1. PENTOSE PHOSPHATE CYCLE
31
The mechanism for drug-induced hemolysis was suggested by Beutler
(219) and by Tarlov et al. (225). When the drug is administered to an
individual, the hemoglobin in the erythrocytes is oxidized. The oxidized
hemoglobin returns to the original state by converting GSH to GSSG.
This occurs only if the activity of G-6-P DH is sufficiently high, as
in the case of nonsensitive (normal) individuals. The drug-sensitive person, on the other hand, lacks this dehydrogenase and consequently the
supply of GSH will be exhausted. Following this the oxidized hemoglobin
becomes denatured and simultaneously forms Heinz bodies. Intervasal
hemolysis thus ensues. Akin to this problem are the findings that human
erythrocytes which are deficient in G-6-P DH cannot maintain their
levels of GSH in the presence of low level steady state concentrations
of hydrogen peroxide (226). It was suggested that this low level H 2 0 2 ,
resulting from the autoxidation of the drug (or intermediates therefrom),
causes in part the oxidative damage to the red blood cells.
The deficiency in the level of G-6-P DH may be due to at least
several factors (227): there is a real lack of the enzyme, there is an
inhibitor present, or there is a deficiency of an activator. Thus stromata
in hemolyzates of primaquine-sensitive and nonsensitive erythrocytes
inactivate G-6-P DH (228). In contrast to these results, Ramot et al.
showed that a factor existing in normal erythrocyte stroma can activate
the dehydrogenase of drug-sensitive red blood cells (229). To confuse
the picture further, Kidson and Gorman demonstrated that although
there is indeed a stromal activating factor, this factor failed to activate
the dehydrogenase in 20% of the cases (280). Hence there seems to be
a definite heterogeneity of response to stromal activation of G-6-P DH,
at least in erythrocytes of Melanesians.
The hemolytic activity of primaquine and primaquine-like drugs has
been clearly demonstrated in American Negroes with an incidence of the
order of 10%, in contrast to that in Caucasians with less than 1% (213,
219). Among the Jewish population the affliction was found in 20% of
the non-Ashkenazic Jews from Iraq and Persia, in 5% from Yemen and
Turkey, and in 2% from North Africa; 3% of the Arabs in Israel also
showed sensitivity to these drugs (231). The Mediterranean population
also has its share of this affliction, Sardinians (232), and Greeks (233)
having the usual symptoms along with sensitivity toward fava beans.
The enzyme deficiency trait is also common among East Africans (234)
and West Africans (235, 236). [It is interesting to note that among these
people difficulty may be encountered in blood sampling so that other
methods of sampling had to be devised. Tests showed that the G-6-P DH
levels in the saliva and skin of drug-sensitive subjects are markedly lower
in activity, 0.54 units, than those of the nonsensitive cases, 8 units (237).]
31
The mechanism for drug-induced hemolysis was suggested by Beutler
(219) and by Tarlov et al. (225). When the drug is administered to an
individual, the hemoglobin in the erythrocytes is oxidized. The oxidized
hemoglobin returns to the original state by converting GSH to GSSG.
This occurs only if the activity of G-6-P DH is sufficiently high, as
in the case of nonsensitive (normal) individuals. The drug-sensitive person, on the other hand, lacks this dehydrogenase and consequently the
supply of GSH will be exhausted. Following this the oxidized hemoglobin
becomes denatured and simultaneously forms Heinz bodies. Intervasal
hemolysis thus ensues. Akin to this problem are the findings that human
erythrocytes which are deficient in G-6-P DH cannot maintain their
levels of GSH in the presence of low level steady state concentrations
of hydrogen peroxide (226). It was suggested that this low level H 2 0 2 ,
resulting from the autoxidation of the drug (or intermediates therefrom),
causes in part the oxidative damage to the red blood cells.
The deficiency in the level of G-6-P DH may be due to at least
several factors (227): there is a real lack of the enzyme, there is an
inhibitor present, or there is a deficiency of an activator. Thus stromata
in hemolyzates of primaquine-sensitive and nonsensitive erythrocytes
inactivate G-6-P DH (228). In contrast to these results, Ramot et al.
showed that a factor existing in normal erythrocyte stroma can activate
the dehydrogenase of drug-sensitive red blood cells (229). To confuse
the picture further, Kidson and Gorman demonstrated that although
there is indeed a stromal activating factor, this factor failed to activate
the dehydrogenase in 20% of the cases (280). Hence there seems to be
a definite heterogeneity of response to stromal activation of G-6-P DH,
at least in erythrocytes of Melanesians.
The hemolytic activity of primaquine and primaquine-like drugs has
been clearly demonstrated in American Negroes with an incidence of the
order of 10%, in contrast to that in Caucasians with less than 1% (213,
219). Among the Jewish population the affliction was found in 20% of
the non-Ashkenazic Jews from Iraq and Persia, in 5% from Yemen and
Turkey, and in 2% from North Africa; 3% of the Arabs in Israel also
showed sensitivity to these drugs (231). The Mediterranean population
also has its share of this affliction, Sardinians (232), and Greeks (233)
having the usual symptoms along with sensitivity toward fava beans.
The enzyme deficiency trait is also common among East Africans (234)
and West Africans (235, 236). [It is interesting to note that among these
people difficulty may be encountered in blood sampling so that other
methods of sampling had to be devised. Tests showed that the G-6-P DH
levels in the saliva and skin of drug-sensitive subjects are markedly lower
in activity, 0.54 units, than those of the nonsensitive cases, 8 units (237).]