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278 / CHAPTER 32
indicated in Figures 32–9 and 32–11. Their oxidation
products, the corresponding porphyrin derivatives,
cause photosensitivity, a reaction to visible light of
about 400 nm. The porphyrins, when exposed to light
of this wavelength, are thought to become “excited”
and then react with molecular oxygen to form oxygen
radicals. These latter species injure lysosomes and other
organelles. Damaged lysosomes release their degradative
enzymes, causing variable degrees of skin damage, in-
cluding scarring.
The porphyrias can be classifiedon the basis of the
organs or cells that are most affected. These are gener-
ally organs or cells in which synthesis of heme is partic-
ularly active. The bone marrow synthesizes considerable
hemoglobin, and the liver is active in the synthesis of
another hemoprotein, cytochrome P450. Thus, one
classification of the porphyrias is to designate them as
predominantly either erythropoietic or hepatic; the
types of porphyrias that fall into these two classes are so
characterized in Table 32–2. Porphyrias can also be
classified as acute or cutaneous on the basis of their
clinical features. Why do specific types of porphyria af-
fect certain organs more markedly than others? A par-
tial answer is that the levels of metabolites that cause
damage (eg, ALA, PBG, specific porphyrins, or lack of
heme) can vary markedly in different organs or cells de-
pending upon the differing activities of their heme-
forming enzymes.
As described above, ALAS1 is the key regulatory en-
zyme of the heme biosynthetic pathway in liver. A large
number of drugs(eg, barbiturates, griseofulvin) induce
the enzyme. Most of these drugs do so by inducing cy-
tochrome P450 (see Chapter 53), which uses up heme
and thus derepresses (induces) ALAS1. In patients with
porphyria, increased activities of ALAS1 result in in-
creased levels of potentially harmful heme precursors
prior to the metabolic block. Thus, taking drugs that
cause induction of cytochrome P450 (so-called micro-
somal inducers) can precipitate attacks of porphyria.
The diagnosisof a specific type of porphyria can
generally be established by consideration of the clinical
and family history, the physical examination, and ap-
propriate laboratory tests. The major findings in the six
principal types of porphyria are listed in Table 32–2.
High levels of leadcan affect heme metabolism by
combining with SH groups in enzymes such as fer-
rochelatase and ALA dehydratase. This affects por-
phyrin metabolism. Elevated levels of protoporphyrin
are found in red blood cells, and elevated levels of ALA
and of coproporphyrin are found in urine.
It is hoped that treatmentof the porphyrias at the
gene level will become possible. In the meantime, treat-
ment is essentially symptomatic. It is important for pa-
tients to avoid drugs that cause induction of cyto-
chrome P450. Ingestion of large amounts of carbohy-
drates (glucose loading) or administration of hematin (a
hydroxide of heme) may repress ALAS1, resulting in di-
minished production of harmful heme precursors. Pa-
tients exhibiting photosensitivity may benefit from ad-
ministration of β-carotene; this compound appears to
lessen production of free radicals, thus diminishing
photosensitivity. Sunscreens that filter out visible light
can also be helpful to such patients.
CATABOLISM OF HEME
PRODUCES BILIRUBIN
Under physiologic conditions in the human adult, 1–2
×10
8
erythrocytes are destroyed per hour. Thus, in 1
day, a 70-kg human turns over approximately 6 g of he-
moglobin. When hemoglobin is destroyed in the body,
globin is degraded to its constituent amino acids,
which are reused, and the ironof heme enters the iron
pool, also for reuse. The iron-free porphyrinportion of
heme is also degraded, mainly in the reticuloendothelial
cells of the liver, spleen, and bone marrow.
The catabolism of heme from all of the heme pro-
teins appears to be carried out in the microsomal frac-
tions of cells by a complex enzyme system called heme
oxygenase.By the time the heme derived from heme
proteins reaches the oxygenase system, the iron has usu-
ally been oxidized to the ferric form, constituting
hemin. The heme oxygenase system is substrate-in-
ducible. As depicted in Figure 32–12, the hemin is re-
duced to heme with NADPH, and, with the aid of
more NADPH, oxygen is added to the α-methenyl
bridge between pyrroles I and II of the porphyrin. The
ferrous iron is again oxidized to the ferric form. With
the further addition of oxygen, ferric ionis released,
carbon monoxide e is produced, and an equimolar
quantity of biliverdinresults from the splitting of the
tetrapyrrole ring.
In birds and amphibia, the green biliverdin IX is ex-
creted; in mammals, a soluble enzyme called biliverdin
reductasereduces the methenyl bridge between pyrrole
III and pyrrole IV to a methylene group to produce
bilirubin,a yellow pigment (Figure 32–12).
It is estimated that 1 g of hemoglobin yields 35 mg
of bilirubin. The daily bilirubin formation in human
adults is approximately 250–350 mg, deriving mainly
from hemoglobin but also from ineffective erythro-
poiesis and from various other heme proteins such as
cytochrome P450.
The chemical conversion of heme to bilirubin by
reticuloendothelial cells can be observed in vivo as the
purple color of the heme in a hematoma is slowly con-
verted to the yellow pigment of bilirubin.
