Date post: | 02-Jan-2016 |
Category: |
Documents |
Upload: | lucinda-barber |
View: | 213 times |
Download: | 0 times |
Phar 722Pharmacy Practice III
Vitamins-
Riboflavin (B2)
Spring 2006
Riboflavin (B2) Study Guide
• The applicable study guide items in the Vitamin Introduction
• History
• Structure including commercial forms of the vitamin
• Conversion to cofactor forms
• Function of the cofactor including the specific types of reactions
• Deficiency condition
History• Shortly after the discovery of thiamine
from yeast concentrates, the presence of a second nutritional factor in such materials was suggested.
• This second factor also was reported to have a pellagra-preventative activity since it alleviated a deficiency-induced dermatitis in rats.
• It was called Vitamin B2 in England and Vitamin G in the United States.
Chemistry• Riboflavin has a characteristic flavin
ring system which gives it a unique spectroscopic and instability properties.
• Two commercial forms.– Riboflavin, itself, is poorly water soluble (1
gm/10,000 ml).– Riboflavin phosphate’s solubility is
0.1 gm/ml
N
N
NH
NH3C
H3C
O
O
CH2 CH
OH
CH
OH
CH
OH
CH2 OH
Riboflavin (Vitamin B2)
N
N
NH
NH3C
H3C
O
O
CH2 CH
OH
CH
OH
CH
OH
CH2 O P
O
O-
O-
Riboflavin PhosphateFlavin Mononucleotide (FMN)
Solubility: 1 gm/10,000 ml;A commercial form
Solubility: 0.1 gm/ml;A commercial form
Riboflavin Uptake and Metabolism• Because of its poor water soluble, uptake of riboflavin is slow since
the vitamin should be in solution in order to enter the intestinal mucosa cell. Therefore, it is recommended that supplemental administration of riboflavin be done with food in order to delay intestinal emptying.
• In the mucosa cell, a flavokinase phosphorylates the terminal alcohol with a phosphate from an ATP forming riboflavin phosphate.
– The latter, as the sodium salt, also is the water soluble (0.1 gm/1 ml) commercial form of the vitamin.
• The conversion of riboflavin phosphate (FMN) to the more common cofactor, flavin adenine dinucleotide (FAD) requires the conversion of ATP to AMP and the formation of an anhydride linkage.
– The pyrophosphate will be cleaved providing enough energy for this synthesis to go to completion. While it is not clear, this step probably occurs in the tissues requiring FAD.
• While flavin chemistry has been studied extensively, there has been little research of riboflavin biochemistry.
N
N
NH
NH3C
H3C
O
O
CH2 CH
OH
CH
OH
CH
OH
CH2 O P
O
O-
O P
O
O-
O CH2
N
NN
N
NH2
O
OHOH
HH
HH
N
N
NH
NH3C
H3C
O
O
CH2 CH
OH
CH
OH
CH
OH
CH2 O P
O
O-
O-
ATP
ADP
PPi
ATPN
N
NH
NH3C
H3C
O
O
CH2 CH
OH
CH
OH
CH
OH
CH2 OH
Riboflavin (Vitamin B2) Riboflavin PhosphateFlavin Mononucleotide (FMN)
Riboflavin Adenine Dinucleotide (FAD)
Flavokinase
FADpyrophosphorylase
Intestinal mucosa
Tissues whereFAD is required
Biochemical Functions-1• Riboflavin, as FMN/FMNH2 or
FAD/FADH2, is the coenzyme/cofactor of flavin enzymes. – It is required for many oxidation-reduction
reactions generally (but not always) of carbon-carbon bonds.
– Even though there is no defined deficiency syndrome, this vitamin is required for several life-supporting oxidation-reduction biochemical reactions.
• Some examples are on the next slides.
N
N
NH
NH3C
H3C
O
O
R
FAD or FMN (oxidized)
e- + H+
N
N
NH
NH3C
H3C
O-
O
R
FADH. or FMNH.
(semiquinone)
H
e- + H+
N
N
NH
NH3C
H3C
O
O
R
FADH2 or FMNH2 (reduced)
H
H
Biochemical Functions-2
• Oxidation-reduction of carbon-carbon bonds.
C C
H
R3H
R1
R2 R4 C C
R4
R3R2
R1FADH2
FADH2
FAD
FAD
Biochemical Functions-3
HN
NNH
N
O
Hypoxanthine
HN
NH
NH
N
O
Xanthine
HN
NH
NH
HN
O
Uric AcidO
O
OO2 H2O2
Xanthine Oxidase
O2 H2O2
Xanthine Oxidase
GuanineAdenine
Severalsteps
Xanthine Oxidase
Biochemical Functions-4
FMN FMNH2
H
H
FADH2FAD
H+
+
+
H+
H+
H+
H
H+
+
Electron (respiratory) transport chain
Biochemical Functions-5
• Oxidation-Reduction of Thiol-Disulfide Systems • Examples: glutathione reductases and lipoic acid in oxidative
decarboxylations of α- ketoacids (pyruvate, α-
ketoglutarate)
FADH2
FADH2
FAD
FAD
R SH R SH+ R S S R
ThiolDisulfide
Biochemical Functions-6
• Monoamine oxidase (MAO)• Examples: Metabolism of dopamine, norepinephrine, epinephrine
and serotonin
CH2 NH2R R C H
OO2 + H2O H2O2 + NH4+
MonoamineOxidase
Biochemical Functions-7• Biochemical Transformations of Other
Vitamins– Folic Acid– Pyridoxine
• NOTE: This illustrates how one vitamin is dependent on there being an adequate concentration of another vitamin. A deficiency of one vitamin may induce a deficiency of another vitamin.
Riboflavin Deficiency• Ariboflavinosis
– Clinical riboflavin deficiency.– There is no deficiency syndrome in humans associated with
this vitamin.– Usually associated with deficiencies of other “B vitamins”.
• Symptoms– Sore throat– Redness and swelling of the lining of the mouth and throat– Cracks or sores on the outside of the lips (cheliosis) and at
the corners of the mouth (angular stomatitis)– Moist, scaly skin inflammation (seborrheic dermatitis)– Vascularization of the cornea
• There is no good assay that correlates a riboflavin deficiency with specific biochemical function.
• It appears that humans do store appreciable amounts (possibly over six months) of the vitamin.
Hypervitaminosis Riboflavin
• Because of its poor solubility, it probably would be difficult to obtain a toxic dose of this vitamin. – Water soluble riboflavin phosphate may be
another matter. Nevertheless, no significant toxicities have been reported.
• Estimated toxic dose: 1,000 mg (1 gm)– There is no UL.
Dosage Forms• Most of the commercial forms of the vitamin are synthetic.
• Stability– Riboflavin is one of the most unstable of the vitamins,
particularly in light. Solutions of the vitamin must be protected from light.
• Riboflavin– This is a neutral molecule. Salt formation is not possible. – Because of its poor water solubility, it is used in dry dosage
forms.
• Riboflavin Phosphate– The sodium salt is very soluble (0.1 gm/1 ml). – It is used in liquid dosage forms.
DRIs-1• AI
– Infants 0.3 - 0.4 mg/day
• EAR– Children (1 - 13 years) 0.4 - 0.8 mg/day– Males (14 - 19 years) 1.1 mg/day– Females (14 - 19 years) 0.9 mg/day– Men (19 - 70+ years) 1.1 mg/day– Women (19 - 70+ years) 0.9 mg/day– Pregnancy 1.2 mg/day– Lactation 1.3 mg/day
DRIs-2
• RDA– Children (1 - 13 years) 0.5 - 0.9 mg/day– Males (14 - 19 years) 1.3 mg/day– Females (14 - 19 years) 1.0 mg/day– Men (19 - 70+ years) 1.3 mg/day– Women (19 - 70+ years) 1.1 mg/day– Pregnancy 1.4 mg/day– Lactation 1.6 mg/day
• UL– None reported
Food Sources• Liver
• Kidney
• Milk
• Yeast
• Plant
• Animal tissue
• Animals have to obtain riboflavin from plants or other animals.