4-Hydroxy-2-nonenal (4-HNE) is a secondary cytotoxic product generated from lipid peroxidation of polyunsaturated fatty acids (PUFAs). The accumulation of 4-HNE can covalently modify biomolecules, such as DNA and proteins, leading to various pathological conditions. Apple phloretin has been shown to be able to trap 4-HNE in vitro, but the trapping mechanisms of 4-HNE by phloretin are not fully understood. Moreover, whether the in vitro trapping efficacy of phloretin toward 4-HNE could be transferred into in vivo environments has never been investigated. In the present study, we observed the formation of 4-HNE conjugates of phloretin increased as phloretin decreased during the in vitro incubation. We then purified and characterized three mono-4-HNE-conjugates of phloretin using NMR and LC–MS/MS techniques. We thereafter demonstrated that apple phloretin could scavenge in vivo 4-HNE via the formation of at least three mono-4-HNE-conjugates of phloretin in a dose-dependent manner in mice after oral administration of three doses of phloretin (25, 100, and 400 mg/kg). The findings from this study pave the way to understanding how dihydrochalcones could act as effective scavengers of 4-HNE by working as sacrificial nucleophiles in vivo, thereby preventing or reducing the risk of 4-HNE-associated chronic diseases.
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