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 metabolite of benzene, although it has not been isolated from benzene administration in vivo. Since the reactivity and further metabolism of MA may preclude its isolation, we have examined the metabolism of MA by: (a) mixtures of yeast alcohol and aldehyde dehydrogenases, (b) mouse liver cytosol, and (c) isolated rat hepatocytes. In all three systems, MA was metabolized rapidly and the major stable end-product of metabolism was the hydroxy/acid (OH/COOH) derivative of MA. The major route 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 formed from MA albeit to a much lesser extent compared to the OH/COOH. The thiol reactivity, metabolism, and cytotoxicity of MA and its different 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 glutathione (GSH) in a cell-free system and was also the most cytotoxic to rat hepatocytes. Apart from MA, only the OH/CHO demonstrated GSH-reactivity and cytotoxicity. The OH/CHO was a major initial metabolite in all three systems and, thus, could represent a less reactive but more 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.
Goon
D
D
Molecular Toxicology and Environmental Health Sciences Program, School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262.
Matsuura
J
J
Ross
D
D
D000426:Alcohol Dehydrogenase / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000494:pharmacology; D000447:Aldehydes / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D001554:Benzene / Q000378:metabolism* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D015003:Yeasts / Q000201:enzymology
D000447:Aldehydes; C034476:muconaldehyde; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D001554:Benzene