Transcript Virtual Free Radical School Bilirubin: Friend or Foe? James K. Friel, Ph.D., Russell W.

Virtual Free Radical School
Bilirubin: Friend or Foe?
James K. Friel, Ph.D., Russell W. Friesen, B.Sc., & Angela C. Miller, B.Sc
University of Manitoba
Department of Human Nutritional Sciences
H511 Duff Roblin Building
Winnipeg, MB R3T 2N2 Canada
Tel: 204-474-8080
Fax: 204-474-7593
E-mail: [email protected]
“Learning is my home.”
Bilirubin 1/2003 – Updated 6/2006 Society For Free Radical Biology and Medicine
Friel, Friesen & Miller 1
The Road Ahead
• Function of Bilirubin
• Bilirubin as an Antioxidant
• Bilirubin as a Toxin
• Biliverdin Reductase
• Cardiovascular Disease
• Jaundice
• Hyperbilirubinemia
• The Premature Infant
• Promise for the Future
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Bilirubin
O
H
N
24
18 17
CH
H
N
23
H
N
CH
8 7
3
CH2 CH3
CH2
O
21
22
13 12
H3C
H 3C
CH2
H2C CH
HOOC H2C
• Is a bile pigment.
H
N
CH2
2
CH3 CH CH2
COOH
Bilirubin
• Results from the degradation of heme, one of
the breakdown products of red blood cells.
• It is thought to be a toxin because it is
associated with neonatal jaundice, possibly
leading to irreversible brain damage due to
neurotoxicity.
Tomaro ML, Batlle AM del C. (2002). Bilirubin: its role in cytoprotection
against oxidative stress. Int J Biol Cell Biol., 34: 216-220
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Fe2+, CO
Globin
Hemoglobin
Heme
HO
O2,
NADPH
Biliverdin
Bilirubin
(insoluble)
Spleen
H2O,
+
NADP
Bilirubin-albumin
conjugate
Formation
The
Bilirubin
ofPathway:
Bilirubin:
Overview
Overview
Blood
Bilirubin
Liver
Bilirubin
diglucuronide
Bilirubin
diclucorinide(soluble)
Excreted
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Formation of Bilirubin
1. Hemoglobin from senescent or hemolyzed red cells is
broken down, releasing heme.
2. Heme is then degraded in humans by the enzyme heme
oxygenase (HO), which is the rate-limiting step in the
formation of bilirubin.
3. HO converts heme to biliverdin IX.
4. Biliverdin is a hydrophilic compound that is reduced by
biliverdin reductase into the hydrophobic compound
bilirubin.
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Formation
of Bilirubin
5. HO catalyses an oxidase
reaction opening the heme
ring to convert one of the
bridge carbons to carbon
monoxide. This step
releases iron from the now
linear tetrapyrrole yielding
biliverdin.
6. Biliverdin reductase reduces
the double bond on nitrogen
inside one of four of the
pyrrole rings leading to the
formation of bilirubin.
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Excretion of Bilirubin
1. Bilirubin is bound to albumin and transported in plasma
from the reticuloendothelial system to the liver, as
unconjugated bilirubin.
2. In the liver, bilirubin is made water soluble by hepatocytes
which conjugate bilirubin with glucuronic acid to form
conjugated bilirubin (BC). This process requires the
enzyme uridine diphosphate-glucuronosyltransferase
(UPD-GT) and produces bilirubin diglucuronide.
3. BC is secreted from hepatocytes to the bile canaliculi of
the liver and is transported from the liver via the gall
bladder and common bile duct to the gastrointestinal tract.
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Excretion of Bilirubin
3.
In the ileum and colon, bacteria converts bilirubin into
stercobilinogen.
4.
Stercobilinogen is oxidized to stercobilin, which is
excreted in the feces.
5.
While most bilirubin is excreted as stercobilin, a small
amount of stercobilinogen is reabsorbed into the blood,
modified by the kidneys, and excreted as urobilinogen in
the urine.
Higgins, Chris. (2002). Neonatal jaundice, breast milk, and Gilbert’s syndrome.
Biomedical Scientist, February.
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Bilirubin as an Antioxidant
As early as 1959, it was suggested that bilirubin might
be an antioxidant.
Bilirubin can suppress oxidation of lysosomes at
oxygen concentrations that are physiologically relevant.
Bilirubin can act as an important cytoprotector of
tissues that are poorly equipped with antioxidant
defense systems, including myocardium and nervous
tissue.
Temme EHM, Zhang J, Schouten EG, & Kesteloot H. (2001). Serum bilirubin and 10-year
mortality risk in a Belgian population. Cancer Causes and Control, 12: 887-894.
Bilirubin 1/2003 – Updated 6/2006 Society For Free Radical Biology and Medicine
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Bilirubin as an Antioxidant
At concentrations as low as 10nM, Bilirubin can protect
against 10,000-fold greater concentrations of H2O2.
Under physiologic conditions, bilirubin provides more
potent protection against lipid peroxidation than αtocopherol, formerly known to be most effective in
preventing lipid peroxidation.
Recent research indicates that bilirubin may be the most
abundant endogenous antioxidant in mammalian tissues.
Baranano DE, Rao M, Ferris CD, & Snyder SH. (2002). Biliverdin reductase: A major
physiologic cytoprotectant. Proc. Natl. Acad. Sci. USA, 99(25): 16093-16098.
Dore S, Takahashi M, Ferris CD, Hester LD, Guastella D, & Snyder SH. (1999). Bilirubin,
formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury.
Proc. Natl. Acad. Sci. USA, 96: 2445-2450.
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Bilirubin as an Antioxidant
A linear relationship (R2 = 0.99) has been identified
between plasma antioxidant capacity and unconjugated
bilirubin concentration in newborn infants.
This both confirms bilirubin’s significance as a plasma
antioxidant and suggests that moderate increases in
plasma bilirubin might be favourable to infants under
oxidative stress.
Belanger S, Lavoie J-C, & Chessex P. (1997). Influence of Bilirubin on the Antioxidant Capacity
of Plasma in Newborn Infants. Biology of the Neonate, 71: 233-238.
Bilirubin 1/2003 – Updated 6/2006 Society For Free Radical Biology and Medicine
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Bilirubin as an Antioxidant
Comparative relative proportions of plasma antioxidants between premature and term
neonates expressed as a percentage of the total antioxidants
Albumin
Urate
Ascorbate
α-tocopherol
Bilirubin
0.63
1.02
0.99
0.97
1.5
49
37.5
9.5
3
1
Term at birth
34.5
47.8
13.8
0.5
3.4
Term - Day 5
41
24.1
10.2
1.6
23
Prem at birth
33.5
38.1
22.7
0.9
4.8
Prem - Day 5
30.8
26.4
8.5
1.2
33.1
TEAC* value
Reference level [9]
*Trolox Equivalent Antioxidant Capacity
(Gopinathan et al., 1994) Expressing the data as relative levels in relation
to the major antioxidants of human plasma emphasises the contribution of
bilirubin to the antioxidant potential at day 5 for both the term and the preterm infants.
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Bilirubin as an Antioxidant
The proposed mechanism is:
Bilirubin can scavenge the chain-carrying peroxyl radical by
donating a hydrogen atom attached to the C-10 bridge of the
tetrapyrrole molecule to form a carbon-centered radical Bil
LOO + Bil  LOOH + Bil
Bil + LOO  Bil-OOL
Bil + O2  Bil-OO
LOO + BV  LOO-BV
Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, & Ames BN. (1987). Bilirubin
is an antioxidant of possible physiological importance. Science, 235: 1043-1046.
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Conjugated & Unconjugated Bilirubin
Serve as Antioxidants in Lipid
Peroxidation
Both unconjugated bilirubin (BU)
and conjugated bilirubin (BC) can
serve as antioxidants, protecting
human LDL from lipid
peroxidation in vitro against
peroxyl radicals (generated by
2,2'-azobis [2-amidinopropane]
dihydrochloride).
Wu T-W, Fung KP, Wu J, Yang C-C, & Weisel
RD. (1996). Antioxidation of human lowdensity lipoprotein by unconjugated and
conjugated bilirubins. Biochem Pharmacol,
51: 859-862.
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The Toxic Side of Bilirubin
Erythrocyte morphological
changes have been seen with
incubation of cells with different
molar ratios of unconjugated
bilirubin.
These changes occur as the
bilirubin/human serum albumin
molar ratio increases.
Brito MA, Silva R, Tiribelli C & Brites D.
(2000). Assessment of bilirubin toxicity to
erythrocytes. Implication in neonatal jaundice
management. European J Clinical Invest, 30:
239-247.
This indicates that bilirubin can
illicit toxicity in the erythrocyte
membrane in a concentration
and temperature-dependent
manner.
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The Toxic Side of Bilirubin
•
Morphological changes have also been observed in microglia
exposed to 50 µM unconjugated bilirubin (BU). These changes
are characteristic of those that normally occur during the activation
of these cells. Therefore, BU stimulates microglial activation.
•
Persistent activation of microglia stimulates the production of
highly neurotoxic species that may be responsible for the neuronal
destruction that occurs in various neurodegenerative diseases.
•
In addition, BU causes microglia to release proinflammatory cytokines (TNF-α, IL-1β and IL-6)
and cytotoxic glutamate in a concentrationdependent manner.
•
When incubated with 50 µM or 100 µM BU,
microglia underwent apoptotic and necrotic cell
death.
Gordo AC, Falcão AS, Fernandes A, Brito MA, Rui F.M. Silva, & Brites D.
(2006). Unconjugated bilirubin activates and damages microglia. Journal
of Neuroscience Research, April 12.
Reactive morphological changes of
microglia exposed to BU (bottom).
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The Toxic Side of Bilirubin
•
Bilirubin (BR) can bind to DNA and copper ions to form a bilirubin-Cu(II)DNA complex. This complex causes oxidative DNA damage through a
DNA cleavage reaction. Biliverdin (BV) acts similarly with DNA.
•
Upon binding to Cu(II), BV/BR reduce Cu(II) to Cu(I), stimulating the
release of reactive oxygen species, particularly the hydroxyl radical. Cu(I)
acts as an essential intermediate in the DNA cleavage reaction.
•
In the presence of light, bilirubin has been shown to generate hydrogen
peroxide and other peroxides that can cause DNA damage.
Under certain conditions, many antioxidants are known to act as
prooxidants, and bilirubin is no exception.
Asad SF, Singh S, Ahmad A, & Hadi SM. (2002) Bilirubin/biliverdin–Cu(II) induced DNA breakage; reaction mechanism and biological
significance. Toxicology Letters, 131: 181-189.
Asad SF, Singh S, Ahmad A, & Hadi SM. (1999) Bilirubin-Cu(II) complex degrades DNA. Biochimica et Biophysica Acta, 1428(2-3): 201208.
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The Role of Biliverdin Reductase
• Reduces water-soluble biliverdin to insoluble, potentially
toxic bilirubin.
• Participates in a catalytic redox cycle which functions to
regenerate bilirubin and amplify its antioxidant activity.
Bilirubin is oxidized to biliverdin which is then immediately reduced
back into bilirubin by biliverdin reductase.
• Therefore, the principle function of the bilirubin generating
system is the cytoprotection provided by the biliverdin
reductase cycle.
• Biliverdin reductase demonstrates potential to become a
new effective target for the treatment of free radicalmediated diseases.
Baranano et al. (2002).
Liu Y, Liu J, Tetzlaff W, Paty DW & Cynader M. (2006). Biliverdin reductase, a major
physiologic cytoprotectant, suppresses experimental autoimmune encephalomyelitis. Free
Radic. Biol. Med., 40(6): 960-967.
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Heme Oxygenase (HO)
• A cytoprotective enzyme that breaks the prooxidant
molecule heme into biliverdin (immediately converted
into bilirubin), iron, and carbon monoxide.
•
HO-2, the constitutive isoform, is highly active in
neurons and accounts for most of the HO activity in
the brain.
• Destroying the HO-2 gene, and thus limiting BR
production, leads to increased oxidative damage
following cerebral ischemia.
Namiranian K, Koehler R, Sapirstein A, & Dore S. (2005). Stroke outcomes in mice lacking
the genes for neuronal heme oxygenase-2 and nitric oxide synthase. Current Neurovascular
Research, 2: 23-27.
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Bilirubin and Cardiovascular Disease
• Low serum bilirubin has been
shown to be strongly correlated
with several
cardiovascular risk
factors,
including age, cigarette
smoking, social class, diabetes,
serum cholesterol, lower FEV1,
and lower serum
albumin.
• Serum bilirubin was found to have
a U-shaped relationship with the
events of ischemic heart disease
(IHD)
Serum bilirubin and adjusted relative risk of major IHD
events in 4916 men measured before 16:00 c.
Relative Risk (95% confidence interval)
Adjusted a
Bilirubin (µmol/L)
Adjusted b
<7
1.00
1.00
7 0.
89(0.66-1.21)
0.92(0.69-1.32)
8
0.69 (0.55-0.91)
0.68 (0.51-0.89)
10
0.78(0.58-1.05)
0.75 (0.55-1.03)
12
0.90 (0.68-1.20)
0.99 (0.73-1.34)
a
Adjusted for age, body mass index, smoking, social class, physical activity,
alcohol intake, preexisting IHO, diabetes, use of antihypertensive treatment.
b
Adjusted for the above and in addition for systolic blood pressure, blood
cholesterol, HDL-C, FEV1, blood glucose, and serum albumin. Complete data on
all covariates were available for 4678 men (444 IHD cases).
c
There was little difference in mean values up to 16:00, but after this, the
concentrations decreased steadily. The explanation for this decrease is uncertain,
but may be the result of food intake, fasting having been shown to increase
bilirubin concentration.
Breimer LH, Wannamethee G, Ebrahim S, & Shap AG. (1995). Serum bilirubin and risk of ischemic heart disease
in middle-aged British men. General Clinical Chemistry, 41(10): 1504-1508.
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Bilirubin and Cardiovascular Disease (cont.)
• Bilirubin perfusion was shown to
significantly decrease infarct damage caused
by IHD.
• Serum bilirubin concentrations in the upper
range of normal values protect against
coronary artery disease (CAD).
• However, concentrations in the lower range
increase atherogenic risk and thus risk of
IHD.
• Schwertner et al. discovered an unexpected
inverse association between serum total
bilirubin and CAD. The strength of the
association with CAD was similar to that of
smoking or of systolic blood pressure.
Prevalence of coronary artery disease, according to
concentration of total bilirubin in 877 patients.
Schwertner HA, Jackson WG, & ToIan G. (1994). Association of low
serum concentration of bilirubin with increased risk of coronary artery
disease. Clinical Chemistry, 40(1): 18-23.
Dore, Sylvain. (2002). Decreased activity of the antioxidant heme
oxygenase enzyme: implications in ischemia and in Alzheimer's
disease. Free Radical Biology and Medicine, 32(12): 1276-1282.
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Bilirubin and Jaundice
• Neonatal jaundice is a yellowing of the skin and eyeballs
and may lead to deposition of bilirubin in brain cells.
• Normally bilirubin is bound (conjugated) by a transport
molecule and excreted.
• However “unconjugated” bilirubin can induce a loss of
neurons and atrophy of involved fiber systems (called
Kernicterus).
• Jaundice has become one of the most common
problems in the neonatal period for both full term and
premature infants (<37 weeks gestation), affecting 5070% of newborns.
Gurses D, Kilic I, & Sahiner T. (2002). Effects of hyperbilirubinemia on cerebrocortical
electrical activity in newborns. Pediatr Res., 52: 125-130.
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Bilirubin and Jaundice:
“Breast Milk Jaundice”
• A type of neonatal jaundice that is associated with
breastfeeding. It develops 6-14 days after birth, occurring
in approximately one third of newborn infants, and
continues beyond physiologic jaundice.
• It is different than breastfeeding jaundice, which occurs as
a result of caloric deprivation in the first few days of life.
• In general, breastfed infants are 3-6 times more likely to
develop moderate or severe jaundice than formula-fed
infants.
Porter ML and Dennis BL. (2002). Hyperbilirubinemia in the term newborn. American Family
Physician, 65(4): 599-606.
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Bilirubin and Jaundice:
“Breast Milk Jaundice” (cont.)
• The cause is unknown, but it is suspected to be a rare
compound present in some breast milk that inhibits Uridine
diphosphoglucuronosyltransferase 1A1 (UGT1A1), the
enzyme required for conjugation of bilirubin.
• Various substances identified in human milk, such as
nonesterified fatty acids and β-glucuronidases, may inhibit
normal bilirubin metabolism.
• Also, in certain populations, mutation of the UGT1A1 gene,
glycine to arginine at codon 71 (G71R), has been identified
as a possible genetic cause of breast milk jaundice.
Ramer, Timothy. (2005). Retrieved May 17, 2006, from http://www.emedicine.com/PED/topic282.htm
Maruo Y and Sato H. (2002). UDP-Glucuronosyltransferase. Japanese Journal of Hygiene, 56(4): 629-633.
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Hyperbilirubinemia:
Elevated Bilirubin in the Blood
Neonatal hyperbilirubinemia is defined as a total
serum bilirubin level above 5 mg/dL. It results
from the overproduction of unconjugated
bilirubin in newborn infants, and their limited
ability to conjugate it or excrete it.
These limitations lead to physiologic jaundice,
where high serum bilirubin concentrations in the
first few days of life color the skin yellow.
Porter ML and Dennis BL. (2002). Hyperbilirubinemia in the term newborn.
American Family Physician, 65(4): 599-606.
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Hyperbilirubinemia
(cont.)
• Hyperbilirubinemia has the potential for neurotoxic
effects.
• Bilirubin can enter the brain if it is free (not bound to
albumin), unconjugated, or if there has been
damage to the blood brain barrier.
• Once inside the brain, precipitation of bilirubin at low
pH may have toxic effects. Neurons undergoing
differentiation are particularly susceptible to injury
from bilirubin, suggesting that prematurity
predisposes infants to bilirubin encaphalopathy.
Dennery PA, Seidman DS, & Stevenson DK. (2001). Neonatal Hyperbilirubinemia.
New England Journal of Medicine, 344: 581-590.
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Hyperbilirubinemia and Plasma
Antioxidant Activity
• Under normal conditions, bilirubin accounts for 2% of
plasma antioxidant activity; in jaundiced infants,
bilirubin accounts for 77%.
• Elevated levels of plasma bilirubin were shown to affect
the concentration of other plasma antioxidants, such as
Vitamin E, which was observed at levels as high as
those in adult blood.
Belanger S, Lavoie J-C, & Chessex P. (1997). Influence of Bilirubin on the Antioxidant Capacity
of Plasma in Newborn Infants. Biology of the Neonate, 71: 233-238.
Bilirubin 1/2003 – Updated 6/2006 Society For Free Radical Biology and Medicine
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Treatment of Hyperbilirubinemia
• Phototherapy
with fluorescent white light
fibreoptic blankets to reduce serum bilirubin.
or
• Exchange blood transfusions to eliminate bilirubin
from circulation.
• Phenobarbital: given to mothers during the last
week of pregnancy to increase conjugation and
excretion in high-risk newborns (with some
success).
• Disadvantages: known risks of blood transfusion;
damage to eyes by UV light; increased risk of
neurotoxic effects and fetal abnormalities
associated with phenobarbital.
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Bilirubin and Exchange
Transfusion
Effect of Exchange Transfusion on Plasma Concentration
Before Exchange
After Exchange
(n = 11)
(n = 11)
363 ± 19
171 ± 12*
Albumin, g/L
31 ± 2
31 ± 1
Iron, μmol/L
13 ± 3
15 ± 2
Vitamin E, μmol/L
13.0 ± 2.9
14.7 ± 1.0
Urate, μmol/L
253 ± 21
265 ± 17
Bilirubin, µmol/L
Means ± SEM
*p < 0.05 vs. samples before exchange
Exchange transfusions
used to treat
hyperbilirubinemia
decrease plasma
unconjugated bilirubin,
and thus total plasma
antioxidant capacity.
Belanger S, Lavoie J-C, & Chessex P. (1997). Influence of Bilirubin on the Antioxidant Capacity of
Plasma in Newborn Infants. Biology of the Neonate, 71: 233-238.
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Bilirubin and Exchange
Transfusion
• The decrease in TEAC after the exchange transfusion
was not likely caused by the transfusion itself.
• Belanger et al. discovered that the decrease could not
have been caused by hemolysis, as the infants with a
hemolytic disease showed no significant difference
from those without. They also verified that exchange
for adult blood was not the cause, as maternal blood
was found to have higher TEAC than neonatal blood.
Belanger S, Lavoie J-C, & Chessex P. (1997). Influence of Bilirubin on the Antioxidant
Capacity of Plasma in Newborn Infants. Biology of the Neonate, 71: 233-238.
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Bilirubin and the Premature Infant
• Premature infants have higher rates of bilirubin
production than do full term infants or adults
because their red blood cells have a higher
turnover rate and shorter life span.
• In addition, the liver of a premature infant is less
mature and therefore, less efficient at conjugating
bilirubin for excretion.
• Premature infants have fewer blood proteins
available to bind bilirubin and prevent it from
crossing the immature blood brain barrier.
Friel JK, Martin SM, Langdon M, Herzberg G, & Buettner GR. (2002). Human milk provides better antioxidant
protection than does infant formula. Pediatr Res, 51: 612-618.
Genna, Catherine W. (2005). Jaundice in the breastfed baby. Retrieved June 1, 2006, from
http://www.medela.com/NEWFILES/faq/jaundice.html
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Bilirubin and the Premature Infant
• Premature infants are also at increased risk of
oxidative stress from hypoxia due to the immaturity
of the lungs, followed by risk of hyperoxia once
mechanical ventilation proceeds. Premature infants
are often exposed to oxygen concentrations as high as
95%.
• Bilirubin administration provides protection against
retinopathy in premature infants.
Friel JK et al. (2002).
Dore S, Takahashi M, Ferris CD, Hester LD, Guastella D, & Snyder SH. (1999). Bilirubin, formed by
activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc. Natl. Acad. Sci.
USA, 96: 2445-2450.
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Oxidative Stress and Prematurity
• Neonates have impaired antioxidant defenses and are
susceptible to the development of oxygen free radical
mediated diseases.
• Neonatal blood has low content of glutathione peroxidase,
superoxide
dismutase,
-carotene,
riboflavin,
proteinase,
vitamin
E,
selenium,
copper,
zinc,
ceruloplasmin and other plasma factors.
• The premature brain is rich in polyunsaturated fatty
acids
that
are
easily
oxidized
compared
to
monounsaturated fatty acids.
Hammerman C. Goldstein R, Kaplan M, Eran M, Goldschmidt D, Eidelman AI, & Gartmer LM.
(1998). Bilirubin in the premature: Toxic waste or natural defense? Clinic Chem, 44: 2551-2553.
Gitto E, Reiter RJ, Karbownik M, Tan D, Gitto P, Barberi S, & Barberi I. (2002). Causes of
oxidative stress in the pre-and perinatal period. Biol Neonate, 81: 146-157.
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Oxidative Stress and Prematurity
(cont.)
For the premature infant, bilirubin has always been
considered a toxin. More recently bilirubin’s antioxidant
properties have been characterized. It is possible therefore,
that elevated bilirubin is an attempt by an immature fetus
to cope with increased exposure to ROS.
Ironically, in an attempt to rid the premature of bilirubin, we
may be eliminating a powerful antioxidant that could assist
the immature defense system under attack.
Is it possible that jaundice might actually be a natural defense
system that is necessary for survival of the premature infant?
Hansen TWR. (2001). Bilirubin production, breast-feeding and neonatal jaundice. Acta Paediatrica, 90: 716-723.
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Serum Bilirubin in Neonates Correlated
with Total Antioxidant Activity
(Hammerman et al., 1998) In contrast we did not find a relation
between bilirubin and tissue damage or antioxidant status in
small premature infants in the first month of life.
Friel J, Widness J, Jiang T, Belkhode SL, Rebouche CJ, & Ziegler EE. (2002). Antioxidant status and
oxidant stress are associated with vitamin E intakes in VLBW infants in early life. Nutr Res, 22: 55-64.
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Hyperbilirubinemia Protects Against
Lipid Peroxidation in Neonatal Gunn
Rats Exposed to Hyperoxia
Serum bilirubin in jaundiced and
non-jaundiced pups exposed to
95% O2 shows a negative
correlation with lipid
hydroperoxides at 3 days of
exposure. Higher serum
bilirubin concentrations resulted
in lower lipid hydroperoxide
levels.
Dennery PA, McDonagh AF, Spitz DR,
Rodgers PA, & Stevenson DK. (1995).
Hyperbilirubinemia results in reduced oxidative
injury in neonatal Gunn rats exposed to
hyperoxia. Free Radic Biol Med., 19: 395-404.
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Friel, Friesen & Miller 36
The Effect of Hyperbilirubinemia in
Neonatal Gunn Rats Exposed to
Hyperoxia
Dennery et al. also
showed that jaundiced
rats exposed to >95%
O2 showed higher
mean serum bilirubin
levels than jaundiced
rats exposed to 95%
O2 and 5% CO2 or
room air.
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Promise for the Future
It remains unclear as to how the knowledge of bilirubin’s
antioxidant properties can be used to assist in defense against
oxidative stress
Should elevated levels of bilirubin be allowed to persist for
an unknown period of time in order to protect the infant?
Where is the crossover to irreparable harm?
Should bilirubin be promoted as a supplemental antioxidant?
Can this important molecule provide similar benefits to a
larger population?
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