METABOLISM AND CYTOTOXICITY OF TRANS,TRANS-MUCONALDEHYDE AND ITS DERIVATIVES - POTENTIAL MARKERS OF BENZENE-RING CLEAVAGE REACTIONS

trans,trans-Muconaldehyde (MA) has been proposed to be a myelotoxic me tabolite of benzene, although it has not been isolated after benzene a dministration in vivo. Since the reactivity and further metabolism of MA may preclude its isolation, we have examined the metabolism of MA b y: (a) mixtures of yeast alcohol and aldehyde dehydrogenases, (b) mous e liver cytosol, and (c) isolated rat hepatocytes. In all three system s, MA was metabolized rapidly and the major stable end-product of meta bolism was the hydroxy/acid (OH/COOH) derivative of MA. The major rout e of metabolism involved initial reduction to the hydroxy/aldehyde (OH /CHO) derivative. trans, trans-Muconic acid (COOH/COOH), which is used as a marker of benzene ring cleavage reactions in vivo, was also form ed from MA albeit to a much lesser extent compared to the OH/COOH. The thiol reactivity, metabolism, and cytotoxicity of MA and its differen t redox forms (i.e., OH/OH, OH/CHO, COOH/CHO, COOH/COOH, OH/COOH) were also investigated. MA was found to react most rapidly with reduced gl utathione (GSH) in a cell-free system and was also the most cytotoxic to rat hepatocytes. Apart from MA, only the OH/CHO demonstrated GSH-re activity and cytotoxicity. The OH/CHO was a major initial metabolite i n all three systems and, thus, could represent a less reactive but mor e diffusible derivative of MA. These studies define the metabolism and cytotoxicity of MA and its redox derivatives and suggest that the OH/ COOH metabolite of MA may have relevance as a marker of ring cleavage reactions of benzene in vivo.