Methemoglobin And Hemolytic Anemia As
Potential Markers For Drug Side-effects
Author(s)
H. Singh & E. T. Purnell
Abstract
Methemoglobinemia and hemolytic anemia are the most prominent side-effects
of a wide variety of arylamine drugs including agricultural and industrial
chemicals. Symptoms of this hemotoxicity include headache, fatigue, dizziness
respiratory and cardiac arrest, and possibly death. Parent compounds are usually
converted to their toxic metabolites (N-hydroxylamine) and react with
oxyhemoglobin with the consequent reduction of molecular oxygen to active
oxygen species leading to hemotoxic damage. We are investigating the role of
redox cycling and an alternative hypothesis; viz., that a \“hydroxylaminecentered”
radical formed during an arylhydroxylamine-oxyhemoglobin reaction
causes hemotoxic damage. We examined the time-course methemoglobin
potential and hemolytic anemia potential of four laboratory synthesized
halogenated phenylhydroxylamines based on their decreasing electronegativity:
phenylhydroxylamine (PHA), p-fluoro-, p-bromo-, and p-iodo-PHA.
Methemoglobin (MetHb) was determined spectrophotometrically and
erythrocyte hemolysis was studied by collecting whole blood from male
Sprague-Dawley rats, labeling the cells with radioactive chromium-51 and by
infusing the labeled erythrocytes via tail vein in isologous rats. The time course
of blood radioactivity was followed by serial sampling of blood from the orbital
sinus for 14 days. Results showed dose- and time-dependent changes in the
induction of methemoglobin by aniline-derivatives. The MetHb levels peaked to
more than 70 percent within 10 minutes at 60 µM and remained elevated for 240
minutes in certain treatments. All tested agents produced dose-dependent
reductions in the labeled red blood cells indicating the loss of blood cells from
circulation. The dose- and time-dependent methemoglobin and hemolytic anemia
responses suggest these hydroxylamines as potential active metabolites and
biomarkers that may mediate aniline-induced hemotoxicity. The minimum dose
required to induce these effects varies with the test agent based on their
electronegativity potential.
Keywords: aniline, methemoglobin, hemolytic anemia, hemoglobin biomarkers,
halogenated phenylhyroxylamines.
Keywords
aniline, methemoglobin, hemolytic anemia, hemoglobin biomarkers,
halogenated phenylhyroxylamines.
Related Book
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