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The red cell as a sensitive target for activated toxic arylamines
Archives of Toxicology. Supplement. = Archiv Fur Toxikologie. Supplement
|January 1, 1983
Summary
Arylamine metabolites can cause toxicity by damaging blood cells. Hydroxylamines and aminophenols trigger reactions with oxyhemoglobin, leading to methemoglobinemia and altered hemoglobin function.
Area of Science:
- Toxicology
- Biochemistry
- Medicinal Chemistry
Background:
- Biotransformation of arylamines produces reactive metabolites.
- These metabolites can escape the liver and cause organ toxicity.
- The blood is the primary site for activation of these toxic compounds.
Purpose of the Study:
- To elucidate the mechanisms by which arylamine metabolites cause toxicity in blood.
- To understand the role of oxyhemoglobin in activating these toxic intermediates.
- To investigate the pathways leading to methemoglobinemia and hemoglobin damage.
Main Methods:
- In vitro studies involving oxyhemoglobin and arylamine metabolites (aminophenols, hydroxylamines).
- Spectroscopic analysis to monitor redox changes and adduct formation.
- Assessment of reactive oxygen species generation and glutathione depletion.
Main Results:
- Hydroxylamines and oxyhemoglobin co-oxidize to nitrosoarenes and ferrihemoglobin, causing methemoglobinemia.
- Nitrosoarenes bind to hemoglobin and deplete glutathione.
- Aminophenols are activated by oxyhemoglobin to radicals and quinonimines, leading to ferrihemoglobin formation and adducts with glutathione and hemoglobin.
- Quinonimine pathways are concentration-dependent, influencing adduct formation.
Conclusions:
- Arylamine metabolites exert toxicity through redox cycling with oxyhemoglobin.
- Methemoglobinemia and hemoglobin adduct formation are key mechanisms of toxicity.
- The reactivity of metabolites and their interactions with hemoglobin can lead to severe blood disorders.