Bilirubin Processing and Degradation

Production
When red blood cells are delivered from the bone marrow
into the circulatory system, they normally circulate an
average of 120 days before being destroyed. Even
though mature red cells do not have a nucleus,
mitochondria, or endoplasmic reticulum, they do have
cytoplasmic enzymes that are capable of metabolizing
glucose and forming small amounts of ATP. These
enzymes also (1) maintain pliability of the cell
membrane, (2) maintain membrane transport of ions, (3)
keep the iron of the cells' hemoglobin in the ferrous form
rather than ferric form, and (4) prevent oxidation of the
proteins in the red cells. Even so, the metabolic systems
of old red cells become progressively less active and the
cells become more and more fragile, presumably
because their life processes wear out.
Once the red cell membrane becomes fragile, the cell
ruptures during passage through some tight spot of the
circulation. Many of the red cells self-destruct in the
spleen, where they squeeze through the red pulp of the
spleen. There, the spaces between the structural
trabeculae of the red pulp, through which most of the
cells must pass, are only 3 micrometers wide, in
comparison with the 8-micrometer diameter of the red
cell. When the spleen is removed, the number of old
abnormal red cells circulating in the blood increases
considerably.
When red blood cells burst and release their hemoglobin,
the hemoglobin is phagocytized almost immediately by
macrophages in many parts of the body, but especially
by the Kupffer cells of the liver and macrophages of the
spleen and bone marrow. During the next few hours to days, the macrophages release iron from
the hemoglobin and pass it back into the blood, to be carried by transferrin either to the bone
marrow for the production of new red blood cells or to the liver and other tissues for storage in
the form of ferritin. The porphyrin portion of the hemoglobin molecule is converted by the
macrophages, through a series of stages, into the bile pigment bilirubin, which is released into
the blood and later removed from the body by secretion through the liver into the bile
Human adults normally destroy about 200 billion erythrocytes per day. Thus, a 70-kg human
turns over approximately 6 g of hemoglobin daily. The globin is degraded to its constituent amino
acids, the released iron enters the iron pool, and all products are reused. The iron-free porphyrin
portion of heme is also degraded, mainly in the reticuloendothelial cells of the liver, spleen, and
bone marrow.
The catabolism of heme from all heme proteins is carried out in the microsomal fraction of cells
by heme oxygenase, EC 1.4.99.3. Heme oxygenase synthesis is substrate-inducible, and heme
also serves both as a substrate and as a cofactor for the reaction. The iron of the heme that
reaches heme oxygenase has usually been oxidized to its ferric form (hemin). Conversion of one

mole of heme-Fe3+ to biliverdin, carbon monoxide, and Fe3+ consumes three moles of O2, plus
seven electrons provided by NADH and NADPH cytochrome P450 reductase:
Fe3+-Heme + 3 O2 + 7 e- biliverdin + CO + Fe3+
Since 1 g of hemoglobin yields about 35 mg of bilirubin, human adults form 250 to 350 mg of
bilirubin per day. This is derived principally from hemoglobin, but also from ineffective
erythropoiesis, and from catabolism of other heme proteins. Conversion of heme to bilirubin by
reticuloendothelial cells can be observed visually as the purple color of the heme in a hematoma
slowly converts to the yellow pigment of bilirubin.
Bilirubin is only sparingly water-soluble, but bilirubin bound to serum albumin is readily
transported to the liver. Albumin appears to have both a high-affinity site and a low-affinity site
for bilirubin. The high-affinity site can bind approximately25 mg of bilirubin/100 mL of plasma.
More loosely bound bilirubin can readily be detached and diffuse into tissues, and antibiotics and
certain other drugs can compete with and displace bilirubin from albumin's high-affinity site
Hepatic catabolism of bilirubin takes place in three stages: uptake by the liver, conjugation with
glucuronic acid, and secretion in the bile.
Bilirubin is removed from albumin and taken up at the sinusoidal surface of hepatocytes by a
large capacity, saturable facilitated transport system. Even under pathologic conditions,
transport does not appear to be rate-limiting for the metabolism of bilirubin. The net uptake of
bilirubin depends upon its removal by subsequent metabolism. Once internalized, bilirubin binds
to cytosolic proteins such as glutathione S-transferase, previously known as a ligandin, to
prevent bilirubin from reentering the blood stream.
Bilirubin is nonpolar, and would persist in cells (eg, bound to lipids) if not converted to a more
water-soluble form. Bilirubin is converted to a more polar molecule by conjugation with
glucuronic acid. A bilirubin-specific UDP-glucosyl transferase (EC 2.4.1.17) of the endoplasmic
reticulum catalyzes stepwise transfer to bilirubin of two glucosyl moieties from UDP-glucuronate:
Secretion of conjugated bilirubin into the bile occurs by an active transport mechanism, which
probably is rate-limiting for the entire process of hepatic bilirubin metabolism. The protein
involved is a multispecific organic anion transporter (MOAT) located in the plasma membrane of
the bile canaliculi. A member of the family of ATP-binding cassette transporters, MOAT transports
a number of organic anions. The hepatic transport of conjugated bilirubin into the bile is
inducible by the same drugs that can induce the conjugation of bilirubin. Conjugation and
excretion of bilirubin thus constitute a coordinated functional unit. Most of the bilirubin excreted
in the bile of mammals is bilirubin diglucuronide. Bilirubin UDP-glucuronosyl transferase activity
can be induced by several drugs, including phenobarbital. However, when bilirubin conjugates
exist abnormally in human plasma (eg, in obstructive jaundice), they are predominantly
monoglucuronides.
Function

Degradation