Fate of 4-hydroxynonenal in vivo: disposition and metabolic pathways

Abstract

Due to the cytotoxicity of 4-hydroxynonenal (HNE), and to the fact that this major product of lipid peroxidation is a rather long-living compound compared with reactive oxygen species, the capability of organisms to inactivate and eliminate HNE has received increasing attention during the last decade. Several recent in vivo studies have addressed the issue of the diffusion, kinetics, biotransformation and excretion of HNE. Part of these studies are primarily concerned with the toxicological significance of HNE biotransformation and more precisely with the metabolic pathways by which HNE is inactivated and eliminated. The other aim of in vivo metabolic study is the characterisation of end-metabolites, especially in urine, in order to develop specific and non-invasive biomarkers of lipid peroxidation. When HNE is administered intravenously or intraperitoneally, it is mainly excreted into urine and bile as conjugated metabolites, in a proportion that is dependent on the administration route. However, biliary metabolites undergo an enterohepatic cycle that limits the final excretion of faecal metabolites. Only a very low amount of metabolites is found to be bound to macromolecules. The main urinary metabolites are represented by two groups of compounds. One comes from the mercapturic acid formation from (i) 1,4 dihydroxynonene-glutathione (DHN-GSH) which originates from the conjugation of HNE with GSH by glutathione-S-transferases and the subsequent reduction of the aldehyde by a member of aldo-keto reductase superfamily; (ii) the lactone of 4-hydroxynonanoic-GSH (HNA-lactone-GSH) which originates from the conjugation of HNE followed by the oxidation of the aldehyde by aldehyde dehydrogenase; (iii) HNA-GSH which originates from the hydrolysis of the corresponding lactone. The other one is a group of metabolites issuing from the ω-hydroxylation of HNA or HNA-lactone by cytochromes P450 4A, followed eventually, in the case of ω-oxidized-HNA-lactone, by conjugation with GSH and subsequent mercapturic acid formation. Biliary metabolites are GSH or mercapturic acid conjugates of DHN, HNE and HNA. Stereochemical aspects of HNE metabolism are also discussed.