iminoquinone and 3-phenylamino-1-2-propanediol

Toxic oil syndrome (TOS) was a massive food-borne intoxication that occurred in Spain in 1981. Epidemiological studies imputed 3-( N-phenylamino)propane-1,2-diol (PAP) derivatives as the toxic agents. The in vitro bioactivation of PAP by rat and human liver microsomes was studied. In both cases, 3-[ N-(4'-hydroxyphenyl)amino]propane-1,2-diol ( 1) was detected as the main metabolite. Inhibition studies with pooled human liver microsomes in the presence and absence of P450-specific inhibitors suggest that 2C8 and 2E1 are the main enzymes involved in PAP bioactivation, followed by 3A4/5, 1A1/2, and 2C9. Incubations of PAP with 10 different recombinant P450 enzymes showed that 2C8, 2C9, 2C18, 2D6, and 2E1 catalyzed PAP 4'-hydroxylation. Incubations of phenol 1 with rat and human liver microsomes in the presence of GSH resulted in the formation of a glutathione conjugate of a quinoneimine metabolite derived from 1. In rat liver microsomes, P450 enzymes play a key role in the bioactivation of 1, whereas in human liver microsomes, autoxidation appears to be the major mechanism. The implications of these results for toxic oil syndrome are discussed.

Topics: Animals; Biotransformation; Catalysis; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Food Contamination; Foodborne Diseases; Humans; Microsomes, Liver; Oxidation-Reduction; Plant Oils; Propylene Glycols; Quinones; Rapeseed Oil; Rats; Recombinant Proteins; Spain; Substrate Specificity; Time Factors

Epidemiological studies have pointed to fatty acid mono- and diesters of 3-(N-phenylamino)propane-1,2-diol (PAP) as the biomarkers of the toxic oil batches that caused toxic oil syndrome (TOS), an intoxication episode that occurred in Spain in 1981, causing over 400 deaths and affecting more than 20000 people. The biotransformation of PAP administered intraperitoneally to two mouse strains produced potentially toxic metabolites. The identification of 3-(4'-hydroxyphenylamino)propane-1,2-diol among those metabolites was important because the compound can generate the quinoneimine intermediate 2. The potential toxicity of quinoneimines has been attributed primarily to their electrophilic character. Accordingly, the reactions of 2 with N-acetylcysteine, N-acetylcysteine methyl ester, and GSH were investigated. Quinoneimine 2 reacts with the N-acetylcysteine methyl ester to give the expected conjugate as a major product, accompanied by the corresponding bis and tris adducts. The monoadduct, when isolated in pure form, undergoes spontaneous oxidation to generate a new quinoneimine intermediate, which in turn rearranges and undergoes hydrolysis to afford the thiol adduct formally derived from the quinoneimine generated from p-aminophenol. The same overall pathway was observed for the reaction of 2 with N-acetylcysteine and GSH. Both thiol reagents reacted with the quinoneimine to give the corresponding adducts in which the addition took place at the ortho position with respect to the amino group. These conjugates were also unstable and ultimately afforded the corresponding adduct derived from p-aminophenol. The relevancy of these results to TOS, as well as their potential generalization for quinoneimines derived from other xenobiotics, is discussed herein.

Topics: Acetylcysteine; Biotransformation; Fatty Acids, Monounsaturated; Food Contamination; Foodborne Diseases; Glutathione; Humans; Plant Oils; Propylene Glycols; Quinones; Rapeseed Oil; Syndrome