Metabolism and toxicity of trans,trans-muconaldehyde, an open-ring microsomal metabolite of benzene.

We have previously hypothesized that ring-opened metabolites may play an important role in benzene toxicity. In this paper we review recent work related to this hypothesis. trans,trans-Muconaldehyde (TTM), a six-carbon diene dialdehyde, was shown by our laboratory to be a microsomal metabolite of benzene. This compound is a ring-opened metabolite of benzene that is hematotoxic in mice. The toxicity of TTM may stem in part from its ability to act as a direct-acting alkylating agent involving interaction with cellular sulfhydryls and/or amino groups. On the other hand, metabolism to the diacid trans,trans-muconic acid (MA), a known urinary metabolite of benzene, may represent detoxification since this results in loss of electrophilicity of the compound. Preliminary results indicate that TTM can be metabolized to MA in vitro and in vivo. The interaction of TTM in vitro with macrophages and neutrophils, key cells in the bone marrow, results in cell membrane changes, including loss of activity in the plasma membrane-bound NADPH-dependent oxidase and decreases in membrane lipid fluidity. Deoxyguanosine also was found to react with TTM, forming several different products. These findings may be due to TTM acting directly as an alkylating agent.