Abstracts

Rationale and Discussion. After an association was recognized between felbamate therapy and idiosyncratic hepatotoxicity and aplastic anemia, our laboratory proposed that 3-carbamoyl-2-phenylpropionaldehyde, an unobserved intermediate in the conversion of the known metabolite, 2 phenyl-1,3-propanediol monocarbamate, to the corresponding carboxylic acid, may be central to these idiosyncratic reactions. If formed, the aldehyde carbamate intermediate could undergo elimination to generate the highly reactive unsaturated aldehyde, 2-phenylpropenal. In fact, the processed glutathione conjugates of 2-phenylpropenal have been identified in the urine of patients receiving felbamate (Thompson, Epilepsia 1999, 40, 769-776). Thus, we propose that the observed idiosyncratic reactions may result from an increase in the levels of 2-phenyl propenal, which reacts with proteins to elicit immune-mediated toxicity. Results. We have found that 2 phenylpropenal conjugation with glutathione is catalyzed by glutathione transferases, most notably human GSTM1-1. Additional work in our laboratory has found that 3-carbamoyl-2-phenylpropionaldehyde is in equilibrium with 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one, which we have now identified in the urine of felbamate patients. The formation of 4-hydroxy-5 phenyl-1,3-oxazaperhydroin-2-one is significant because it may represent a stable reservoir of 2 phenylpropenal which is capable of traveling to distant sites in the body and releasing 2-phenylpropenal. The work presented here addresses: 1) the equilibrium reversion of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one to 3-carbamoyl-2-phenyl propionaldehyde in a pH dependent manner; 2) the cytotoxicity of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one to cultured cells; 3) the identification of this metabolite in the urine of humans treated with felbamate; and 4) the catalysis of 2-phenylpropenal conjugation with glutathione by glutathione transferases and their possible role in enabling the idiosyncratic reactions.