Metabolism of (R)- and (S)-3-(phenylamino)propane-1,2-diol in C57BL/6-and A/J-strain mice. Identification of new metabolites with potential toxicological significance to the Toxic Oil Syndrome

The Toxic Oil Syndrome was a massive food-borne intoxication that occurred in Spain in 1981. Epidemiological studies point to 3-(phenylamino)propane-1 ,2-diol (PAP) derivatives as the putative toxic agents. We report further i dentification of metabolites cleared in urine of A/J and C57BL/6 mice in wh ich (R)- and (S)-3-(phenylamino)propane-1,2-diol were administered intraper itoneally. This investigation is an extension of previous studies carried o ut with the racemic compound [Ladona, M. G., Bujons, J., Messeguer, A., Amp urdanes, C., Morato, A., and Corbella, J. (1999) Chem. Res. Toxicol. 12, 11 27-1137]. Both PAP enantiomers were extensively metabolized, and several me tabolites were eliminated in urine. The HPLC profiles of the urine samples of both mouse strains treated with each enantiomer were qualitatively simil ar, but differences were found in a relatively higher proportion of several detected metabolites in mice treated with (R)-PAP compared with those trea ted with (S)-PAP. The main urine metabolite continues to be 2-hydroxy-3-(ph enylamino)propanoic acid (1), which confirms our previous results obtained with rac-PAP. In addition to the detection of other metabolites already rep orted in our previous paper, interesting evidence is provided on the presen ce of 4-aminophenol and paracetamol conjugates in the urine samples from bo th mouse strains. The detection of these metabolites suggests the in vivo f ormation of quinoneimine PAP derivatives. Indeed, some quinoneimine species (11 and 12), as well as other PAP metabolites (13) that bear modifications in the alkyl chain, have been tentatively identified in mouse urine. These metabolic findings might imply a potential toxicological significance for the Toxic Oil Syndrome.