Peroxidation of common ω-6 polyunsaturated fatty acids (PUFAs) such as linoleic acid, DGLA, and arachidonic acid can give rise to 4-HNE. 4-HNE is cleared rapidly from the plasma and undergoes enterohepatic circulation as a glutathione conjugate in the rat. About two thirds of an administered dose of 4-HNE is excreted within 48 hours in the urine, primarily in the form of mercapturic acid conjugates. The C-1 aldehyde of 4-HNE is reduced to an alcohol in about half of these metabolites. The remainder are C-1 aldehydes or have been oxidized to C-1 carboxylic acids. These aldehydes and carboxylic acids can also form γ-lactols and γ-lactones, respectively, producing at least 4 or 5 end urinary metabolites of 4-HNE in vivo.