Identification of Modified Atropaldehyde Mercapturic Acids in Rat and Human Urine after Felbamate Administration

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Abstract
3-Carbamoyl-2-phenylpropionaldehyde has recently been proposed [Thompson et al. (1996) Chem. Res. Toxicol.9, 1225−1229] as a potential reactive metabolite of the anti-epileptic drug felbamate. This aldehyde was found to undergo rapid elimination to generate 2-phenylpropenal and reversible cyclization to generate 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one at physiological pH. 2-Phenylpropenal, an α,β-unsaturated aldehyde commonly termed atropaldehyde, is a potent electrophile and undergoes rapid conjugation with glutathione. We sought to demonstrate the formation of atropaldehyde in vivo through the identification of mercapturic acids in rat and human urine after felbamate administration. In this paper, we describe the identification of both the reduced (N-acetyl-S-(2-phenylpropan-3-ol)-l-cysteine) and oxidized (N-acetyl-S-(2-phenyl-3-propanoic acid)-l-cysteine) mercapturic acids of atropaldehyde in rat and human urine. The reduced species was the more abundant in human (∼2:1) and rat (∼6:1) urine. These findings establish the possibility that atropaldehyde is formed from felbamate in vivo, undergoes glutathione conjugation, and is ultimately excreted in urine in the form of mercapturic acids. Thus, the proposed pathway of felbamate biotransformation, if confirmed in patients, could contribute to our understanding of the toxicities observed during felbamate treatment.