section 29.3
Heme Catabolism
synthase, produces
congenital erythropoietic porphyria.
Type I porphyrins (principally uroporphyrin I) are formed,
accumulate in the tissues, and are excreted in the urine.
The deficiency in production of the type III isomer
further increases levels of the type I isomers by re-
ducing the regulatory effect on ALA synthase. Exces-
sive amounts of porphyrins in erythrocytes may produce
hemolysis. A compensatory increase in hemoglobin for-
mation can then exaggerate the already increased pro-
duction of type I porphyrins. Their accumulation pro-
duces a pink to dark red color in teeth, bones, and urine.
Red-brown teeth and urine are pathognomonic. Patients
are sensitive to long-wave ultraviolet light and sunlight.
The abnormality is transmitted as an autosomal recessive
Erythropoietic protoporphyria
results from deficiency
of ferrochelatase in reticulocytes in bone marrow. It is
transmitted as an autosomal dominant trait with variable
penetrance and expressivity. In general, it is a benign dis-
order whose most prominent symptom is photosensitivity.
Occasionally, it leads to liver disease. Reduced fer-
rochelatase activity results in accumulation of protopor-
phyrin in maturing reticulocytes and young erythrocytes.
When a smear of these cells is exposed to fluorescent light,
they exhibit red fluorescence. The protoporphyrin appears
in the plasma, is picked up by the liver, and is excreted
into the bile. Protoporphyrin accumulation in the liver can
lead to severe liver disease. In contrast to individuals af-
flicted by other porphyrias, these patients have normal uri-
nary porphyrin levels. High levels of protoporphyrin are
found in erythrocytes, plasma, and feces. The photosen-
sitivity may be caused by stimulation of protoporphyrin
in dermal capillaries to an excited (triplet) state by visible
light. This in turn converts molecular oxygen to singlet
oxygen, which produces cell damage. Oral administration
of /
-carotene decreases the photosensitivity, possibly ow-
ing to a quenching effect on singlet oxygen and free-radical
29.3 Heme Catabolism
When heme proteins are degraded in mammals, the
polypeptides are hydrolyzed to amino acids while the
heme groups are freed of their iron, which is salvaged,
and are converted to bilirubin. After transport to the liver,
bilirubin is coupled to glucuronic acid and the conjugated
bilirubin is excreted into bile as the principal bile pig-
ment. When increased production or decreased excretion
of bilirubin causes its plasma concentration to exceed
1.0 mg/dL (2-17 /zmol/L), it diffuses into tissues and
produces jaundice. Although jaundice is relatively harm-
less unless due to extremely high concentrations of un-
conjugated bilirubin, it indicates the presence of a disease
process that requires medical attention. The yellow col-
oration of jaundiced skin and sclerae has aroused much
interest and has made bilirubin the subject of extensive
research. Fractionation and quantitation of serum biliru-
bin are now widely used for diagnosis and prognosis of
hepatobiliary disease.
Bilirubin is a waste product and has no known benefi-
cial physiological function. However, both the conjugated
and the unconjugated forms of bilirubin show antioxida-
tive properties (e.g., inhibition of lipid peroxidation). The
physiological role of the antioxidative property of biliru-
bin is not known.
Bilirubin is a yellow-orange pigment that in its un-
conjugated form is strongly lipophilic and cytotoxic. It
is virtually insoluble in aqueous solutions below pH
but readily dissolves in lipids and organic solvents and
diffuses freely across cell membranes. Bilirubin toxicity
is normally prevented by tight binding to serum albu-
min. Only when the binding capacity of albumin is ex-
ceeded can a significant amount of unconjugated biliru-
bin enter cells and cause damage. Conjugated bilirubin is
hydrophilic and does not readily cross cell membranes,
even at high concentrations. Of the 250-300 mg (4,275-
5,130 /zmol) of bilirubin normally produced in 24 hours,
about 70-80% is derived from hemoglobin. The remain-
der comes from several sources, including other heme
proteins (e.g., cytochromes P-450 and bj, catalase), in-
effective hemopoiesis (erythrocytes that never leave the
marrow), and “free” heme (heme never incorporated into
protein) in the liver. Hemoglobin heme has a life span
equal to that of the red cell (about 125 days), whereas
heme from other sources (with the exception of myo-
globin, which is also quite stable) turns over much more
rapidly. Hepatic P-450 enzymes have half-lives of 1-2
days. When radioactively labeled glycine or ALA is in-
jected and radioactivity in fecal bile pigments is moni-
tored, two peaks are seen. The rapidly labeled bilirubin
(early bilirubin) peak appears 3-5 days after injection
and contains about 15-20% of the injected label. It is in-
creased by drugs that induce hepatic P-450 oxygenases and
in erythropoietic porphyria and anemias associated with
ineffective erythropoiesis (lead poisoning, thalassemias,
and some hemoglobinopathies). Thus, the bilirubin in
the early peak is partly derived from these sources. The
slowly labeled bilirubin (late bilirubin) peak appears
at approximately 120 days, contains about 80-85% of
the label, and is due to heme released from senescent
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