Detoxification of Lipid Peroxidation Aldehyde 4-Hydroxynonenal by Hesperetin Dihydrochalcone, a Microbial Metabolite of Neohesperidin Dihydrochalcone, In Vitro and In Vivo

Neohesperidin dihydrochalcone (NHDC) is a safe and widely used sweetener from citrus hesperidin. Beyond its sweetening properties, the potential health benefits and mechanisms of NHDC remain underexplored. This study investigated whether NHDC could reduce lipid peroxidation through its microbial metabolite, hesperetin dihydrochalcone (HDC), which traps 4-hydroxynonenal (4-HNE), a reactive carbonyl species generated during lipid peroxidation. In vitro, HDC formed covalent conjugates with 4-HNE through 1,2-addition at the aldehyde site and 1,4-Michael addition at the α,β-unsaturated aldehyde, resulting in three distinct adducts that were purified and characterized by NMR spectroscopy. Mouse studies confirmed that HDC is the primary metabolite of NHDC and can trap 4-HNE in vivo, forming 4-HNE–HDC conjugates. Further research showed a dose-dependent increase in 4-HNE–HDC conjugates, particularly the mono-4-HNE HDC conjugate formed via 1,2-addition. These findings demonstrate the ability of HDC to reduce carbonyl stress by trapping 4-HNE and highlight the role of microbial metabolism in the transformation of dietary polyphenols into bioactive metabolites. The 4-HNE-scavenging ability of HDC suggests its potential in the development of dietary strategies for reducing lipid peroxidation and preventing chronic diseases associated with carbonyl stress.