Biotransformation and Clearance of 3-(Phenylamino)propane-1,2-diol, a Compound Present in Samples Related to Toxic Oil Syndrome, in C57BL/6 and A/J Mice

Abstract

In May 1981, a massive food-borne intoxication occurred in Spain. The so-called toxic oil syndrome (TOS) was associated with the consumption of aniline-denatured and refined rapeseed oil that was illegally sold as edible olive oil. Fatty acid anilides and fatty acid derivatives of 3-(phenylamino)propane-1,2-diol were detected in oils and implicated as potential toxic agents and markers of toxic oil batches. Epidemiological evidence points to 3-(phenylamino)propane-1,2-diol derivatives as the putative toxic agents, which were generated during the refining process at the ITH refinery. Here we present the biotransformation and clearance of 3-(phenylamino)propane-1,2-diol (PAP) administered intraperitoneally to A/J and C57BL/6 mice that have been proposed as a murine model for the immunological features of TOS. Mice eliminated 6 microCi of [U-(14)C]PAP during a 24 h period, mostly in urine. Animals exhibited urine elimination rates of 70 and 36% in A/J and C57BL/6 strains, respectively. A/J mice exhibited no increase in the elimination rate when induced with beta-naphthoflavone, whereas C57BL/6 did increase the rate of elimination to 57%. Feces contributed to a lesser extent to the elimination rate (0.6 and 3.3% in A/J and C57BL/6 mice, respectively). Radioactivity remaining in organ tissues was lower than 1% (liver, lung, kidney, spleen, heart, and muscle). Metabolic species in urine were identified by HPLC coupled to UV and radioisotope detectors and further GC/MS analyses. 2-Hydroxy-3-(phenylamino)propanoic acid metabolite was the major chemical species excreted in urine in both strains, in both control and induced animal groups. This compound was the main urinary metabolite of PAP, and unmetabolized PAP excreted in urine constituted less than 1% of the total administered dose. Two additional highly polar metabolites also detected in urine were identified as 3-[(4'-hydroxyphenyl)amino]propane-1,2-diol and 2-hydroxy-3-[(4'-hydroxyphenyl)amino]propanoic acid. These findings are the first reported on PAP metabolism and clearance in mice strains and suggest that PAP can be extensively metabolized in vivo and potential reactive species can be generated.

Absorption and effects of 3‐(N‐phenylamino)‐1,2‐propanediol esters in relation to toxic oil syndrome

“…Moreover, this observation suggests that the aniline-containing part of the molecule was preferentially excreted through urine, while constituent fatty acids were incorporated into the body pool of fatty acids. This observation would be in line with a recent report describing the biotransformation and clearance of the parent PAP, which was found to be highly metabolized in mice and excreted in urine in the form of 2-hydroxy-3-(phenylamino) propanoic acid (18). Results obtained measuring the radioactivity present in the aqueous phase of a Bligh and Dyer lipid extraction ( Fig.…”

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

“…Finally, this equilibrium is shifted by hydrolysis of the imine to yield 4-aminophenol and glyceraldehyde as final metabolites. In addition, previous in ViVo studies had shown that intraperitoneal administration of PAP to two mouse strains produced the 4′-hydroxy derivative 1 and paracetamol, among other metabolites (20,21). Thus, as occurred with PAP, the bioactivation of PAA by HLM involves the generation of a highly reactive quinoneimine intermediates.…”

Pharmacogenetic Profile of Xenobiotic Enzyme Metabolism in Survivors of the Spanish Toxic Oil Syndrome

“…The study of Berking et al (65) suggests that acetylation may afford protection from reactive metabolites derived from oleylanilide, leading to toxicity. Using the same mouse strains, ongoing studies in our laboratory have shown that PAP oxidized metabolites at the aniline moiety (66) and oxidized acetanilide metabolites (67) were present in the animals' urine after intraperitoneal administration of 14 C-labeled PAP or oleylanilide.…”