title: Generation of quinoneimine intermediates in the bioactivation of 3-(N-phenylamino)alanine (PAA) by human liver microsomes: a potential link between eosinophilia-myalgia syndrome and toxic oil syndrome.
abstract: Eosinophilia-myalgia syndrome (EMS) was an intoxication episode that occurred in the US in 1989 and affected 1,500 people. EMS was associated with the ingestion of manufactured L-tryptophan, and 3-(N-phenylamino)alanine (PAA) was identified as one of the contaminants present in the L-tryptophan batches responsible for intoxication. In previous studies (Martínez-Cabot et al., Chem Res. Toxicol., in press), we have shown that the incubation of 3-(N-phenylamino)propane-1,2-diol (PAP), a toxic biomarker of the oil batches that caused Toxic Oil Syndrome in Spain, with human liver microsomes generates a reactive quinoneimine intermediate. The structural similarity between PAA and PAP led Mayeno and co-workers (Mayeno et al. (1995) Chem. Res. Toxicol. 8, 911-916) to hypothesize that both xenobiotics could be linked to a common etiologic agent. We thus set about to study the bioactivation of PAA by human liver microsomes. Under these conditions, PAA is converted to its 4'-hydroxy derivative, an unstable intermediate that is rapidly transformed into the final metabolites 4-aminophenol and formylglycine, which were identified in the incubations by GC/MS using the H2(18)O-labeled medium. We also provide evidence that 4-aminophenol and formylglycine are formed from a quinoneimine intermediate via a pathway similar to that demonstrated for PAP bioactivation. This quinoneimine, in the absence of nucleophiles in the incubation medium, could isomerize to give the corresponding imine, which could undergo hydrolysis to yield the aforementioned final products. These findings establish that EMS and TOS are linked by a common toxic metabolite (4-aminophenol) and that they may be further linked by the concomitant release of potentially hazardous carbonyl species.
authors: Department of Biological Organic Chemistry, Institut d'Investigacions Químiques i Ambientals de Barcelona, Spain.
authors: Anna
authors: A
authors: Martínez-Cabot
authors: Angel
authors: A
authors: Messeguer
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004196:Disease Outbreaks; D016603:Eosinophilia-Myalgia Syndrome / Q000209:etiology / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated; D005506:Food Contamination; D005517:Foodborne Diseases / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010938:Plant Oils / Q000633:toxicity*; D011809:Quinones / Q000378:metabolism*; D000074262:Rapeseed Oil; D013030:Spain; D021241:Spectrometry, Mass, Electrospray Ionization; D014364:Tryptophan / Q000633:toxicity*
chemical_list: D005229:Fatty Acids, Monounsaturated; D010938:Plant Oils; D011809:Quinones; D000074262:Rapeseed Oil; C116897:iminoquinone; C078798:3-(phenylamino)alanine; D014364:Tryptophan; D000409:Alanine