Metabolism
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An adverse response to antimalarial medication -
Samuel
W is an African-American recruit to the army. He was given the antimalarial
drug primaquine, and suffered a delayed reaction with kidney pain, dark urine,
and low red blood cell counts that led to anaemia and weakness. Centrifugation
of a blood sample showed a low haematocrit, and the plasma was red coloured.
Similar acute haemolytic attacks have been observed, predominantly in men of Afro-Caribbean origin, in response to primaquine and a variety of other drugs, including dapsone, the antipyretic acetylphenylhydrazine, the antibacterial bactrim/septrim, sulphonamides and sulphones, whose only common feature is that they all undergo cyclic non-enzymic reactions in the presence of oxygen to produce hydrogen peroxide and a variety of oxygen radicals that can cause oxidative damage to membrane lipids, leading to haemolysis. Moderately severe infection can also precipitate a haemolytic crisis in susceptible people.
Why do you think that infection can lead to a haemolytic crisis in susceptible people?
Part of the response to infection is activation of macrophages to produce a mixture of oxygen and other radicals that are cytotoxic to engulphed micro-organisms. This leads to an increase in whole body radical burden, and increased oxidative damage to cell membranes.
One way of screening for sensitivity to primaquine is based on the observation that the glutathione concentration of erythrocytes from sensitive subjects is somewhat lower than that of control subjects, and falls considerably on incubation with acetylphenylhydrazine.
Glutathione (GSH) is a tripeptide, gamma-glutamyl-cysteinyl-glycine, which readily undergoes oxidation to form a disulphide-linked hexapeptide, oxidised glutathione, generally abbreviated to GSSG
The table below shows the concentrations of GSH and GSSG in red cells from 10 control subjects, and Samuel W, before and after incubation with acetylphenylhydrazine.
The effect of incubation with 330 µmol /L acetylphenylhydrazine on erythrocyte glutathione.
controls |
Samuel W |
|||
GSH mmol /L |
GSSG µmol /L |
GSH mmol /L |
GSSG µmol /L |
|
| initial | 2.01 ± 0.29 |
4.2 ± 0.61 |
1.61 |
400 |
| + acetylphenylhydrazine | 1.82 ± 0.24 |
190 ± 28 |
0.28 |
1540 |