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CHAPTER 28
Hemoglobin
binding of CO and to its action as an allosteric activator,
with the result that hemoglobin is trapped in the R-state.
Carbon monoxide poisoning may result from breath-
ing automobile exhaust, poorly oxygenated coal fires
in stoves and furnaces, or incomplete combustion of a
carbon-containing compound. Breathing air containing
1% CO for 7 minutes can be fatal; automobile exhaust
contains about 7% CO. Unconsciousness, a cherry-red dis-
coloration of the nail beds and mucous membranes (due to
large amounts of R-state carbon monoxide-hemoglobin),
and spectrophotometric analysis of the blood are useful
for clinical diagnosis.
Treatment of carbon monoxide poisoning consists of
breathing a mixture of 95% O
2
and 5% CO
2
, which
will usually eliminate carbon monoxide from the body in
30-90 minutes, or of breathing hyperbaric oxygen.
The enzymatic oxidation of heme produces CO and
biliverdin in equimolar amounts (Chapter 29). The CO is
transported via the blood to the lungs, where it is released.
Although no cases are known in which endogenous CO
proved toxic, this carbon monoxide may contribute sig-
nificantly to air pollution, particularly in crowded and en-
closed areas.
Carbaminohemoglobin
Some of the CO
2
in the bloodstream is carried as car-
bamino compounds (Chapter 1). These compounds form
spontaneously in a readily reversible reaction between
CO
2
and the free a-amino groups in the N-terminal
residues of the Hb chains.
h 2n
n h 2
/ “ < > -<
+ 4 C 0 2
*
H2N
NHj
Hemoglobin
Although Hb can carry as many moles of CO
2
as of O
2
,
the HCO
3
system is a more important way of transporting
CO
2
. When the N-terminal amino groups are blocked by
carbamylation with CNO , no marked degree of acido-
sis develops. The carbamino groups decrease the affinity
of Hb for O
2
. The PCo
2
thus can affect oxygen affinity
independently of any effect it may have on pH and may
influence the position of the oxygen dissociation curve
under various conditions.
Methemoglobin
In the presence of oxygen, dissolved hemoglobin is slowly
oxidized to methemoglobin, a derivative of hemoglobin
in which the iron is present in the ferric (Fe3+) state. In
metHb, the ferric ion is bound tightly to a hydroxyl group
or to some other anion. The heme porphyrin (protopor-
phyrin IX) that contains an Fe3+ ion is known as
hemin.
A small but constant amount of methemoglobin is pro-
duced in the body. It is reduced by specific enzymes
(methemoglobin reductases) and NADH, which is gener-
ated in glycolysis. Reductases isolated from human red
cells also use NADPH but to a lesser extent. Inability
to reduce metHb produces
methemoglobinemiaand
tissue
anoxia.
Hereditary methemoglobinemia may arise from the
following:
1. Deficiency of one or more of the metHb reducing
enzymes (usually a recessive trait). MetHb values may
range from 10% to 40% of the total Hb (normal =
0.5%). Treatment involves administration of an agent
that will reduce the metHb (e.g., ascorbic acid,
methylene blue).
2. Defects in the hemoglobin molecule that make it
resistant to reduction by metHb reductases and
ascorbate or methylene blue. These hemoglobins are
collectively called the M hemoglobins (Table 28-5).
HbM is inherited as a dominant trait, since
homozygosity for an M /3-chain hemoglobin would
be lethal. In four types that involve an His -» Tyr
substitution, the phenolic hydroxyl group forms a
stable complex with Fe3+, making it resistant to
reduction to Fe2+. In HbM Milwaukee, a glutamic
acid residue substitutes for a valine at position 67 near
the distal histidine and forms a stable complex with
Fe3+. Although a brownish cyanosis is characteristic
of blood containing HbM, in contrast to the purplish
cyanosis caused by excess deoxyhemoglobin,
diagnosis should be confirmed by the absorption
spectrum of either the Hb or its CN- derivative. The
spectrum of the cyanide derivative is preferred, since
it differs more from that of HbA. Some of the M
hemoglobins cannot form CN- derivatives,
presumably because a Tyr or Glu blocks the sixth iron
position. In these cases, the absorption spectrum of
the methemoglobin itself must be examined. Because
of the change in the environment of the heme due to
the change in the globin structure, the spectra of M
