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chapter 29
Metabolism of Iron and Heme
Heme proteins
Proteins»-'
Amino acids
(reutilized)
Heme
Heme oxygenase
system
Mononuclear
phagocytic cells
of spleen, bone
marrow, and liver
Urinary urobilinogen
(upto4mg/d)
Kidney
Î
Systemic
circulation
Biliverdin
- NAD(P)H + H+
Biliverdin reductase
—NAD(P)+
Bilirubin (250-300 mg/d)
Transported to the liver
complexed to albumin in the plasma
Enterohepatic
circulation
Biirubin in the
hepatocytes (bound
predominantly to ligandin)
,___ UDP-glucuronic acid
Bilirubin UDP-
glucuronyltransferase
^ — -UDP
Bilirubin monoglucuronide
,___ UDP-glucuronic acid
Bilirubin UDP-
alucuronyltransferase
* — -UDP
Secretion into bile
Biirubin diglucuronide
in bile and gall bladder
l
Bilirubin diglucuronide
in small bowel
1
Bilirubin large bowel
Metabolism by
fecal flora
-Urobilinogen (UBQ)
and other compounds
Excretion in the feces
(50-250 mg of urobilinogen per day)
F IG U R E 2 9 -1 0
Catabolic pathway for the heme group from hemoproteins (predominantly
hemoglobin).
Formation of Bilirubin
A summary of the pathway for bilirubin metabolism and
excretion is shown in Figure 29-10. Release of heme
from heme proteins and its conversion to bilirubin oc-
cur predominantly in the mononuclear phagocytes of
liver, spleen, and bone marrow (previously known as
the reticuloendothelial system), sites where sequestration
of aging red cells occurs. Renal tubular epithelial cells,
hepatocytes, and macrophages may also contribute to
bilirubin formation under some conditions. Structures of
the intermediates in the conversion of heme to bilirubin
are shown in Figure 29-11. The initial step after the re-
lease of heme is its binding to heme oxygenase, a micro-
somal enzyme distinct from the microsomal P-450 oxyge-
nases. Fleme oxygenase catalyzes what appears to be the
rate-limiting step in catabolism of heme. It is induced by
heme and requires O
2
and NADPH for activity. The activ-
ity of the inducible isoenzyme form of heme oxygenase
is highest in the spleen, which is involved in the seques-
tration of senescent erythrocytes. The constitutive form of
heme oxygenase is mainly localized in the liver and brain.
After binding, the a-methene carbon of heme is oxidized
(hydroxylated) to a-hydroxyhemin, which undergoes
autoxidation to biliverdin (a blue-green pigment) with con-
sumption of O
2
and release of iron and carbon monox-
ide (derived from oxidation of the a-methene bridge).
Since CO production in mammals occurs primarily by
this pathway, measurement of expired CO has been used
to estimate heme turnover. Values obtained exceed those
derived from plasma bilirubin measurements by about
15%, probably because of bilirubin produced in the liver
and excreted into the bile without entering the circula-
tion. A potent competitive synthetic inhibitor of heme
oxygenase is tin (Sn) protoporphyrin, which has a po-
tential therapeutic use in treatment of neonatal jaundice
(see below).
In nonmammalian vertebrates, biliverdin is the final
metabolite in heme catabolism. Transport of biliverdin is
much easier than that of bilirubin because biliverdin is
water-soluble. Conversion of biliverdin to bilirubin may
have evolved in mammals because, unlike biliverdin,
bilirubin readily crosses the placenta. In this way, the fetus
can eliminate heme catabolites via the mother’s circula-
tion. However, this explanation may not be complete, since
the rabbit (a placental mammal) excretes biliverdin as the
major bile pigment.
Biliverdin
is
reduced
to
bilirubin
by
NAD(P)H-
dependent biliverdin reductase, a cytosolic enzyme that
acts
at
the
central
methene bridge.
Although both
molecules have two propionic acid groups, the polarity
of biliverdin is greater than that of bilirubin. Bilirubin
can form six internal hydrogen bonds between the car-
boxylic groups, the two lactam carbonyl oxygens, and
four pyrrolenone ring nitrogens, and thus prevents these
groups from hydrogen-bonding with water (Figure 29-12).
Biliverdin cannot form these hydrogen bonds because of
the lack of free rotation imposed by the double bond at
the central methene bridge. Esterification of the propi-
onyl side chains of bilirubin with glucuronic acid disrupts
the hydrogen bonds and increases its solubility and la-
bility. “Activators,” such as ethanol and methanol, used
in the van den Bergh test to measure “indirect bilirubin,”
and phototherapy for neonatal jaundice also act by dis-
rupting the hydrogen-bonded structure of unconjugated
bilirubin.
Hemoglobin and heme released from intravascular
hemolysis or blood extravasations (e.g., subcutaneous
hematomas) are bound, respectively, by
haptoglobin
and
