Is It Possible to Trap 4HNE, the Main Degradation Product of Omega-6? A Theoretical Study of Potential Scavengers

Omega-6 is a polyunsaturated fatty acid with potential therapeutic applications in humans. The main degradation product of Omega-6 is the α-β-unsaturated aldehyde 4-hydroxynonenal (4HNE). This compound induces DNA damage by forming covalent adducts with nitrogenous bases. To prevent this, there are strategies to trap this molecule with scavengers. The main scavengers are phloretin (Phr) and hesperetin dihydrochalcone (HDC). In this research, we investigate 4HNE forming covalent bonds with scavengers (Phr and HDC) and with nitrogenous bases (thymine, guanine, cytosine, and adenine). We first analyze the electron transfer properties, seeking a correlation between chemical parameters and the toxicity of 4HNE. We obtained the stabilization energies and electron transfer properties of the adducts. The question is whether the adducts with 4HNE can maintain similar electron transfer properties. The stabilization energies of 4HNE with the scavengers are similar to the stabilization energy with guanine (approximately 30-40 kcal/mol). The adducts are worse electron acceptors than 4HNE. This means that the adducts are worse oxidants than 4HNE, which is an advantage. The ability of 4HNE to oxidize nitrogenous bases decreases when the adducts are formed. The scavenger capacity of Phr and HDC reduces the toxicity of 4HNE for two reasons: they trap 4HNE, preventing it from reacting with biomolecules, and the adducts formed are not as effective oxidants as 4HNE, resulting in less damage to biomolecules.