Download Lead (Pb) - American Nutrition Association

Week 13 & 14 Notes
Heavy Metals
Exposure
Review
Absorption,
Distribution, &
Excretion
Lead (Pb)
Lead paint
 Drinking water
Paint banned containing
>0.06% Lead
-NORMAL urinary conc of lead
is < 80ug/L
-Patients with Lead poisoning
have urine levels from 150300 ug/L.
Major routes of absorption are
GI and respiratory tracts.
Adults absorb = 10%
Kids absorb = 40%.
Pb excreted in sweat, urine,
milk, & deposited in hair and
nails.
Pb can cross placenta.
-Fe deficiency ↑ Pb absorption.
-Ca has reciprocal relationship
w/ Pb
-90% inhaled Pb is absorbed.
-99% of absorbed Pb binds to
RBCs.
-Pb goes to tissues but
eventually 95% is found in
bone.
-Pb in bone resembles Ca
AND doesn’t contribute to
toxicity.
-Pb interferes w/ Vitamin D
metabolism.
-Decreased sperm count in Pb
exposed males.
-Lead Lines, diagnostic,
traverse lines in the diaphyses
on X-Ray
-Half-life of Pb is 1-2 months
(achieved in 6 months).
Half-life in bone is 20-30
years.
-Average daily intake of Pb is
0.2mg & positive Pb balance
starts at 0.6mg.
Mercury (Hg)
Arsenic (As)
Industrial uses:

Thermometers

Bleach

Paint

Dental amalgams

Fungicides
CHEMICAL FORMS OF Hg:

Methyl Vapor (elemental
mercury)

Salts of mercury
(Inorganic)

Methylmercury (organic
mercurials)
Elemental mercury as
amalgams is the major source
of mercury exposure to the
general public.
Arsenicals are important in
treatment of tropical diseases
(African trypanosomiasis).

-used as a
chemotherapy

-exposure is usually
environmental and
industrial.

In the soil and by
product of coal
combustion and
mining

Major source is
herbicides and
pesticides.
Daily intake of Arsenic is
300ug through food and water.
Mercury
forms
covalent
bonds with sulfur. Divalent
mercury replaces the hydrogen
atoms to form mercaptides. At
low conc., mercurials can
inactivate sulfhydryl enzymes
and interfere with cellular
metabolism and function.
Chemical Forms of As:
-oxidation states are trivalent
and pentavalent.
Mercury combines with thiols,
phosphor, carboxyl, amide and
amine groups.
Elemental Mercury:
-low absorption from GI  non
toxic.
-Inhaled mercury is completely
absorbed by lung & oxidized to
divalent mercuric cation by
catalase in RBCs.
-Significant amount of vapor
mercury enters brain before it
is oxidized CNS toxicity.
Inorganic Salts of Mercury:
-Soluble mercuric salts (Hg2+)
-Two oxidation states (mono
and divalent)
-Mercurous chloride, calomel
-10% is absorbed in GI when
taken orally and may remain in
alimentary
mucosa
or
intestine.
-Non-uniform distribution after
absorption; calomel makes in
more soluble.
-Highest
conc
found
in
KIDNEYS and retained longer
than in other tissues.
-does not readily cross BBB.
-Half-life is 60 days excreted
in urine.
Organic Mercurials:
-more completely absorbed
from GI tract b/c they are lipid
soluble and less corrosive to
intestinal mucosa.
->90% methylmercury
(alkylmercury salt) is absorbed
in GI tract
-Able to cross BBB and
placenta
and
produce
Organic Arsenics
-arsenic linked covalently to
carbon atom

Trivalent

Pentavalent
-they are excreted more
rapidly than inorganic arsenic.
Pentavalent Arsenicals
-Arsenate
-low affinity for thiol groups
and are much less toxic.
-well-known uncoupler of
mitochondrial oxidative
phosphorylation. Process
called arsenolysis.
Trivalent Arsenicals:
- inorganic arsenite
-primarily sulfhydryl reagents
-inhibit many enzymes by
reacting with biological ligands
containing –SH groups.
-the Pyruvate Dehydrogenase
system is sensitive to trivalent
arsenicals b/c of their
interaction w/ 2 sulfhydryl
groups of lipoic acid to form a
stable 6-membered ring.
ABSORPTION
-high degree of absorption in
GI of both tri and pentavalent
Arsenic.
-Arsenic trioxide, poorly watersoluble.
-coarsely powdered material is
less toxic b/c it is eliminated in
the feces.
DISTRIBUTION
-dependant upon duration of
administration and arsenic
involved.
-Stored in:

Liver

Kidney

Heart
Cadmium (Cd)
-ranks close to lead and
mercury and is associated in
nature with zinc and lead.
-high resistance to corrosion
used in:

Paint pigments

Batteries

Plastics

Electroplating

Galvanizing

Most population gets
cadmium in food
contamination
Average daily intake is 50ug.
Drinking water doesn’t
contribute significantly BUT
smoking does.
One cigarette contains 1-2ug
cadmiuim
Cadmium occurs in only ONE
valency state, Cd2+.
-Does not form stable alkyl
compounds or other
organometallic compounds
ABSORPTION
-Cd is absorbed poorly in GI
tract, about 5%.
-Respiratory absorption is
more complete.
-smokers may absorb 10-40%
of inhaled cadmium.
DISTRIBUTION
-transported in blood, bound to
blood cells and albumin.
-FIRST distributed to Liver
-then redistributed to kidney as
cadmium-metallothionein.
- 50% of total body burden is
found in liver and kidney
METALLOTHIONEIN-Protein with high affinity for
metals like zinc and copper.
-1/3 of its AA residues are
cysteine
-elevated levels of
metallothionein may be
protective and function to
prevent the interaction of
cadmium with other functional
macromolecules.
EXCRETION-With continuous
environmental exposure,
concentrations of the metal in
tissues increases throughout
life.
-The body burden in a 50year
old is about 30mg.
-Half-life of cadmium the
body is 10 to 30 years.
--the long half-life renders
cadmium an environmental
poison very prone to
accumulation.
-FECAL elimination is more
important over urinary
excretion.
-Urinary is only significant after
1
Week 13 & 14 Notes
Acute
Poisoning
-Occurs from acid-soluble lead
compounds or inhaled vapors.
-Metal taste, nausea, and
vomiting,
abdominal
pain.
Milky vomit from PbCl2.
-Black stools from lead sulfide.
-Shock Syndrome- mass GI
fluid loss.
-Acute CNS symptoms are
pain, muscle weakness and
paresthesias.
-Hemolytic
anemia
&
hemoglobinuria.
-Damaged kidneys
DEATH 1-2 days
neurological and teratogenic
effects over inorganic mercury.
-methylmercury combines with
CYSTEINE to form a structure
like methionine and the
structure is accepted by
capillary endothelial cells.
-More uniformly distributed
after absorption. The burden
is in the rbcs with a ratio of
20:1
-Concentrates in hair b/c of its
high Sulfhydryl content.
-Excretion of methylmercury is
in the FECES in a conjugate
form with glutathione.
-<10% appears in urine.
-Half-life of methylmercury is
40-105 days.
-Minamata disease is due to
methylmercury
poisoning.
Microorganisms can convert
inorganic
mercury
to
methylmercury.



Elemental Mercury:
Short term exposure: within
several hours

Weakness

Chills

Metallic taste

Nausea

Vomiting

Diarrhea

Dyspnea

Cough

Tightness in chest
Pulmonary toxicity: could
progress to an interstitial
pneumonitis with a
compromise of respiratory
function.
Chronic Exposure: insidious
form that is dominated by
neurological effects.
-referred to as ASTHENIC
VEGETATIVE SYNDROME
and consists of neurasthenic
symptoms plus 3 of the
following:

Goiter

↑ uptake of
radioiodine by
-The TOXICITY is related to its
clearance rate from the body
and degree of accumulation.
Lung
Muscle (small amounts)
Neural tissue (small
amounts)

Hair & Nails (b/c of high
conc of sulfhydryl content
of keratin)

Found in the teeth and
bone (b/c chemically
similar to phosphorus)
-Evident in hair 2 weeks after
exposure and lasts for years.
-Crosses the BBB
substantial renal toxicity.
EXCRETION
-Pentavalent (arsenate) is
coupled to the oxidation of
glutathione (GSH) to form
GSSG to form the trivalent
(arsenite), which is methylated
to form methyl and
dimethylarsenite which is
readily eliminated in the body.
Eliminated by many routes:

Feces

Sweat

Urine (MOST)

Milk

Hair

Skin

Lungs
-Half-life for urinary
excretion of arsenic is 3-5
days.
Symptoms:

GI discomfort w/in 1hour
to 12 hours after oral
ingestion

Burning lips

Constriction of the throat,
difficulty swallowing are
first symptoms.

Severe gastric pain

Projectile vomiting

Severe diarrhea

Oliguria, proteinuria,
hematuria eventually
anuria

Marked skeletal cramps

Severe thirst

Loss of fluid proceeds,
SHOCK appears.

Hypoxic convulsions

Coma and death
In severe arsenic poisoning:
DEATH CAN OCCUR WITHIN
ONE HOUR, but usually 24
hrs.
Results from inhalation of
cadmium dusts and fumes and
from the ingestion of cadmium
salts.
Toxic Effects: Oral intake

Nausea

Vomiting (bloody)

Salivation

Diarrhea (bloody)

Abdominal cramps
CADMIUM is more toxic when
inhaled.
Short-Term: after a few hours

Irritation of respiratory
tract

Severe early pneumonitis

Chest pains

Nausea

Dizziness

Diarrhea

MAY PROGRESS TO
FATAL PULMONARY
EDEMA

Or residual emphysema
2
Week 13 & 14 Notes
Chronic
Poisoning
Neuromuscular Effects
GI Effects
-PLUMBISM
-CNS syndrome more common
in kids
-GI more common in adults.
-Affects smooth muscle of gut
intestinal symptoms are
EARLY sign of exposure.
-Anorexia, muscle discomfort,
malaise, & headache.
Constipation over diarrhea
usually.
-METALLIC taste.
-Intestinal spasm  severe ab
pain  LEAD COLIC (most
distressing feature)
-Calcium
gluconate,
administered via IV, relieves
pain better than morphine.
-LEAD PALSY- manifestation
of advanced subacute
poisoning.
-Muscle weakness, fatigue,
later paralysis
-Muscle groups involved:
Forearm, wrist, fingers,
extraocular.
-Wrist-drop or Foot-drop are
pathognomonic for Pb
poisoning.
-NO sensory involvement
thyroid.

Tachycardia

Labile pulse

Gingivitis

Dermographia

↑ Mercury in urine
as mercury exposure
continues:

tremor

depression

irritability

excessive shyness

insomnia

reduced selfconfidence

emotional stability

forgetfulness

confusion

impatience

vasomotor
disturbances
(perspiration and
blushing or erethism)
-Renal dysfunction reported
-TRIAD OF SYMPTOMS:
1. ↑ EXCITABILITY
2. TREMORS
3. GINGIVITIS
Major manifestations.
Inorganic Salts of Mercury:
-inorganic mercury can
produce severe toxicity.
-ashen gray appearance of
the mucosa of mouth, pharynx,
intestine and causes intense
pain  Vomiting.
-vomiting removes unabsorbed
mercury from the stomach
protective.
-Corrosive effect on mucosa of
GI results in HEMATOCHEZIA,
with mucosal sloughing in
feces.
-Hypovolemic shock and death
may occur.
-Systemic toxicity may begin
w/in a few hours and last a few
days.
-Strong METALLIC taste
followed by stomatitis, gingival
irritation, foul breath, &
loosening of teeth.
-RENAL TOXICITY is the most
serious effect of inorganic
mercury leading to oliguria and
anuria.
--with long term exposure the
glomerular injury predominates
with direct effects on basement
membrane and mediated by
immune complexes.
-Acrodynia (pink disease)- is
an erythema of the extremities,
chest, and face WITH

photophobia,

diaphoresis,

anorexia

tachycardia
Symptoms of chronic arsenic
poisoning: (most common)

Muscle weakness and
aching

Skin pigmentation
(nipples, eyelids, axilla,
neck)

Hyperkeratosis

Edema
Other signs:

Garlic odor of breath

Excessive salivation and
sweating

Stomatitis (inflammatory
disease of the mouth),
generalized itching

Sore throat

Coryza (upper respiratory
disease, inflammation,
common cold)

Lacrimation

Numbness

Burning or tingling of the
extremities

Dermatitis

Vitiligo (skin disorder with
smooth white spots)

Alopecia
Dermatitis and keratosis of the
palm’s and soles are common
features.
-Mee’s Lines found on
fingernails (white transverse
lines of deposited arsenic that
usually appear 6 weeks after
exposure)
-small doses of trivalent
arsenic cause splanchnic
hyperemia.
-larger doses cause capillary
transudation
Tissue damage and bulk
cathartic action of the
increased fluid in the lumen
lead to increased peristalsis
and CHARACTERISTIC
WATERY DIARRHEA (ricewater stools)
-normal proliferation of
epithelium is suppressed
damaged is accentuated.
-feces become bloody
-upper GI tract damage leads
to hematemesis.
CARDIOVASCULAR
EFFECTS:
-Small doses induce mild
vasodilation leading to facial
edema.
-larger doses evoke capillary
dilation, increased capillary
permeability mostly in
splanchnic area.
-gangrene results in
extremities, especially the feet,
aka Blackfoot disease.
-Myocardial damage and
hypotension.
-ECG abnormalities (prolonged
Q T interval and abnormal T
waves)
Long- Term exposure:
Depends on routes of
exposure.
The KIDNEY is affected
following either PULMONARY
or GI exposure.
-lung affects are observed
after inhalation.
N/A
CARDIOVASCULAR
EFFECTS:
-cadmium may play a role in
hypertension.
-
3
Week 13 & 14 Notes
CNS Effects
Hematologic
Effects
Renal Effects
-LEAD ENCEPHALOPHATHY
-most serious and more
common in kids than adults.
-Early symptoms:

Clumsiness

Vertigo

Ataxia

Falling

Headache

Insomnia

Restlessness

Irritability
Then as it develops, they
become confused or excited.
-Projectile vomiting is common.
-HYPOCHROMIC,
MICROCYTIC ANEMIA
-resulting from ↓ lifespan of
RBCs & inhibition of Heme
synthesis.
-Very low conc of Pb interfere
with Heme synthesis at:

α- aminolevulinate
(alpha-ALA)
dehydratase

ferrochelatase
both are sulfhydryl-dependant
enzymes.
-Accumulation of:
protoporphyrin IX
nonheme iron
in RBCs by accumulation of
alpha-ALA in plasma and ↑
urinary excretion of alpha-ALA.
-Also urinary excretion of
coproporphyrin III.
-THE ↑ IN ALPHA-ALA
SYNTHASE ACTIVITY IS DUE
TO THE REDUCTION OF
CELLULAR CONC. OF HEME,
WHICH REGULATES THE
SYNTHESIS OF ALPHA-ALA
SYNTHASE BY FEEDBACK
INHIBITION.
-Renal Toxicity occurs in 2
forms:
1. a reversible renal
tubular disorder
2. an irreversible
interstitial
nephropathy
-Fanconi-like syndrome with:

proteinuria

hematuria

casts in urine
-Hyperuricemia w/ Gout
-Histologically revealed by
nuclear inclusion body, leadprotein complex.

diarrhea or
constipation
This is after ingestion and is
cause by hypersensitivity to
mercury.
Organic Mercurials:
-information on methylmercury
is because of large-scale
accidents
-Symptoms of Methylmercury
exposure are mainly
NEUROLOGICAL:

visual disturbance

ataxia

paresthesias

neurasthenia

hearing loss

dysarthria (difficulty
in articulating words)

mental deterioration

muscle tremor

movement disorders

PARALYSIS &
DEATH on severe
exposure.
Cerebral cortex (visual cortex)
is sensitive to the toxic effects
of methylmercury.
-Fetus can have mental
retardation and neuromuscular
deficits even if mother is
asymptomatic.
DIAGNOSIS:
-history of exposure
-laboratory analysis
-UL of non-toxic mercury is 34ug/dl.
-blood level of >4ug/dl is
abnormal
-methylmercury is
concentrated in RBCs and
inorganic mercury is NOT.
The distribution of total
mercury between rbcs and
plasma can indicate what type
of mercury poisoning it is.
-METHYLMERCURY in RBCs
gives total body burden of
organic mercury.
-Mercury in PLASMA gives
total body burden of Inorganic
mercury levels.
-UL of urinary mercury is
5ug/dl in normal adults
-Hair is rich in sulfhydryl
groups and is 300 times that in
blood. Hair gives a good
history of mercury exposure.
Short & Long term exposure
can cause
ENCEPHALOPATHY.
-most common is peripheral
neuropathy with a “stocking
glove” distribution of
dysesthesia. (Similar to
Guillain-Barre syndrome)
-Followed by muscular
weakness in the extremities.
-cerebral lesions occur in both
gray and white matter
-characteristic multiple,
symmetrical foci of
hemorrhagic necrosis occurs.
N/A
Symptoms:

Anemia

Leukopenia (slight to
moderate)

Eosinophilia

Anisocytosis with
increased arsenic
exposure
N/A
Some of the chronic
hematologic effects may be a
result from impaired absorption
of folic acid.
Serious, irreversible blood and
bone marrow damage from
organic arsenic is rare.
The action of arsenic on the
renal capillaries, tubules, and
glomeruli may cause severe
renal damage.
-initially the glomeruli are
effected and Proteinuria
results.

Oliguria

Proteinuria

Hematuria

Casts
Cd is taken up by the liver and
can combine with glutathione
and be excreted in the bile.
-cadmium binds to
metallothionein and is stored.
-In the lysosomes of the
kidney, cadmium is released.
-a sufficient concentration
(200ug/g) damages the kidney
cell, resulting in:

Proximal tubular
injury

Proteinuria
Followed by:

Glomerular injury
occurs and filtration
decreases

Aminoaciduria

Glucosuria

Proteinuria
Beta-microglobulin is a
sensitive but not specific
marker of cadmium induced
nephrotoxicity.
-RETINOL BINDING
PROTEIN- is a better marker.
4
Week 13 & 14 Notes
Other Effects
Organic
-ashen color of face
-pallor of lips
-retinal stippling
-appearance of “premature”
aging.
-black/blue lead-line along the
gingival margin from
periodontal deposited lead
sulfide. Also seen in
MERCURY, BISMUTH,
SILVER, THALLIUM OR
IRON.
-children with Pb levels of >10
ug/dl are at risk for
developmental disabilities.
-adults with Pb levels <30 have
no symptoms BUT will have a
decrease alpha-ALA
dehydratase, in crease in
urinary ALA & ↑ in rbc
protoporphyrin.
-Levels of 30-75 ug/dl have
laboratory abnormalities and
mild symptoms.
-Levels above 100ug/dl, lead
encephalopathy is observed.
-Tetraethyllead &
tetramethyllead, lipid-soluble,
absorbed from skin, GI and
Lungs. Tetraethyllead
metabolically converts to triethyllead and inorganic lead
and becomes toxic.
-symptoms are common with
CNS
-anemia and basophilic
stippling are Uncommon in
organic lead poisoning. If
patient survives, recovery is
usually complete.
LIVER Effects
-inorganic arsenicals are very
toxic to the liver and produce
fatty infiltration, central
necrosis, and cirrhosis.
-severe damage results in
DEATH
-injury is usually to hepatic
parenchyma BUT some
appear to resemble occlusion
of the bile duct
SKIN effects
Short term:
Vesicant effect on skin that
results in necrosis and
sloughing.
Long term:
Low dose ingestion causes
cutaneous vasodilation and a
“milk and roses” complexion.
-also prolonged use causes
hyperkeratosis of the palms
and soles and
hyperpigmentation on the trunk
and extremities  possibly
leading to cancer.
Carcinogenesis &
Teratogenesis effects
Long term exposure to
inorganic arsenicals
predisposes one to intraepidermal squamous-cell and
superficial basal cell CA. Also
suspected to cause lung and
liver cancer
PULMONARY EFFECTSLoss of ventilatory capacity
and corresponding increase in
residual lung volume occurs
with excessive and continual
inhalation of cadmium dusts
and fumes.
-Symptoms

Dyspnea

Emphysema
Cadmium specifically inhibits
the synthesis of plasma alphaantitrypsin and there is an
association between severe
anti-trypsin deficiency of
genetic origin and emphysema
in human beings
BONE EFFECTSHallmarks of itai-itai (ouchouch) is osteomalacia.
-inverse relationship with
cadmium exposure and
calcium body stores.
CANCER
-produces tumors when
administered to animals
-lung and prostate tumors of
occupational exposure.
Measurement in BLOOD of
concentration of Mercury (or
any other metal) done first.
Treatment
-Pb concentrations determined
by blood and protoporphyrin in
RBCs.
-Since lead interferes with
heme synthesis then there is a
build-up of alpha-ALA &
coproporphyrin in Urine &
ZINC.
-Prevention of further exposure
-Seizures are treated with
diazepam
-Edema treated with mannitol
and dexamethasone.
Chelation
Indicated in symptomatic
patients w/ Pb levels of >50-60
ug/dl in blood.
Four chelators:
1. CaNa2EDTA (IM or IV)
2. Dimercaprol (IM)
3. D-penicillamine (oral)
4. Succimer (oral, first for
kids)
Dimercaprol and CaNa2DTA
combined are better than
singly.
Elemental Mercury (Vapor):
-terminate exposure
-monitor pulmonary status
-chelation therapy
Inorganic Mercury:
-attention to fluid/ electrolyte
balance and heme status in
oral exposure.
-Emesis (vomiting) can be
induced. Little effect after 3060 minutes of oral exposure.
-endoscopic evaluation
-coagulation parameters are
watched.
-Activated Charcoal may be
given.
The affinity of Mercury for
thiols provides the basis for
treatment of mercury poisoning
with Dimercaprol and
penicillamine.
-Chelation Therapy

Dimercaprol (high level
exposures or
symptomatic patients) By
IM, and the chelatormercury complex is
excreted in feces/urine.
TREATMENT
Short-term exposure to
arsenic:
-prevent further absorption
-watch intravascular volume,
since the effects on the GI can
result in fatal hypovolemic
shock.
-Hypotension requires fluid
replacement
Chelation Therapy
-begun with Dimercaprol until
abdominal symptoms subside
and charcoal is passed in
feces.
-oral treatment of penicillamine
may be used after dimercaprol.
-Succimer, derivative of
dimercaprol, is a promising
agent.
Long-Term Exposure:
-oral penicillamine alone is
Short –term exposure

Removed from the
source

Pulmonary
ventilation should be
monitored.

Medical respiratory
support and
steroidal therapy
may be necessary
NO PROVEN BENEFIT
-some doctors recommend
chelation with CaNa2EDTA.
-should be instituted as soon
as possible after exposure b/c
rapid decrease in chelation
therapy effectiveness parallels
the sites of distribution.
Chronic exposure:

Dimercaprol

Substituted
dithiocarbamates
Appear helpful.
5
Week 13 & 14 Notes

Penicillamine (low level
exposures or
asymptomatic patients).
The chelator-mercury
complex is excreted in the
urine only.

Succimer- oral chelator,
effective but not yet
approved by FDA.
Exposure to elemental or
inorganic poisonings.
okay but can be used with
dimercaprol.
-duration of therapy is
dependant upon clinical
condition and is aided by
urinary arsenic levels.
-hemodialysis may be required
when chelation therapy
becomes limited or there is
arsenic-induced nephropathy.
Organic Mercury
-reacts poorly with chelators
-dimercaprol is CONTRAindicated b/c it ↑ brain
concentrations of
methylmercury.
-Penicillamine works but it isn’t
very effective and the
concentration increases
before it decreases.
Caused by mobilization of
metal from tissues to
blood.
-conventional hemodialysis is
of little value b/c
methylmercury
accumulates in the RBCs
and little is in the plasma.
-HOWEVER, l-cysteine can be
infused during dialysis to turn
methylmercury into a diffusible
form.
6
Week 13 & 14 Notes
Water
Soluble
Vitamins
Chemistry
Physiological
Functions
TPP, active form of thiamin,
functions:
-Carbohydrate metabolism,
in DECARBOXYLATION of
alpha-Keto acids (pyruvate &
alpha-ketoglutarate)
-Utilization of Pentose in
Hexose monophosphate
shunt involving TPPdependant enzyme
transketolase.
THIAMIN Deficiency:
-oxidation of alpha-keto acids
is impaired
-increase in blood pyruvate
(DIAGNOSTIC)
Thiamin, B1
-Thiamin is a pyrimidine & a
thiazole nucleus linked by a
methylene bridge.
-Conversion of thiamin to its
coenzyme form, TPP
(thiamin pyrophosphate),
by thiamin
diphosphokinase.
-The enzyme is inhibited by
antimetabolites to thiamin,
like neopyrithiamine and
oxythiamine.
NUTRITURE Assessment
-measurement of
transketolase activity in
RBCs
CHRONIC ALCOHOLICSwith polyneuritis and motor
or sensory defects should
receive a minimum of 40mg,
oral thiamin daily.
-Wernicke-Korsakoff
SyndromeAcute emergency that should
be treated with 100mg daily
thiamin via IV.
PREGNANCY
-pregnancy increases the
thiamin requirement slightly
-neuritis is in the form of
peripheral nerve involvement
Riboflavin,
B2
Riboflavin carries out
functions in the body as
riboflavin phosphate aka
Flavin mononuculeotide
(FMN) and flavin adenine
dinucleotide (FAD).
Riboflavin is converted to
FMN and FAD by two
enzyme-catalyzed reactions:
1. Riboflavin + ATP 
FMN + ADP
2. FMN + ATP  FAD +
FMN and FAD, the
physiologically active
forms of riboflavin, serve a
vital role in metabolism as
coenzymes for respiratory
flavoproteins, some of which
contain metals (xanthine
oxidase which contains
molybdenum)
ANEMIA- that develops is
NORMOCYTIC,
Symptoms of
Deficiency
Thiamin Deficiency:
-Leads to condition known as
BERIBERI (Asia).
-In US, Alcoholism or alcoholic
neuritis is most common cause
of thiamin deficiency.
1. poor appetite
2. caloric intake is
mostly alcohol
Wernicke’s Syndrome(respond to vitamin B1 only)
ophthalmoplegia
nystagmus (rapid eyeball
movement, from dizziness)
ataxia
acute global confusional state
Patients w/ Wernicke’s
encephalopathy have an
abnormality in thiamin
dependant enzyme,
transketolase. Therefore
thiamin supplementation
may produce neurological
damage.
Untreated this encephalopathy
can lead to:
Korsakoff’s Psychosis

learning and memory
impairment

confabulation

less likely reversible.
Infantile BERIBERI
-Rare In modern societies
-Significant still in third world
countries.
-Related to LOW thiamin
content in breast milk of
thiamin-deficient mothers.
Symptoms:

loss of appetite

vomiting

greenish stools

paroxysmal attacks of
muscular activity

APHONIA, due to
loss of laryngeal
nerve function, is
DIAGNOSTIC

Infants respond to
10mg thiamin

IF acute collapse
occurs, doses of
25mg IV are given.
Riboflavin Deficiency:
Symptoms

Sore throat

Angular stomatitis

Glossitis

Cheilosis (red
denuded lips)

Seborrheic dermatitis
of face

Dermatitis of trunk
and extremities
Other
Subacute Necrotizing
Encephalomyelopathy:

Fatal inherited disease of
children

Neuropathological features
resemble WernickeKorsakoff syndrome

Clinical features include:

Difficulties feeding and
swallowing

Vomiting

Hypotonia

External ophthalmoplegia

Peripheral neuropathy

Seizures
Distribution of lesions and
elevated pyruvate and lactate
suggest a relationship to thiamin.
Some cases have a circulating
INHIBITOR of the enzyme that
synthesizes thiamin triphosphate
from TPP
Defects in pyruvate
dehydrogenase and cytochrome
c oxidase have been found in
tissue samples.
CARDIOVASCULAR Disorder
-CVD due to thiamin deficiency
responds markedly to
supplementation.
-cardiac output is reduced and
oxygen utilization returns to
normal.
-Edema responds to diuresis
Chronic deficiency:
-require protracted therapy
-usual dose is 10-30mg three
times daily, given parenterally.
-glucose admin may precipitate
heart failure in individuals with
marginal thiamin status.
GI Disorders
-thiamin has been used
uncritically for

Ulcerative colitis

GI Hypotonia

Chronic diarrhea
BUT it is not efficacious.
Nutriture Assessment:\


dietary history with clinical
and laboratory findings.
Evaluation of urinary
excretion (<50 ug of
riboflavin daily is
considered deficient)
Flavin evaluation in blood is not
of diagnostic value.
7
Week 13 & 14 Notes
PP
Riboflavin,
B2
NORMOCHROMIC and is
associated reticulocytopenia.
-leukocytes & platelets are
normal.
-riboflavin supplementation
causes reticulocytosis and
hemoglobin to return to
normal.
-Anemia, in riboflavin
deficiency can be related to
disturbances in folic acid
metabolism.
NAD and NADP are the
physiologically active forms
of Nicotinic acid. They serve
as coenzymes for metabolic
redox reactions, essentially
for tissue respiration.
The coenzymes, bound to
dehydrogenases, function as
OXIDANTS by accepting
electrons and hydrogen from
substrates and thus become
REDUCED. The reduced
pyridine nucleotides, in turn,
are reoxidized by
FLAVOPROTEINS. NAD
also participates as a
substrate in the transfer of
ADP-ribosyl moieties to
proteins.
Niacin, B3
Nicotinic acid functions in the
body after the conversion to
either nicotinamide adenine
dinucleotide (NAD) or
nicotinamide adenine
dinucleotide phosphate
(NADP).
Nicotinamide is the precursor
of NAD, which is in all
tissues.
The metabolic pathway of
NAD to tryptophan is
complicated. 60mg of
tryptophan generates 1mg
of niacin.
Oxidative Reactions in which
NAD is reduced to NADH

Glycolysis

Oxidative
decarboxylation of
pyruvate

Oxidation of Acetyl CoA
by Krebs cycle

Beta Oxidation of Fatty
acids

Oxidation of ethanol
NADPH generated from
NADP:
Part of Hexose
Monophosphate Shunt &
mitochondrial membrane
malate-pyruvate shuttle.

Fatty acid synthesis

Cholesterol and
hormone synthesis



Anemia
Neuropathy
Corneal
vscularization and
cataract formation (in
some)
The most sensitive method for
determining riboflavin nutriture is
the measurement of the activity
of erythrocyte glutathione
reductase, an enzyme requiring
FAD as a coenzyme.
Riboflavin deficiency rarely
occurs in isolation, and is
associated along with other
vitamins deficiencies.
Associated with:
1. alcoholics
2. low income status
3. hospitalized patients
4. children in urban area.
5. newborns treated with UV
light for hyperbilirubinemia.
6. breast fed infants b/c of
low riboflavin in milk
Niacin Deficiency
PELLAGRA- signs and
symptoms in the skin, GI, and
CNS.
Triad of Symptoms referred to
as the “three Ds”
1. Dermatitis
2. Diarrhea
3. Dementia
Pellagra occurs mostly with

Alcoholics

Protein calorie
malnutrition

Deficiencies of
multiple vitamins
First symptoms: Erythematous
eruption resembling sunburn
appears on back of hand.
-The lesions become
widespread, are symmetrical,
darken, desquamate and finally
scar the skin.
Chief symptoms:

Stomatitis

Enteritis

Diarrhea (watery/
maybe bloody)

Tongue- red/swollen

Excessive salivation

Nausea

Vomiting

STEATORRHEA
CNS Symptoms:

Headache

Dizziness

Insomnia

Depression

Memory impairment
Severe Cases:

Delusions

Hallucinations

Dementia

Motor & sensory
disturbances of
peripheral nerves
Nutriture Assessment
Biochemical assessment of
deficiency is attempted by the
measurement of urinary
excretion of methylated
metabolites of nicotinic acid
(eg N-methylnicotinamide)
-Does NOT provide unequivocal
evidence of deficiency.
NIACIN Status:
-measurement of nicotinamide in
blood & urine has NOT been
useful in determining niacin
status.
DIAGNOSIS:
Based on clinical findings with
response to nicotinamide
supplementation.
NICOTINIC ACID (2 to 6 g/day)
IS USED TO TREAT
HYPERLIPOPROTEINEMIA.
Toxicity of Nicotinic acid:

Flushing

Pruritus

GI distress

Hepatotoxicity

Activation of peptic
ulcer disease.
ANEMIA- that develops is
Macrocytic.
-Other lab findings:

Hypoalbuminemia

Hyperuricemia
8
Week 13 & 14 Notes



Niacin, B3

Oxidation of glutamate
Synthesis of DNA and
precursors
Regeneration of
glutathione, Vitamin C
and thioredoxin
Reactions in folate
metabolism
Nicotinic acid and
Nicotinamide are identical in
their functions as vitamins.
HOWEVER, they differ
markedly as pharm. agents.
NICOTINIC acid is NOT
DIRECTLY CONVERTED
TO NICOTINAMIDE, which
arises from metabolism of
NAD.
Coenzyme A serves as a
cofactor for enzymecatalyzed reactions involving
the transfer of acetyl (twocarbon) groups…bound to
the sulfhydryl group of
Coenzyme A.
Pantothenic
Acid, B5
Pantothenate consists of
PANTOIC acid complexed to
BETA-ALANINE. This is
transformed in the body to 4PHOSPHOPANTETHEINE
by phosphorylation and
linkage to cysteamine.
-Incorporated into the
functional forms of the vitamin
as:

Coenzyme A

Acyl Carrier Protein
Oxidative metabolic
reactions of Coenzyme A
include:

Carbohydrates (Krebs
cycle)

Gluconeogenesis

Degradation of Fatty
acids

Synthesis of cholesterol
(sterols), steroid
hormones, and
porphyrins, bile salts,
ketone bodies.

Heme synthesis (w/ AA
glycine)

Post-translation
modification of proteins,
including acetylation of
internal AA, fatty acid
acylation.
Component of Acyl Carrier
Protein:

Pantothenate
participates in fatty
acid synthesis
Three forms of Vitamin B6:
1. Pyridoxine (PN)
2. Pyridoxal (PL)
3. Pyridoxamine
(PM)
Pyridoxine,
B6
The compounds differ in the
nature of the substituent on
the carbon atom in position 4
of the pyridine nucleus: a
primary alcohol (pyridoxine),
the corresponding aldehyde
(pyridoxal) and an aminoethyl
group (pyridoxamine).
Mammals can utilize each of
the three forms after
PLP, as a coenzyme is
involved in metabolic
transformations of AA
including:

Decarboxylation
(formation of GABA
from glutamate,
serotonin from 5-HTP
(or tryptophan to 5hydroxytryptamine),
histamine synthesis,
dopamine synthesis
from tyrosine.)

Transamination (AST
and ALT PLP forms
schiff base)
Enzyme-bound
PLP
is
Pantothenic Acid Deficiency
Symptoms:

Neuromuscular
degeneration

Adrenocortical
insufficiency
Syndrome devoid of B5 is
characterized by:

Fatigue

Headache

Sleep disturbances

Nausea

Vomiting

Abdominal cramps

Flatulence

Paresthesias in
extremities

Muscle cramps

Impaired coordination
Nutriture Assessment
Plasma pantothenic acid
concentrations <100mg/dL are
thought to reflect low
pantothenate intakes.
HOWEVER, plasma levels are
not a good correlate.
Urinary pantothenate excretion is
considered to be a better
indicator of status, with excretion
of <1mg/day considered
indicative of poor status.
Not seen in humans consuming
a normal diet probably because
food sources are ubiquitous.
Pyridoxine Deficiency
SKIN:
Seborrhea like skin lesions
about the eyes, nose, & mouth
accompanied by glossitis and
stomatitis appear within a few
weeks of deficiency.
Nutriture Assessment
NERVOUS SYSTEM:
-Convulsion seizures occur and
can be prevented with the
vitamin.
-The cause of these seizures
could be the result of:

a lowered concentration of
gamma-aminobutyric acid
(GABA).
An abnormally high xanthurenic
acid excretion (>25mg in 6
hours) is found in B6 deficiency
b/c 3-hydroxykynurenine, an
intermediate in tryptophan
metabolism, cannot lose its
alanine moiety and be converted
to 3- hydroxyanthranilate, as
should occur in the Liver.
-The measurement of
Xanthurenic Acid excretion
following TRYTOPHAN
LOADING (2g or 100mg of
tryptophan/ kg body weight).
9
Week 13 & 14 Notes
conversion in the LIVER to
pyridoxal 5’-phosphate (PLP).
The reaction is catalyzed by
an FMN-dependent oxidase.
PLP is the active form of the
vitamin.
Pyridoxine,
B6
animated to PMP by the
donor acid, and the bound
PMP is then DEAMINATED
to PLP by the acceptor
alpha-keto acid.

Racemization (PLP
required by racemases
that catalyze the
interconversion of Dand L- amino acids.)

Transulfhydration &
Desulfhydration (where
PLP is required for
Transulfhydration
reactions in which
cysteine is synthesized
from methionine.)
Enzymatic steps in the
metabolism of sulfurcontaining and hydroxyamino acids.

Cleavage (requiring
PLP for the removal of
hydroxymethyl group
from serine and
transfers it to THF so
glycine is formed.



The enzyme, glutamate
decarboxylase requires
PLP, which synthesizes
this inhibitory CNS
neurotransmitter (GABA).
PLP deficiency leads to
decreased concentrations
of the neurotransmitters,
norepinephrine and 5hydroxytryptamine.
INSTEAD, 3-hydroxykynurenine
is converted to xanthurenic acid
 and excreted in urine.
CARPAL TUNNEL
SYNDROME:
-peripheral neuritis associated
with carpal synovial swelling
and tenderness has been
attributed to PLP deficiency.
If supplementation works
then there was probably a
vitamin deficiency.
Biotin Deficiency
The forms of biotin:

Free biotin

Biocytin

D & L sulfoxides of
biotin
Biotin, B7
Or
Vitamin H
Biocytin could represent a
degradation product of a
biotin-protein complex
because in its role as a
coenzyme, the vitamin is
covalently linked to an amino
group of a LYSINE residue of
the apoenzyme involved.
In human tissues biotin is a
cofactor for the enzymatic
carboxylation of four
substrates:
1. Pyruvate
Carboxylase
2. Acetyl CoA
Carboxylase
3. Propionyl CoA
Carboxylase
4. -Methylcrotonyl
CoA Carboxylase
Biotin also plays a role in
BOTH carbohydrate and fat
metabolism.
CO2 fixation occurs in a twostep reaction
1. Involving binding of
CO2 to the biotin moiety
of the holoenzyme.
2. Involving transfer of
biotin-bound CO2 to an
appropriate acceptor.
Choline is made in the body
from methylation of SERINE
using S-adenosyl methionine
(SAM).
Choline
Not a vitamin as defined
above.
Serine is its source of
Nitrogen.
In the body, Choline
functions as:

a methyl donor

neurotransmitter,
acetylcholine

Phospholipid,
phosphatidyl choline
(lecithin) &
sphingomyelin.

Effects the mobilization
The vitamin is SYNTHESIZED
by intestinal bacteria in
humans.
Therefore to obtain deficiency
one must:

Eliminate bacteria

Eat raw eggs (Avidin)

Administer antimetabolites of biotin to
produce deficiency.
Signs & Symptoms:

Dermatitis

Atrophic glossitis

Hyperesthesia

Muscle pain

Lassitude

Anorexia

Slight anemia

Changes in ECG.
Inborn errors of biotindependent enzymes are known
and respond to massive doses
of biotin.
Choline Deficiency
Choline deficient animals reflect
many defects including:

fat accumulation in
the liver

cirrhosis

increased incidence
of HEP CA

Hemorrhagic renal
lesions

Motor incoordination
NONE of these manifestations
have been identified in
HUMANS.
Acetylcholine Formation:
Nutriture Assessment
Assessment is either blood or
urine. Low plasma levels do not
reflect adequately biotin status.
Decreased urinary biotin
excretion coupled with increased
urinary excretion of 3-hydroxy
isovaleric acid generated from
altered metabolism of Bmethylcrotonyl CoA has been
shown to be a sensitive indicator
of biotin status.
Phospholipid constituent
Choline is a component of the
major phospholipid, LECITHIN
and also a constituent of
PLASMALOGENS, which are
abundant in mitochondria and
SPHINGOMYELIN, which is in
the brain. CHOLINE IS A
STRUCTURAL COMPONENT.
Lipotropic Action
Substances that stimulate the
removal of excess fat from the
liver are known as lipotropic
agents and include:

Choline

Inositol

Methionine
10
Week 13 & 14 Notes

of fat from the liver
(lipotropic action)
AUTACOID plateletactivating factor (PAF).

Methyl Donor
Choline can donate methyl
groups necessary for the
synthesis
of
other
compounds. The first step in
transfer is the formation of
BETAINE, which is the
immediate donor of the
methyl group. Thus choline
can transfer a methyl group
to HOMOCYSTEINE to form
METHIONINE.
Inositol
Inositol
(hexahydroxycyclohexane) is
an ISOMER of GLUCOSE.
There are SEVEN optically
inactive and ONE pair of
optically active stereoisomeric
forms of inositol possible.
The optically INactive,
MYOINOSITOL, is
nutritionally active.
Choline is transported b/n the
brain and the plasma by a bidirectional system localized in
the endothelium of brain
capillaries.


Vitamin B12
Folic Acid
Some of these components
provide methyl groups for the
synthesis of choline. Formation
of the lipid components of
plasma lipoproteins thus is
permitted and this facilitates
transport of fat from the liver.
The physiological role of inositol resembles that of choline in part.
Inositol is present in the form of PHOSPHATIDYLINOSITOL in the phospholipids of cell membranes
and plasma lipoproteins.
Phosphorylated derivatives of inositol are released from such phospholipids in membranes in
response to a variety of hormones, autacoids, and neurotransmitters.
Only L-Carnitine is synthesized in tissues. It possesses
biological activity.
Carnitine, another nitrogen-containing compound is MADE in
the liver (and kidney) from LYSINE (Gropper, 189) which has
bee methylated using methyl groups from SAM, made from
the amino acid, methionine.
Participate in synthesis of Carnitine:

Iron

Vitamin B6

Vitamin C

Niacin, B3
Muscle represents the primary carnitine pool, although no
carnitine is made there. Carnitine is found in most body
tissues and is needed for the transport of fatty acids,
especially long chain fatty acids across the inner mitochondrial
membrane for oxidation. The inner mitochondrial membrane
is impermeable to long chain (>10) fatty acyl CoAs.
Carnitine also forms acylcarnitines from short chain acyl
CoAs. These Acylcarnitines may serve to buffer the free
Coenzyme A pool.
Carnitine
Acetylcholine is synthesized
from choline and acetyl CoA by
CHOLINE
ACETYLTRANSFERASE and is
broken down by
ACETYLCHOLINESTERASE.
Carnitine:

Important for the oxidation of Fatty acids

Facilitates the metabolism of carbohydrates

Enhances the rate of oxidative phosphorylation

Promotes the excretion of certain organic acids.

These functions result from the following circumstances:
1. There exists a number of carnitine
acyltransferases that catalyze the interconversion
of fatty acid esters of coenzyme A (CoA) and
carnitine. These are strategically located in the
cytosol and the mitochondrial membranes.
2. The esters of CoA and carnitine are
thermodynamically equivalent, such that the net
formation of either depends solely on the relative
concentrations of reactants.
3. Specific translocases exist in the mitochondrial and
plasma membranes. Mitochondrial translocases
transports BOTH free carnitine and its esters in
either direction. The renal tubular cell (luminal
plasma membrane) transports ONLY free carnitine
from tubular urine. FREE CARNITINE IS
ACTIVELY TRANSPORTED INTO CELLS AND
Carnitine Deficiency
Primary carnitine deficiency- observed in a group of uncommon
inherited disorders. Lipid Metabolism is affected resulting in storage
of fat in muscle and functional abnormalities of cardiac and skeletal
muscle. They are either systemic or myopathic.
Systemic Disorders- low concentration of carnitine in plasma,
muscle and liver.
Symptoms include:

Muscle weakness

Cardiomyopathy

Abnormal hepatic function

Impaired ketogenesis

Hypoglycemia during fasting
Myopathic Disease is characterized primarily by muscle weakness.
Fatty infiltration of muscle fibers is observed at biopsy and the
concentration of carnitine is low BUT plasma concentrations of
carnitine are normal.
Secondary forms of Carnitine deficiency:

Renal tubular disorders (excessive carnitine excretion)

Chronic renal failure (hemodialysis may promote
excessive loss(

Inborn errors of metabolism associated with increased
circulating concentrations of organic acids may become
deficient in carnitine.

Patients receiving total parental nutrition (TPN) lacking
carnitine.
In the presence of genetic deficiency of one of the Acyl CoA
dehydrogenases, carnitine serves to promote the removal of the
corresponding organic acid from cells and the blood b/c the
acylcarnitine can be transported out of the mitochondria and into
circulation BUT CANNOT be reabsorbed from renal tubules. Such
removal of acylcarnitines from the blood or cells carries the risk of
producing a state of relative carnitine deficiency.
Primary Carnitine Deficiency- the mainstay of treatment of
systemic carnitine deficiency is a high-carbohydrate, low fat diet.
Variable response to carnitine supplementation (up to 4 g daily).
Renal Disease- patients receiving chronic hemodialysis can
11
Week 13 & 14 Notes
4.
ACYLCARNITINES ARE TRANSPORTED OUT OF
CELLS.
Fatty acid esters of CoA are formed almost
exclusively in the cytosol and are NOT transported
across membranes. They also INHIBIT enzymes of
the Krebs cycle and those involved in oxidative
phosphorylation. Hence, the oxidation of fatty acids
requires the formation of acylcarnitines and their
translocation into mitochondria, where the CoA
esters are reformed and metabolized.
develop skeletal and possibly myocardial muscle carnitine
deficiency. Treatment with L-carnitine may minimize deficiency and
improve symptoms like muscle weakness and cramps.
Cardiomyopathies & Ischemic cardiovascular diseasemyocardial energy needs are satisfied by fatty acid oxidation.
Myocardial ischemia causes depletion of cardiac carnitine and
accumulation of long-chain FA esters of CoA and carnitine. The
acylcarnitines may be important in the genesis of arrhythmias.
-Carnitine maintains a favorable ratio of FREE to Esterified
CoA in the mitochondria that is optimal of oxidative
phosphorylation and also the consumption of acetyl CoA.
-In ISCHEMIC cardiac or skeletal muscle, this results in
reduced formation of lactate and increased capacity to
perform mechanical work.
Ascorbic acid functions as a cofactor in a number of
HYDOXYLATION and amidation reactions by transferring
electrons to enzymes that provide reducing equivalents.
Ascorbic acid is a six-carbon
keto-lactone structurally
related to glucose and other
hexoses. It is reversibly
oxidized in the body to
DEHYDROASCORBIC ACID,
which has full activity.
Ascorbic
Acid,
Vitamin C
Ascorbic acid has an optically
active atom and
ANTISCORBUTIC activity
resides almost totally in the Lisomer. Also erythorbic (Disoascorbic acid, Daraboascorbic acid) have
weak antiscorbutic action but
a similar redox potential.
BOTH compounds have been
used to prevent
NITROSAMINE FORMATION
from nitrites cured in meats.
One of the consequences of
ascorbic acid oxidation is the
readiness with which it can be
DESTROYED by exposure to
air, especially in an
ALKALINE medium and if
COPPER is present as a
catalyst.
UNABLE TO SYNTHESIZE
VITAMIN C

Humans

Other primates

Guinea pigs

Bats
Humans, monkeys, and
guinea pigs lack the hepatic
enzyme (gulonolactone
oxidase) required to carry out
the last reaction, which is the
conversion of Lgulonolactone to L-ascorbic
acid.
Functions and MOA1. Carnitine Synthesis- oxidation of lysine side chains in
proteins to provide hydroxytrimethyllisine
2. Collagen synthesis- required for the conversion of proline
and lysine residues in Procollagen to hydroxyproline and
hydroxylysine.
3. Tyrosine synthesis and catabolism- tyrosine synthesis
requires hydroxylation of phenylalanine via the irondependent enzyme phenylalanine monooxygenase
(hydroxylase) and requires tetrahydrobiopterin. Vitamin C
is thought to function in the regeneration of
tetrahydrobiopterin from dihydrobiopterin.
4. Neurotransmitter synthesis- Norepinephrine: the
hydroxylation of dopamine (copper-dependent enzyme).
Serotonin: hydroxylation of tryptophan.
5. Other neurotransmitters & Hormones- Ascorbic acid
promotes the activity of an enzyme (peptidylglycine αamidating monooxygenase) thought to be involved in the
processing of certain peptides, such as, oxytocin, ADH,
CCK, bombesin or GRP, calcitonin, CRP, gastrin,
thyrotropin, CRF, and GHRF. As a reductant fro the
required amidating enzyme, vitamin C assumes an
INDIRECT role in many regulatory processes.
6. Microsomal metabolism- Endogenous: various hormones
and steroids, such as, cholesterol. Vitamin C plays an
undefined role in synthesis of bile salts from cholesterol.
Vitamin C also participates in aldosterone and cortisol
synthesis. Exogenous: substrates for microsomal
metabolism are usually xenobiotics, such as, drugs,
alcohol, carcinogens, pesticides, food additives and
pollutants. The hydroxylation reactions are catalyzed by
monooxygenase or cytochrome P450 and require reducing
agents such as vitamin C and NAD(P)H and oxygen.
7. Antioxidant activity- Vitamin C functions as a reducing
agent or electron donor to regenerate other antioxidants
such as Vitamin E and glutathione and urate. It also
reduces reactive oxygen and nitrogen species such as the
hydroxyl radical (OH·), hydroperoxyl radical (HO2·),
Superoxide radical (O2-), alkoxyl radical (RO·), and peroxyl
radical (RO2·). Also H2O2, singlet 1O2, and hypochlorous
acid (HOCl) are scavenged by vitamin C.
8. Folate metabolism- maintains folate in a reduced state (as
tetrahydrofolate, THF, the active form, or dihydrofolate) &
the conversion of folic acid to folinic acid. Folate is
necessary for hemoglobin synthesis and hence vitamin C is
indirectly.
9. Other functions- collagen gene expression, synthesis of
bone matrix, proteoglycans, fibronectin & elastin, regulation
of cellular nucleotide (cAMP and cGMP) concentrations,
immune function, and complement synthesis.
10. Pro-Oxidant- Vitamin C can act as a pro-oxidant because
Vitamin C Deficiency
Scurvy- associated with a defect
in collagen synthesis that is
apparent in the failure of wounds
to heal, in defects in tooth
formation, and in the rupture of
capillaries, which leads to
numerous petechiae and their
coalescence to form
ecchymoses.
Petechiae is attributed to
leakage from capillaries because
of inadequate adhesion of the
endothelial cells.
Scurvy encountered in:

Elderly people living
alone

Alcoholics

Drug addicts

Inadequate diets
including infants
Spontaneous cases:

Loosening of the teeth

Gingivitis

Anemia due to
ascorbic acid in
hemoglobin synthesis

Infants don’t want to
be touched b/c of
hemorrhages under
the periosteum of the
long bones which
result in hematomas
Lower vitamin C plasma levels
are observed in SMOKERS
because of a high metabolic
turnover rate of the vitamin. The
RDA is 100mg/day for smokers.
Oral Contraceptives also lower
vitamin C levels and higher
requirements may be needed
following surgery or infection
(infectious diseases).
12
Week 13 & 14 Notes
it can reduce transition metals like cupric to cuprous (Cu2+
to Cu1+) and ferric to ferrous (Fe3+ to Fe2+), while itself
becoming oxidized to semi-dehydroascorbate. Vitamin C
enhances the intestinal absorption of nonheme iron either
by reducing it to ferrous or by forming a soluble complex
with the iron in the alkaline pH of the small intestine.
Fat
Soluble
Vitamins
Chemistry
Physiological Functions
Supplied exogenously and most actions of
Vitamin A are exerted through hormone-like
receptors.
Vitamin A

Retinol (vitamin A1)-an alcohol is present
in an esterified form in the liver of animals
and saltwater fish.

Retinoid

Retinoic acid

Retinal- an aldehyde

Carotene (provitamin A)- most active is
beta-carotene.

3- Dehydroretinol (vitamin A2)- obtained
from tissues of freshwater fish and mixed
with retinol.
Physiological functions of Vitamin A:
-plays a central role in the function of the retina b/c it
is necessary for the growth and differentiation of
epithelial tissue and is required for growth of bone,
reproduction, and embryonic development.
Vitamin A and its analogs

enhance immune system

reduce the consequences of infectious
diseases

protect against the development of
malignancies.

Used to treat a number of skin diseases
associated with aging and sun-exposure
b/c of its effects of epithelial tissues.
A number of geometric isomers of retinol exist
b/c of the cis-trans configurations around the
double bonds in the side chain.
Interconversion b/n isomers readily takes place
in the body
In the VISION CYCLE:
Vitamin
A
The reaction b/n retinal and opsin to from
rhodopsin only occurs with the 11-cis isomer.
1. oxidation of retinol to all-trans retinal
2. conversion of all-trans retinal to 11-cis
retinal
3. binding of 11-cis retinal to opsin
4. uptake of retinol into photoreceptor
rod cells
Potency:
Of all the derivatives, all-trans-retinol and its
aldehyde, retinal, exhibit the greatest biological
potency in vivo. 3-dehydroretinol has 40% of
the potency of all-trans retinol.
Retinoic acid is very POTENT in promoting
growth and controlling cell differentiation and
maintenance of epithelial tissue in vitamin-A
deficient animals.
HOWEVER it is
INEFFECTIVE
in
restoring
visual
or
reproductive function in certain species where
retinol is effective.
Retinoic supports the
development of cells by influencing gene
expression.
All-trans retinoic acid (tretinoin) appears
to be the active form in vitamin A in all tissues
EXCEPT the RETINA and is 10-100 fold more
potent than retinol in various systems in vitro.
The functional and structural integrity of epithelial
cells throughout the body is also dependent upon an
adequate supply of vitamin A. The vitamin plays a
major role in the induction and control of epithelial
differentiation in MUCOUS-SECRETING or
KERATINIZING tissues. In the presence of retinol or
retinoic acid, basal epithelial cells are stimulated to
produce mucus. Excessive concentrations of the
retinoids lead to the production of a thick layer of
MUCIN, the inhibition of keratinization, and the
display of goblet cells.


Retinal- the functional vitamin in vision
Retinoic acid- the active form in functions
associated with growth, differentiation, and
transformation.
Vitamin A reduces the risk of carcinogenesis and
enhances the immune system function. Because
vitamin A regulates epithelial cell differentiation and
proliferation, it may interfere with carcinogenesis.
The basal cells undergo marked hyperplasia and
reduced cellular differentiation. The administration
of retinol or other retinoids to animals reverses these
changes in the epithelium of the respiratory tract,
mammary gland, urinary bladder, and skin. The
progression of pre-malignant cells to cells with
invasive, malignant characteristics is slowed,
delayed, arrested, or even reversed in experimental
animals. The EXACT mechanism of the anticarcinogenic effect of vitamin A supplementation is
not understood, there might be an association of the
ability of the retinoids to regulate the synthesis or
specific proteins necessary for the differentiation of
epithelial tissues. The ANTI-CARCINOGENIC
effect associated with Vitamin A does not appear
to be related to direct CYTOTOXIC action.
Vitamin A appears to have biochemical functions in
Symptoms of
Deficiency
Vitamin A deficiency
The effects:

Night Blindness
(Nyctalopia)- deficiency
interferes with vision in
dim light.

Keratinization of tissuesin the absence of vitamin
A, goblet cells that
produce mucous
disappear and are
replaced by basal cells
that are stimulated to
proliferate. The
suppression of normal
secretions leads to
irritation and infection.

Immunity- increased
susceptibility to bacterial,
parasitic, or viral
infections in deficient
individuals. May be
associated with Cell
mediated or humoral
immunity, which is
enhanced with
supplementation.

Xerosis
(Xeropthalmia)

REVERSAL of these
deficiencies is achieved
by administration of
retinol, retinoic acid, or
other retinoids.
List the signs of vitamin A
toxicity.
UL = 3mg/day or 10,000 IU
bone pain
headache
liver damage
skin irritations
Plasma retinol is a good
reflection of vitamin A status
under the following conditions:

individual has exhausted
his stores

or the stores are filled to
capacity
hence, partially depleted stores
13
Week 13 & 14 Notes
An isomer of tretinoin is 13-cis-retinoic acid
which is almost as potent but with 5-fold less
toxic symptoms of hypervitaminosis A.
2nd Generation retinoids:
The beta-ionone ring is aromatized. More
active than tretinoin in some systems and less
in others.
3rd Generation retinoids:
Highly potent retinoids have two aromatic rings
that serve to restrict the flexibility of the
polyenoic side chain. This class is called the
arotinoids.
the synthesis of cell-surface glycoproteins and
glycolipids that may be involved in cell
ADHERENCE and COMMUNICATION.
do not reflect status best.
CHIEF DISCOVERY:
The RXR receptor system, a series of companion
receptors involved in the cellular actions of retinoic
acid, calcitriol (active form of vitamin D) and thyroid
hormone. In addition, 9-cis retinoic acid has been
identified as the natural endogenous ligand for these
receptors, making this vitamin A analog very
important in the actions of retinoic acid on cellular
differentiation.
As an antioxidant, vitamin E prevents the oxidation
of cellular constituents or prevents the formation of
toxic oxidation products such as peroxidation
products formed from unsaturated fatty acids that
have been detected in its absence.
There appears to be a relationship b/n vitamin E
and vitamin A. The intestinal absorption of vitamin
A is enhanced by vitamin E, and hepatic and other
cellular concentrations of vitamin A are elevated; this
effect could be related to the protection of vitamin A
by the antioxidant properties of vitamin E. Vitamin
E protects against various effects of
hypervitaminosis A.
Vitamin
E
There are 8 isomers of vitamin E (4
tocopherols and 4 tocotrienol). Alpha
tocopherols (5,7,8-trimethyl tocol) is
considered to be the most important b/c it
displays the greatest activity and this 90% of
vitamin E is in the form of alpha-tocopherol.
Chemical features:

Redox agents- act as antioxidants

Deteriorate slowly when exposed to
air or UV light.
The lesions produced in skeletal muscle by a vitamin
E deficiency are also found in CARDIAC MUSCLE.
The oxidation of LDL is contributory to
ATHEROGENESIS.
Oxidized LDL is more
effectively taken up than native LDL by
macrophages,
adversely
affects
vascular
endothelial cells, and might be vasoconstrictive.
Pharmacological
amounts
of
vitamin
E
(1600mg/day) appear to protect LDL from oxidation
and second reducing agent like coenzyme Q10 will
allow vitamin E to work as an effective antioxidant.
Studies:

Vitamin E reduces the risk of coronary
heart disease in middle-aged women.

Supplementation added to dietary vitamin
E intake proved beneficial. Diet alone was
not good enough.

Men taking 100 IU/day vitamin E for 2
years showed a reduced risk of CHD.
Vitamin E Deficiency

Structural and functional
abnormalities. These
defects involve Fatty acid
metabolism and other
enzyme systems.

Hemolytic anemia

Neuromuscular
degeneration
The fat-soluble micronutrient,
tocotrienol shows the greatest
promise as therapy for
hypercholesterolemia
Regeneration of oxidized vitamin E requires three
cofactors:
1. reduced glutathione
2. NADPH
3. Vitamin C
Vitamin
K
Chemistry and Occurrence
Vitamin K activity is associated with at least
TWO distinct natural substances

Vitamin K1, Phylloquinone (or
phytonadione)

Vitamin K2, Menaquinone (a series
of compounds)
Vitamin K3, Menadione is a synthetic
supplement.
Phylloquinone is found in plants and is the
only natural vitamin K available for therapeutic
use. Menaquinones replace the phytyl side
chain of phytonadione with 2-13 prenyl units.
Considerable synthesis of menaquinones
occurs in gram-positive bacteria and bacteria
In normal animals and human beings, phytonadione
and the menaquinones are devoid of
pharmacodynamic activity.
The vitamin K-dependent blood clotting factors
(prothrombin or factor II, VII, IX, X) are
synthesized in the liver. These factors, in the
absence of vitamin K (or coumarin anticoagulant)
are biologically INACTIVE precursor proteins in the
liver.
Vitamin K functions as an essential cofactor for the
MICROSOMAL enzyme system that activates these
precursor proteins by the conversion of multiple
residues of glutamic acid (Glu) near the amino
terminus of each precursor to –carboxyglutamyl
Vitamin K Deficiency
List the reasons why adequate
amounts of vitamin K are
usually present in the body?
1. recycling of vitamin K is
efficient
2. a normal diet contains
much more than
recommended
requirements
3. intestinal bacteria
synthesize significant
amounts
Population groups and clinical
14
Week 13 & 14 Notes
in the GI tract and they are responsible for a
large amount of vitamin K contained in human
and animal feces. In animals, menaquinone-4
can be synthesized from vitamin K3 or
menadione.
(Gla) residues in the completed protein. The
formation of this new amino acid, carboxyglutamic
acid, allows the protein to bind to CALCIUM, Ca2+,
and in turn be bound to a phospholipid surface,
BOTH of which are necessary in the CASACADE of
events that lead to CLOT FORMATION.
The active form of vitamin K is the reduced form,
hydroquinone which in the presence of O2, CO2,
and microsomal carboxylase, is converted to its 2,3
–epoxide at the same time carboxylation takes
place.
Carboxyglutamate is found in a variety of proteins
other than vitamin K-dependent blood clotting
factors. One of these is OSTEOCALCIN in bone,
which is a secretory product of osteoblasts. Its
synthesis is regulated by CALCITRIOL, the active
form of vitamin D, and its plasma concentration
correlates with bone turnover.
Carboxyglutamate is found in:

Osteocalcin

Protein S

Protein C
Proteins C and S play an anticoagulant role by
INACTIVATING factors VII and V.
Bone proteins that depend upon vitamin K for their
production.

Osteocalcin

Matrix Gla protein
situations that are associated
with increased risk for vitamin
K deficiency:
1. those with liver damage or
disease
2. chronic antibiotic therapy
3. newborn infants
4. fat malabsorption
Disorders that lead to Vitamin
K deficiency and
hypoprothrombinemia:

Cystic fibrosis

Sprue

Crohn’s disease &
enterocolitis

Ulcerative colitis

Dysentery

Extensive resection
of bowel
Nutriture Assessment
List the methods for
determining vitamin K status.

Prothrombin time

Des gammacarboxyglutamyl
prothrombin/ prothrombin
ratio

Plasma prothrombin
Vitamin K prevents calcification in soft tissue
structures.
The blood disorder associated with a vitamin K
deficiency is hemorrhagic disease.
Vitamin D must be hydroxylated in the LIVER &
KIDNEY in order to achieve full potency.




Vitamin
D


Vitamin D3 produced in the skin
Cholecalciferol
Synthetic vitamin D2 available commercially
Ergocalciferol (ercalciol)
Most abundant form of vitamin D in the blood
Calcidiol
Fully activated form of vitamin D
Calcitriol
Precursor to pre-vitamin D3
7-dehydrocholesterol
Vitamin D precursor found only in plant
ergosterol
Osteomalacia is the disorder associated with
insufficient serum calcium and phosphorus,
which leads to defective bone mineralization
with preservation of bone matrix.
Factors that will stimulate 1-alpha hydroxylase in the
synthesis of calcitriol are:

Low plasma calcium concentrations

Elevated blood PTH

Low concentrations of 1,25-(OH)2 D3
(calcitriol)

Low P intake
List the functions of calcitriol in the intestine.
1. increased absorption of calcium and
phosphorous
2. synthesis of calbindin D9k
3. induce changes in brush border
composition and topology
4. increase activity of alk phos
5. transcaltachia (endocytosis)
6. opening of voltage gated calcium
channels
7. biosynthesis of mRNA
List the risk factors for vitamin
D deficiency.
In infants- human milk is low
in vitamin D
In children: rickets, failure of
the bones to mineralize
In adults: osteomalacia

inadequate sun exposure

the elderly- aging reduces
synthesis of
Cholecalciferol in the skin
and reduces the activity of
renal 1-hydroxylase

fat malabsorption like
tropical sprue or Crohn’s
disease

disorders affecting
parathyroid, liver or
kidney

people on anti-convulsant
medicines.
15