The red cell as a sensitive target for activated toxic arylamines.
During biotransformation of arylamines, activated phase I metabolites, like aminophenols and hydroxylamines, occasionally escape the liver and exert allergic, toxic or carcinogenic effects in sensitive target organs. The first organ in contact with these proximate toxic compounds is the blood where oxyhemoglobin activates proximate to ultimate toxic derivatives. Thereby hydroxylamines and oxyhemoglobin are co-oxidized to nitrosoarenes and ferrihemoglobin. Because of an enzymic cycle, severe methemoglobinemia can occur even with small, catalytic amounts of hydroxylamines. Reactive oxygen intermediates, if not eliminated enzymically, may be responsible for hemolysis, Heinz body formation, and green pigments. In addition, nitrosoarenes bind covalently to hemoglobin and membranes and deplete glutathione by formation of glutathione-sulfinamides. Aminophenols, on the other hand, have to be activated first by oxyhemoglobin to phenoxyl radicals and quinonimines, which are reduced back with simultaneous ferrihemoglobin formation. Hence, aminophenols catalytically transfer electrons from iron to oxygen. This catalytic cycle is terminated by side reactions: p-quinonimines form adducts with glutathione and hemoglobin. Thereby the physiological functions of hemoglobin can be greatly altered as shown for 4-dimethylaminophenol. o-Quinonimines either condense to the respective phenoxazones, or if condensation is hindered, they form adducts, mainly with thiols. The different pathways for o-aminophenols are concentration-dependent, with adduct formation being favoured at low concentrations. Thus, methemoglobin formation poorly correlates with the implications of reactive electrophilic intermediates.
D000588:Amines / Q000633:toxicity*; D000627:Aminophenols / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D004912:Erythrocytes / Q000187:drug effects*; D006801:Humans; D007536:Isomerism; D051381:Rats
D000588:Amines; D000627:Aminophenols