title: Methoxyacetaldehyde, an intermediate metabolite of 2-methoxyethanol, is immunosuppressive in the rat.
abstract: 2-Methoxyethanol (ME) is metabolized to 2-methoxyacetic acid (MAA) via the intermediate metabolite methoxyacetaldehyde (MAAD). Both ME and MAA have been shown in this laboratory to be immunosuppressive in rats following oral dosing. In this study, the plaque-forming cell (PFC) response to trinitrophenyl-lipopolysaccharide (TNP-LPS) was used to determine if MAAD is immunosuppressive in rats. Rats pretreated with the aldehyde dehydrogenase inhibitors disulfiram (2 mmol/kg) or cyanamide (0.48 mmol/kg) followed by oral dosing with ME (2.64 mmol/kg) resulted in suppressed PFC responses equivalent to the suppressed responses of rats dosed with ME alone. Rats pretreated with disulfiram and then dosed with 2.64 mmol/kg 2-methoxyethyl acetate (MEA), also resulted in suppressed PFC responses similar to that of MEA alone. In contrast, coadministration of the alcohol dehydrogenase inhibitor 4-methylpyrazole (1.2 mmol/kg) with ME or MEA blocked suppression of the PFC response following exposure to ME or MEA alone. Oral dosing with equimolar (2.64 mmol/kg) concentrations of ME, MAA, or MAAD resulted in equivalent suppression of the TNP-LPS PFC response. Rats exposed to either disulfiram or cyanamide and MAAD also resulted in suppression of the PFC response. These results indicate that metabolism of ME to either MAAD or MAA is required for immunosuppression, and that these two metabolites are equipotent immunosuppressants in the rat.
authors.affiliation: Environmental Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
authors.forename: R J
authors.initials: RJ
authors.lastname: Smialowicz
authors.forename: M M
authors.initials: MM
authors.lastname: Riddle
authors.forename: W C
authors.initials: WC
authors.lastname: Williams
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000633:toxicity; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D003484:Cyanamide / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D005026:Ethylene Glycols / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077604:Fomepizole; D007108:Immune Tolerance / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D011720:Pyrazoles / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D012997:Solvents / Q000378:metabolism
chemical_list: D005026:Ethylene Glycols; D008070:Lipopolysaccharides; D011720:Pyrazoles; D012997:Solvents; C048761:trinitrophenyl-lipopolysaccharide; D003484:Cyanamide; C049826:2-methoxyacetaldehyde; D000077604:Fomepizole; D000426:Alcohol Dehydrogenase; C005219:methyl cellosolve; D000079:Acetaldehyde; D004221:Disulfiram