IDENTIFICATION OF MODIFIED ATROPALDEHYDE MERCAPTURIC ACIDS IN RAT ANDHUMAN URINE AFTER FELBAMATE ADMINISTRATION

3-Carbamoyl-2-phenylpropionaldehyde has recently been proposed [Thomps on et al. (1996) Chem. Res. Toxicol. 9, 1225-1229] as a potential reac tive metabolite of the anti-epileptic drug felbamate. This aldehyde wa s found to undergo rapid elimination to generate 2-phenylpropenal and reversible cyclization to generate 4-hydroxy-5-phenyltetrahydro-1,3-ox azin-2-one at physiological pH. 2-Phenylpropenal, an alpha,beta-unsatu rated aldehyde commonly termed atropaldehyde, is a potent electrophile and undergoes rapid conjugation with glutathione. We sought to demons trate the formation of atropaldehyde in vivo through the identificatio n of mercapturic acids in rat and human urine after felbamate administ ration. In this paper, we describe the identification of both the redu ced (N-acetyl-S-(2-phenylpropan-3-ol)-L-cysteine) and oxidized (N-acet yl-S-(2-phenyl-3-propanoic acid)-L-cysteine) mercapturic acids of atro paldehyde in rat and human urine. The reduced species was the more abu ndant in human (similar to 2:1) and rat (similar to 6: 1) urine. These findings establish the possibility that atropaldehyde is formed from felbamate in vivo, undergoes glutathione conjugation, and is ultimatel y excreted in urine in the form of mercapturic acids. Thus, the propos ed pathway of felbamate biotransformation, if confirmed in patients, c ould contribute to our understanding of the toxicities observed during felbamate treatment.