to nicotinamide, N-methylated and oxidized to metabolites which are then excreted in urine.

80
Q

Niacin deficiency

A

AKA Pellagra

Symptoms include four Ds: dermatitis, dementia, diarrhea, and death. Paralysis of extremities, dementia or delirium, nausea, vomiting.

Deficiency promoted by drugs that react with pyridoxal (vit B6) such as isoniazid and hydralazine.

Chronic diarrhea can impair niacin and Trp absorption. Hartnup disease will also impair Trp absorption.

Excessive alcohol can cause niacin deficiency.

81
Q

Nicotinic acid for treatment of hyperlipidemia

A

Lower serum LDL and triglycerides and increases HDL by inhibiting lipoloysis in adipose, decreasing VLDL secretion from liver and inhibiting triglyceride synthesis by inhibiting DGAT.

Side effects: vasodilation, flushing, redness in face, itching and headaches. Caused by induced prostaglandin synthesis and prevented by co-administration of acetylsalicylic acid. Liver damage, hyperuricemia and gout as well as elevated blood glucose can all result.

Nicotinamide does NOT have antihyperlipidemic effects.

82
Q

Vitamin B6 also called _____________

A

Pyridoxal (PNP, PLP, PMP - all interchangeable)

83
Q

Dietary B6 sources

A

PNP found almost exclusively in plant foods. Can also occur in glycoside form.

PLP and PMP also found in animal products such steak, salmon and chicken.

Other sources are whole-grains, vegetables, some fruits, and nuts.

Heating and sterilizing will destroy the vitamin.

84
Q

Form of B6 found in supplements (in general)

A

pyridoxine hydrochloride

85
Q

Digestion, absorption, transport and storage of B6.

A

Phosphorylated form de-phosphorylated by alkaline phosphatase in brush border for absorption. Free vitamers (PN, PL, and PM) absorbed in jejunum passively. Overall absorption 70%.

PN, PL and PM released unchanged in portal blood and converted to phosphates in the liver by ATP-dependent kinases.

PLP main form found in blood, bound to albumin. PL, PN, PM and PMP also found in blood. Erythrocytes will take up free vitamers and convert them to PLP. Tissues will take up unphosphorylated forms.

Main storage site is muscles. Phosphorylation will prevent diffusion out of cells. Protein binding prevents hydrolysis.

The liver will convert PNP or PMP to PLP with an FMN-dependent oxidase

86
Q

Functions and mechanism of action for B6

A

PLP (coenzyme form) is involved in amino acid metabolism.

PLP and PMP are cofactors for transamination reactions.

PLP functions as a cofactor for decarboxylation reactions (GABA formation from glutamate and serotonin from 5-hydroxytryptophan)

B6 is cofactor in synthesis of heme, sphingolipids, niacin and carnitine.

87
Q

Metabaolism and excretion of B6

A

4-pyridoxic acid is major metabolite of B6 and is excreted in urine. Large doses will result in excretion of unchanged vitamin.

88
Q

B6 deficiency

A

Symptoms include sleepiness. fatigue, cheilosis, glossitis, stomatitis. Abnormal EEGs, seizures and convulsions in infants. Hypochromic, microcytic anemia may result due to impaired heme synthesis.

Deficiency also impairs niacin synthesis from tryptophan.

Deficiency leads to inhibition of metabolism of homocysteine, which results in hyperhomocysteinemia, a risk for hear disease.

89
Q

How to assess Vitamin B6 status

A

High xanthurenic acid excretion found in B6 deficiency because 3-hydroxykynurenine can’t be converted to 3-hydroxyanthranilate (instead converted to xanthurenic acid).

Urinary 4-pyridoxic acid excretion considered a short-term indicator of B6 status.

Also measured by erythrocyte transaminase activity before and after adding B6 through examination of erythrocyte glutamic oxaloacetate transaminase (EGOT).

Erythrocyte glutamic pyruvic transaminase also used to index B6 deficiency.

90
Q

Vitamin B12 also called ______________. Describe its structure.

A

Cobalamin (group of structural compounds based on corrin ring).

4 of 6 coordinators provided by corrin ring nitrogens; 5th by dimethylbenzimidazole moiety; 6th by cyano, hydroxyl or methyl

91
Q

What forms of cobalamin are active as coenzymes?

A

Methylcobalamin and 5’ - deoxyadenosylcobalamin (the human body can usually convert to these forms)

92
Q

Dietary B12 sources

A

Animal products: meat, shellfish, eggs (primarily 5’-deoxyadenosyl and hydroxocobalamin)

Vegetables devoid of vitamin.

Cyanocobalamin and hydroxocobalamin are available in supplements.

93
Q

Digestion, absorption, transport and storage of B12.

A

Ingested cobalamins must be released from proteins and peptides, mediated by pepsin and HCl acid in stomach, followed by binding to R protein, or cobalophilins (produced by stomach cells).

Complex enters small intestine and R protein hydrolyzed by pancreatic proteases, releasing cobalamin.

IF produced by stomach parietal cells binds freed cobalamin in ileum. Complex is absorbed via cubulin receptor into intestinal cell.

Movement across basolateral membrane occurs after B12 binds transcobalamin 2 (1 and 3 less common).

TC2 receptor allows uptake of B12 TC 2 complex into cells, where TC 2 is degraded in a lysosome.

Vitamin B12 is mainly stored in the liver, erythrocytes, kidney and brain. It can be retained in the body for months to years.

94
Q

Functions of B12

A

Methylcobalamin needed for synthesis of methionine from homocysteine.

Also plays a role in threonine catabolism to form succinyl CoA: (1) 5’-deoxyadenosylcobalamine dissociates into cobalamin and 5’-deoxyadenosyl radical; (2) methylmalonyl CoA rearranged to succinyl CoA, mediated by methylmalonyl CoA mutase and is 5’-deoxyadenosylcobalamin dependent

95
Q

Metabolism and excretion of B12

A

Not extensively degraded prior to excretion. Little urinary excretion, some in bile. bound to R protein. 0.1% estimated turnover each day.

96
Q

Vitamin B12 deficiency

A

When cobalamin stores become depleted, DNA synthesis decreases and methylmalonyl concentrations increase. Deficiency signs are neurologic and hematologic (skin pallor, fatigue, shortness of breath, palpitations, insomnia, tingling and numbness in extremities, memory loss and dementia)

Megaloblastic macrocytic anemia corrected with large folate doses, but neuropathy will not be responsive.

Strict vegetarian diet can result in deficiency.

Most cases result of inadequate absorption (Pernicious anemia damages parietal cells; atrophic gastritis causes lack of IF; achlorhydria, Zollinger-Ellison syndrome, prolonged use of H2 receptor blockers and PPIs all associated)

97
Q

Treatment of pernicious anemia as it relates to B12

A

Monthly B12 injections of 500-1000 ug OR 2 mg po Vitamin B12

98
Q

Vitamin B12 toxicity

A

No toxicity established.

Hydroxocobalamin used to treat cyanide poisoning (accelerating clearance of cyanide).

DONT GIVE CYANOCOBALAMIN FOR CYANIDE POISONING

99
Q

How to assess B12 status

A

Radio immuno assay to measure B12 bound to TC2 in serum.

Measurement of methylmalonic acid in serum or urine (will increase in deficiency)

Schilling test using oral radioactive B12 and measuring urinary excretion to determine absorption.

100
Q

Vitamin B9 also called ________________. Describe the general structure and function.

A

Folate

Consists of 4-hydroxypteridine, para-aminobenzoic acid (PABA) and glutamic acid

Humans synthesize all of the components but lack the enzyme to link the pteridine with the PABA

Reduced folate form, tetrahydrofolate, functions as a carrier of one-carbon groups needed for amino acid and nucleotide metabolism.

101
Q

Dietary Folate sources

A

Mushrooms, green vegetables, peanuts, beans, strawberries, oranges and liver.

Raw foods higher in folate than cooked foods.

Flours, grains, cereals and some juices.

Folate in foods primarily in reduced form and usually contains up to nine Glu residues. Principal forms in foods are N5-methylTHF and N10-formylTHF. Oxidized and stable (folic acid) form in supplements.

Folate in milk bound to high-affinity folate binding protein, enhancing bioavailability.

102
Q

Digestion/absorption of folate.

A

Poly glu forms hydrolyzed to mono glu forms before absorption, mediated by at least 2 FGCPs (one form soluble, other membrane bound in brush border). Brush border hydrolase is zinc-dependent exopeptidase. Chronic alcohol and hydrolase inhibitors decrease digestion. Folic acid in supplements is already in mono glu form.

Absorption occurs throughout small intestines but is most efficient in the jejunum.

103
Q

Transport and storage of Folate.

A

In intestinal cells, folate reduced to DHF which is reduced to THF. THF converted to a 1-carbon carrier which is the main form found in blood.

Other forms found in liver: 10-formyl THF and 5-formimino TFH (3 to 9 glu attached). These poly-glu forms are better cofactors.

Erythrocytes will take up folate during erythropoiesis, not when they have reached maturity.

The liver stores about one-half of total body folate, mainly in poly-glu form. Found in cytoplasm and mitochondria.

104
Q

Functions of folate

A

Functions as a one-carbon acceptor or donor. One carbon units can be formyl, formimino, methenyl, methylene and methyl.

Involved in amino acid metabolism:

(1) accepts an hydroxymethyl methyl from Ser to form Gly
(2) donates a methyl to regenerate Met from homocysteine - mediated by methionine synthase, using methylcobalamin as cofactor - occurs when SAM needed for methylation of DNA and RNA

105
Q

Folate and diseases

A

Low folate = high plasma HomoCys = premature coronary artery disease, cerebral or peripheral vascular disease

Low folate linked to dementia and Alzheimer’s; also early cancer development, especially colon (could result from decreased DNA methylation of tumor suppressing genes)

Polymorphisms of methylene-THF reductase can increase risk of colorectal cancer

106
Q

Folate interaction with other nutrients

A

Synergistic relationship with folate and vitamin B12. Without B12 the methyl of N5-methyl THF is trapped and HomoCys is not converted to Met

107
Q

Metabolism and excretion of folate

A

Excreted in urine and feces. Recovered from lumenal fluid by tubular reabsorption.

Oxidative cleavage yields PABA mono Glu or PABA polyGly. The amino group of PABA is N-acetylated and excreted as such in urine (N-acetly PABA mono Glu is major urinary metabolite).

Folate excreted in bile undergoes enterohepatic recirculation.

108
Q

Folate deficiency

A

In absence, bone marrow cells and other rapidly dividing cells become megaloblastic due to failure of blood cells to divide properly. Deficient humans exhibit fatigue, weakness, headaches, irritability, difficulty concentrating, shortness of breath, and palpitations.

Megaloblastic macrocytic anemia: fewer, larger and immature erythrocytes. Abnormal DNA synthesis and continued RNA synthesis leading to excess production of other cytoplasmic contents such as hemoglobin.

More common in those with excessive alcohol consumption, malabsorption disorders such as IBD and those on certain medications (phenytoin, methotrexate)

Genetic polymorphism of methylene-THF reductase 677C causes N5,N10 methylene-THF to not be converted to N5-methyl-THF with normal capacity.

109
Q

Folate toxicity

A

Up to 15mg/day can cause insomnia, malaise, irritability, gastro-intestinal distress.

Folic acid supplementation can mask B12 deficiency (neurological symptoms)

Use of folic acid discouraged in those receiving chemotherapy with methotrexate.

110
Q

Vitamin A also referred to as ______________

A

Retinoids (retinol, retinal, retinoic acid, and fatty acid esters of retinol)

Some carotenoids (C40) can be converted to Vitamin A and are therefore called pro-Vitamin A

111
Q

Vitamin A needed for

A

Rodopsin and other light receptor pigments, for growth, cell differentiation and proper immune system function

112
Q

Form of Vitamin A needed for vision

A

all-trans-retinol –> 11-cis retinal followed by binding to opsin in the retina via a Schiff base link with Lys to give red pigment rodopsin.

Light energy will cause cis–>trans isomerization, activating cGMP breakdown, hyperpolarization of receptor cells, inhibition of NT release (glutamine = inhibitory NT) and action potentials to form visual signals

113
Q

B-Carotene

A

Cleaved by 15,15’ - carotenoid dioxygenase to form two molecules of retinal

a-Carotene is also a pro-vitamin A

114
Q

Lycopene

A

Another prominent dietary carotenoid with no pro-vitamin A properties

115
Q

Dietary Vitamin A sou. rces

A

Found in foods of animal origin, especially liver and dairy products. Products such as margarine may be fortified with Vitamin A.

In pharm formulations, all-trans retinyl acetate and all-trans retinyl palmitate are common. Aquasol A, a water-miscible form is available for those with a fat malabsorptive disorder.

Carotenoids are synthesized by a wide variety of plants (generally yellow, orange and red fruits and veggies).

116
Q

Astaxanthin

A

Carotenoid pigment in salmon

117
Q

Digestion, absorption, transport and metabolism of Vitamin A

A

Retinyl esters and carotenes complexed with protein. Carotenes released by heat in food but still requires peptic digestion in stomach. Ingestion of fat simultaneously improves absorption.

Vitamin A vitamers depend on retinoid binding proteins for transport from intestine to liver and peripheral tissues. Retinoic acid can be transported to liver via portal vein bound to albumin. Retinol travels in circulation complexed with RBP and transthyretin (TTR).

Carotenoids don’t bind specific proteins BUT are incorporated into chylomicrons and lipoproteins (VLDL and LDL).

Retinol and retinoic acid can be glucuronidated in liver and excreted in bile and urine. Oxidation at 4 position followed by glucuronidation also possible.

118
Q

Function of Vitamin A in vision

A

In epithelium, all-trans retinol converted to 11-cis-retinal, complexed with RBP and transported to photoreceptor cell. Aldehyde of retinal forms Schiff base with lysine of opsin, forming rhodopsin.

Irradiation causes electron of cis-double bond to become single temporarily, yielding a trans bond when the electron returns to pi orbital, forming all-trans-retinal. Opsin is released in this process, starting cascade that degrades cGMP, blockade of sodium channels, hyperpolarization of receptor cells, inhibition of glutamate release, causing action potential signal to brain.

All-trans retinal must be converted back to 11-cis retinal, or night blindness occurs.

119
Q

Vitamin A and gene expression

A

Retinoic acids act as ligands for nuclear receptors RAR and RXR. All-trans RA is ligand for RAR, 9-cis RA for RXR.

RAR and RXR form homodimers or heterodimers. Dimer complexes bind to specific DNA nucleotide sequences, called retinoic acid response elements (RARE) in promoter regions.

120
Q

Growth, development and cell differentiation and role of Vitamin A

A

Impaired growth linked with vitamin A. Retinyl B-glucuronide actively supports growth.

Retinoic acid shown to increase synthesis of specific gap junctions. Also plays a role in glycoprotein synthesis for cell-cell recognition (retinyl phosphate accepts mannose from GDP-mannose and transfers to glycoprotein receptor, affecting differentiation)

121
Q

Vitamin A and bone metabolism

A

Affects osteoblast and osteoclast function. Deficiency = excessive deposition of bone and reduced degradation.

Excessive vitamin A stimulated bone resorption.

122
Q

Immune function and Vitamin A

A

Deficiency leads to impaired ability to resist and fight infections

123
Q

Carotenoids

A

Possess antioxidant functions (especially lycopene)

Can also stop radical propagation by quenching oxygen radicals (Tocopherols are superior to carotenoids)

Carotenoids also promote eye health and prevent age-related macular degeneration, prevent atherosclerosis and cancer. Little evidence for these claims.

Excessive consumption may increase risk of developing lung cancer in smokers. Supplements NOT advised for general public.

124
Q

Metabolism and excretion of Vitamin A

A

Retinol and retinoic acid oxidized at carbocycle. Retinol, retinoic acid, and their 4-oxo metabolites glucuronidated and excreted in urine and bile. Those excreted in bile undergo enterohepatic recirculation.

Carotenoids excreted in bile eliminated in feces.

125
Q

Vitamin A deficiency

A

Symptoms include xerophtalmia, changes in conjunctiva (Bilot’s spots), anorexia, retarded growth, increased susceptibility to infection and night blindness.

Those with malabsorptive disorders like steatorrhea need more Vitamin A.

Measles depresses vitamin A status.

Zinc required for RBP synthesis. Retinol dehydrogenase is zinc dependent.

126
Q

Vitamin A toxicity

A

Single high dose may result in hypervitaminosis A (nausea, vomiting, double vision, headache, dizziness and general skin desquamation)

CHronic oral intake can also cause hypervitaminosis (skin desquamation, hair loss, ataxia, bone and muscle pain)

Excess vitamin A is teratogenic (e.g. Acutaine, containing 13-cis retinoic acid)

Carotenoids appear to have few side affects. B-carotene generally safe and approved as food colorant. Hypercarotenosis may cause discoloration of skin (yellowing), especially in palms and soles of feet.

127
Q

Vitamin D

A

Fat soluble

D2 and D3 are main forms

128
Q

Why is vitamin D3 conditionally essential?

A

Sunlight, AKA UV radiation, can produced vitamin D from steroids in the body

129
Q

What needs to happen if Vitamin D is to play a key role in calcium homeostasis?

A

Hydroxylation at 1 and 25 positions

130
Q

Dietary vitamin D sources

A

Liver, beef, egg yolk, cheese, milk, butter, salt water

Many products in the US are fortified

131
Q

How is D2 produced?

A

By UV radiation of plant sterol ergosterol

132
Q

Describe D3 formation from cholesterol in the body

A

Cholesterol converted to 7-dehydrocholesterol in sebaceous glands, secreted on to skin surface and reabsorbed.

Exposure of 7-dehydrocholesterol to sunlight causes B-ring to open, forming vitamin D3 (AKA cholecalciferol).

133
Q

Cholecalciferol

A

Only product that enters the blood (does so by binding to blood-born a-2 globulin, also called vitamin D-binding protein OR transcalciferin) which is synthesized in the liver.

Other products remain in skin and are eventually lost.

134
Q

What is the active form of Vitamin D made from cholesterol?

A

1,25-(OH)2 cholecalciferol

135
Q

Absorption, transport and storage of Vitamin D

A

D3 absorbed in the small intestines with fat, phospholipids and bile salts. Incorporated into chylomicrons in intestinal cells, followed by delivery to liver or extrahepatic tissue.

In liver, cholecalciferol converted to 25-hydroxycholecalciferol (25-OH D3) by 25-hydroxylase. Bound to DBP, this enters general circulation to be taken up by kidney, hydroxylated at 1 position to form calcitriol. 1,25 OH D2 is also produced in this manner.

1,25-OH2 D3 circulates in systemic blood bound to DBP and is taken up bound to vitamin D receptor by various tissues. Peripheral tissues are capable of hydroxylating the 1 position.

136
Q

Describe 1-hydroxylase activity

A

Stimulated by parathyroid hormone and by low calcium and phosphorus in body.

Activity inhibited by high 1,25-OH2 D3 levels.

137
Q

What happens if 1,25-OH2 D3 is overproduced?

A

Inactivation by 24-hydroxylation of 1,25-OH2-D3 OR 25-OH2-D3 (substrate removal)

138
Q

Nongenomic effects of Vitamin D

A

In intestine, bone, parathyroid, liver and pancreatic B-cells, binding triggers increased calcium absorption

139
Q

Genomic effects of Vitamin D

A

In cytosol of target cells, vtamin D complex transported to nucleus to form heterodimer with RXR (RXR-VDR) which has high affinity for VDRE.

Genes usually code for calcium homeostasis, 24-hydroxylase and certain calcium channel proteins.

140
Q

Calcium homeostasis and Vitamin D

A

Primarily increases absorption in intestines (same with phosphorus) by promoting calbindin D9k synthesis (binds Ca at brush border) as well as Transient Receptor Potential subfamily V member 6 (TRPV6) calcium channel at brush border.

Also increases alkaline phosphatase activity at brush border, leading to enhanced phosphate uptake.

In kidney, causes increase calcium reabsorption at distal renal tubule by promoting calbindin D28k.

141
Q

Bone and Vitamin D

A

PTH with 1,25-OH2-D regulates blood calcium and phosphorus by stimulating bone resporption in osteoclasts by releasing HCl, alkaline phosphatase and collagenase.

If calcium levels get too high, bone mineralization promoted by release of calcitonin from thyroid.

142
Q

Other functions of Vitamin D

A

Stimulates stem cell monocytes to become osteoclasts. Stimulates skin epidermal differentiation and prevents cell proliferation (psoriasis treatment).

Potential use in bone diseases, skin cancer and hyperthyroidism.

May prevent autoimmune disorders by down-regulating inflammatory mediators and increasing insulin sensitivity.

143
Q

Metabolism and excretion of Vitamin D

A

1,25-OH2 D converted to 1,24,25… and then oxidized to 24-oxo-metabolite (or side-chain cleavage) to then be glucuronidated and excreted primarily in bile.

144
Q

Vitamin D deficiency in adults and children

A

Rickets in infants and children: growth retardation, impaired bone mineralization, seizures (breast fed children may be at risk) –> leg bones may ‘bow’

Osteomalacia in adults: less calcium absorption, declining serum calcium, triggering PTH secretion (promoting bone resporption) –> indicated by presence of hydroyproline in urine, bone pain and weak bones

145
Q

Vitamin D deficiency in elderly

A

Elderly at high risk since they spend less time outdoors, reducing 7-dehydrognase activity in skin as well as 1-hydroxylase activity in kidney (in response to PTH)

146
Q

Renal disease and Vitamin D

A

Calderol, a supplement containing 25-OH D3 often given since those with renal disease can’t synthesize 1,25-OH2 D as well.

147
Q

Ergocalciferol

A

Treatment for vitamin D deficiency and insufficiency for up to 6 years.

Currently the only Vitamin D pharmaceutical available in the US.

50,000 IU given once a week for up to 8 weeks. Given every other week for recurrent deficiency

148
Q

Vitamin D toxicity

A

25-hydroxylase is not well regulated and can be produced in excess with over-supplementation.

Hypercalcemia may result from consumption of over 10,000 IU/day for a few months, causing calcinosis of soft tissues. Calcinosis of kidney may lead to renal dysfunction, causing polyuria, polydipsia, high nitrogen in the blood, kidney stones, or renal failure in severe cases.

149
Q

Calcitonin

A

After a thyroidectomy, calcitonin levels will drop at first but secondary organs (intestines, lungs) will kick in.

Used to treat Paget’s disease of bone in conjunction with pain relievers and bisphosphonates.

Salmon calcitonin available as nasal spray for post-menopausal osteoporosis.

Antibodies may develop after long term therapy.

Pharmacy School 2015-16 (34 decks)

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