Glycerolphosphorylethanolamine and Several Other Biochemical Amines Are Targets of Furan’s Reactive Metabolite in Rodents

Furan, a potent toxicant and liver carcinogen, is present in tobacco smoke and may contribute to smoking-related adverse health effects. Furan requires metabolic activation to its reactive metabolite, cis-2-butene-1,4-dial (BDA), to exert its toxic effect. Chemical characterization of hepatocellular and urinary metabolites indicates that the reaction of BDA with glutathione (GSH) generates a reactive GSH conjugate, 2-(S-glutathionyl)succinaldehyde (GSH-BDA), that targets protein lysine residues and polyamines to form GSH-BDA-amine cross-links. In this report, five additional amine targets of BDA following its reaction with GSH are identified as GSH-BDA-amine cross-links in furan-exposed rodent hepatocytes. They are ethanolamine, glutamic acid, citrulline, glycerolphosphorylethanolamine (GPE), and taurine. Furthermore, the corresponding mercapturic acid metabolites and their sulfoxides were identified in urine from furan-treated rats and mice, indicating that these amines are targets in vivo. Of particular interest is the modification of GPE, which is an important component of lipids. Since other reactive dialdehydes target GPE and the result of its alkylation is linked to toxicity, lipid alkylation by furan metabolites may play an important role in the toxicity associated with furan exposure. This study generates important new possible biomarkers of effect that can be used in human epidemiological studies to assess furan’s human health effects.