Enzymatic and non-enzymatic detoxification of 4-hydroxynonenal: Methodological aspects and biological consequences

4-Hydroxynonenal (HNE), an electrophilic end-product deriving from lipid peroxidation, undergoes a heterogeneous set of biotransformations including enzymatic and non-enzymatic reactions. The former mostly involve red-ox reactions on the HNE oxygenated functions (phase I metabolism) and GSH conjugations (phase II) while the latter are due to the HNE capacity to spontaneously condense with nucleophilic sites within endogenous molecules such as proteins, nucleic acids and phospholipids. The overall metabolic fate of HNE has recently attracted great interest not only because it clearly determines the HNE disposal, but especially because the generated metabolites and adducts are not inactive molecules (as initially believed) but show biological activities even more pronounced than those of the parent compound as exemplified by potent pro-inflammatory stimulus induced by GSH conjugates. Similarly, several studies revealed that the non-enzymatic reactions, initially considered as damaging processes randomly involving all endogenous nucleophilic reactants, are in fact quite selective in terms of both reactivity of the nucleophilic sites and stability of the generated adducts. Even though many formed adducts retain the expected toxic consequences, some adducts exhibit well-defined beneficial roles as documented by the protective effects of sublethal concentrations of HNE against toxic concentrations of HNE. Clearly, future investigations are required to gain a more detailed understanding of the metabolic fate of HNE as well as to identify novel targets involved in the biological activity of the HNE metabolites. These studies are and will be permitted by the continuous progress in the analytical methods for the identification and quantitation of novel HNE metabolites as well as for proteomic analyses able to offer a comprehensive picture of the HNE-induced adducted targets. On these grounds, the present review will focus on the major enzymatic and non-enzymatic HNE biotransformations discussing both the molecular mechanisms involved and the biological effects elicited. The review will also describe the most important analytical enhancements that have permitted the here discussed advancements in our understanding of the HNE metabolic fate and which will permit in a near future an even better knowledge of this enigmatic molecule.