section 28.4
Derivatives of Hemoglobin
673
hemoglobins differ among themselves and from that
of normal metHb.
Theoretically, hereditary methemoglobinemia could oc-
cur if the hemoglobin was altered in that region where
methemoglobin reductase binds in performing its func-
tion. In such a mutant Hb, the reductase would not bind.
Acquired acute methemoglobinemia is a relatively com-
mon condition caused by a variety of drugs such as
phenacetin, aniline, nitrophenol, aminophenol, sulfanil-
amide, and inorganic and organic nitrites and nitrates.
The condition is less commonly produced by chlorates,
ferricyanide, pyrogallol, sulfonal, and hydrogen perox-
ide. These compounds appear to catalyze the oxidation
of Hb by oxygen. Symptoms include brownish cyanosis,
headache, vertigo, and somnolence. Diagnosis is based
on occurrence of brownish cyanosis and presence of ex-
cessive amounts of metHb (measured spectrophotometri-
cally). Treatment usually consists of removal of the of-
fending substance and administration of ascorbic acid (in
mild cases) or methylene blue (in severe cases). These re-
ducing agents function according to the reactions below
(MB = methylene blue, oxidized; MBH
2
= methylene
blue, reduced).
MBH
2
MB + H2(gas)
2H2(gas) + Hb(Fe
3 + ) 4
-* Hb(Fe2+) + 4H+
(The release of H
2
by MBH
2
is spontaneous because
methylene blue is autoxidizable.)
/ o=c-------\
HO—c
I
HO—c
H—c
HO—CH
\
CH2OH
y
O
Ascorbic acid
(vitamin C)
4H+
Hb(Fe+3)4
Hb(Fe+2)4
/ o = c -
o=c
o=c
H—c—
HO— CH
\
o
\
ch2oh
7
Dehydroascorbic acid
Sulfhemoglobin
Many drugs that cause methemoglobinemia also stimu-
late production of sulfhemoglobin, a greenish derivative.
Methemoglobin and sulfhemoglobin may appear together
in poisoning by phenacetin, acetanilid, or sulfanilamide.
Dapsone (used to treat leprosy) and exposure to sulfur-
containing compounds either occupationally or from air
pollution can also produce sulfhemoglobinemia. The sul-
fur appears to attach covalently to the porphyrin ring rather
than to the iron atom. It is unclear whether the sulfur
is derived from hydrogen sulfide generated by anaerobic
metabolism of intestinal bacteria, from glutathione, or
from some other source.
Because of its color, patients with circulating sulfhe-
moglobin appear cyanotic like those with methemoglo-
binemia. However, unlike methemoglobinemia, sulfhe-
moglobinemia cyanosis becomes clinically apparent at
extremely low concentrations and is usually not accom-
panied by cardiopulmonary pathology. This fact, together
with the overlap in the list of causative agents, may lead
to underdiagnosis of sulfhemoglobinemia. Both sulfHb
and metHb show an absorption peak at about 620 nm that
is not present in deoxyHbA (the most common cause of
cyanosis). They can be discriminated by changes in this
peak on addition of cyanide, carbon monoxide, or dithio-
nite (a reducing agent). Isoelectric focusing of samples
treated with the same chemicals is also useful for differ-
ential diagnosis.
Oxygen does not bind to a subunit having a sulfurated
porphyrin ring. The presence of one or two such subunits,
together with normal subunits in a hemoglobin tetramer,
alters the cooperativity, favors the deoxy structure, and
thereby decreases the oxygen affinity of the normal sub-
units. Thus, at low levels of sulfuration, the percentage
of affected hemoglobin tetramers is greater than the per-
centage of sulfurated monomers. (This is also true of the
methemoglobins). In contrast, binding of carbon monox-
ide to one or two subunits increases the oxygen affinity
of the tetramer, since CO stabilizes the oxyhemoglobin
conformation.
In
a person
who
has
HbA
as
the
predominant
hemoglobin, the presence of sulfhemoglobin is probably
innocuous. Tissue oxygenation is relatively normal be-
cause the decrease in the number of binding sites for oxy-
gen is offset by the lower binding affinity. However, since
sulfuration stabilizes the deoxy form, sulfhemoglobin,
in individuals who have sickle cell anemia, should in-
crease the likelihood of sickling and thereby exacerbate
the disease. No way is known to reverse formation of
sulfhemoglobin. If the causative agent is removed, sulfhe-
moglobin will disappear from the circulation at the same
rate as that of the erythrocytes that contain it.
Cyanmethemoglobin
Cyanide poisoning does not cause production of cyanohe-
moglobinemia or cyanosis. It does produce cytotoxic
anoxia by poisoning cytochrome oxidase and other res-
piratory enzymes, thereby preventing utilization of
0
2
by
tissues. Cyanide poisoning is detected by the character-
istic odor of HCN gas (odor of bitter almonds) on the
breath and by laboratory tests (absorption spectra, tests for
CN-).
