The toxicity of free heme has been documented in several
disease types. For example, in hemolytic anemias such as sickle cell disease
and thalassemia, release of heme from hemoglobin following lysis of red bloodcells is known to cause cell death. In a critical care situation such as
hemorrhagic injury, neuronal cell death is caused by the lysis of red blood
cells, which release hemoglobin and its breakdown product hemin. Physiological
levels of free heme in the blood are maintained at low levels (0.1 -1 μM) by
the high binding affinity of proteins such as serum albumin, hemopexin and
haptoglobin.
When internalized, free heme is catabolized by heme oxygenases
(HO1 and HO2 isoforms) and therefore the amount of cellular damage free hemeproduces is limited by the stress-responsive HO1 isoform. In addition to HO1
and HO2 isoform regulated cellular damage, the oxidative state of iron (from
Fe2+ to Fe3+ via the Fenton reaction) within heme can produce harmful
superoxide free radicals in the brain that can lead to oxidative stress,
initiation of lipid peroxidation and neuronal death.
