3-(n-phenylamino)-1-2-propanediol-1-2-dioleoyl-ester and Poisoning

The ingestion of rapeseed oil batches denatured with aniline and illegally refined and distributed by street vendors was responsible for toxic oil syndrome (TOS), an intoxication episode that took place in Spain in 1981, causing over 400 deaths and affecting more than 20,000 people. Despite the intense research efforts carried out to date, the compounds responsible for that intoxication have not been elucidated. Nevertheless, epidemiological studies have pointed to fatty acid mono- and diesters of 3-phenylamino-1,2-propanediol (PAP) as the biomarkers of those toxic oil batches. The structure of these esters bears common features with that of triglycerides, which suggested that PAP esters could follow the route of lipids metabolism up to a certain extent. The incubation of racemic PAP dioleyl ester with human pancreatic lipase (hPL) led to the formation of the corresponding stereoisomeric monoesters bearing the oleyl residue at C-2, although a kinetic resolution in favor of the (S)-enantiomer was observed. These monoesters are unstable and in equilibrium with their corresponding regioisomers with the acyl residue at C-1, apparently without the intervention of the lipase. Finally, incubations of these latter monoesters with hPL led to the formation of the respective PAP enantiomers. Again, the kinetic resolution of this hydrolytic process favored the formation of the enantiomer with the (S)-configuration. Taken together, these results showed that PAP esters are substrates of hPL and that the two hydrolytic steps exhibit kinetic resolution in favor of the (S)-enantiomers.

Topics: Brassica rapa; Fatty Acids, Monounsaturated; Humans; Hydrolysis; Lipase; Pancreas; Plant Oils; Poisoning; Propylene Glycols; Rapeseed Oil; Stereoisomerism; Syndrome

The etiologic agent(s) that was responsible for the 1981 toxic oil syndrome [TOS] epidemic in Spain has not been identified. Liquid chromatography combined with atmospheric pressure ionization tandem mass spectrometry was used for the analysis of oils associated with TOS. Analyses focused on measuring 3-(N-phenylamino)-1,2-propanediol [PAP], the 3-oleyl ester of PAP [MEPAP], and the 1,2-di-oleyl ester of PAP [DEPAP]. DEPAP and MEPAP were found more frequently and at higher concentrations in TOS case-associated oils than in control oils with odds ratios of 13.7 (95% CI 5.0-38) and 21.9 (95% 6.1-78), respectively. Other fatty acid esters of PAP are also likely to be present in the TOS case-associated oils. More significantly, DEPAP and MEPAP were found in aniline-denatured rapeseed oil refined at ITH, the oil refining company with the clearest link to TOS cases, yet these PAP esters were not detected in unrefined aniline-denatured samples of rapeseed oil delivered to ITH. These results show that the esters of PAP were products of the ITH refining process and were not formed spontaneously during storage. PAP esters were not detected in samples of other aniline-denatured rapeseed oils that were refined elsewhere, and which were not associated with illness. These findings provide strong support for the hypothesis that one or more of the fatty acid esters of PAP were the etiologic agents for TOS.

Topics: Aniline Compounds; Brassica; Esters; Fatty Acids; Fatty Acids, Monounsaturated; Plant Oils; Poisoning; Propylene Glycols; Rapeseed Oil; Spain; Syndrome