Differences in the reactions of isomeric ortho- and para-aminophenols with hemoglobin.
The metabolites of phenacetin, 2-hydroxyphenetidine and 4-nitrosophenetol, rapidly produced ferrihemoglobin both in vivo (dogs) and in vitro. At low concns, 2-hydroxyphenetidine was superior to 4-nitrosophenetol in ferrihemoglobin formation. The kinetics of ferrihemoglobin formation by 2-hydroxyphenetidine in solutions of purified human hemoglobin was biphasic and exhibited an unusual dose response. Similar to p-aminophenols, 2-hydroxyphenetidine was oxidized by oxyhemoglobin, and the oxidation product(s) were reduced by ferrohemoglobin with the formation of ferrihemoglobin. In addition, these oxidation products condensed to 2-amino-7-ethoxy-3H-phenoxazine-3-one (u.v., i.r., 1H-NMR and mass spectroscopy). This metabolite produced ferrihemoglobin by itself and was responsible for the slow phase of ferrihemoglobin formation observed with 2-hydroxyphenetidine. This condensation reaction, which was also observed with 2-aminophenol, prevented thioether formation of the transient o-quinonimines with the cysteine residues of hemoglobin and reduced glutathione as observed with 4-aminophenol and 4-dimethylaminophenol. Phenoxazone formation, which depends on the square of the o-quinonimine concn, was negligible at micromolar concns. At similar concns addition reactions to thiols prevailed also with 2-hydroxyphenetidine and 2-aminophenol. Other electrophilic reactions, e.g. with primary amino groups of amino acids, were insignificant. These dose-dependent differences in the reactions of isomeric aminophenols may explain the low nephrotoxicity of those o-aminophenols capable of forming phenoxazones when given in a single dose. This self-detoxication of some o-quinonimines, however, should not function during long-term exposure to repetitive low doses of such o-aminophenols.
D000627:Aminophenols / Q000097:blood*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007536:Isomerism; D011485:Protein Binding
D000627:Aminophenols; D006454:Hemoglobins