Metabolic Investigation on the Interaction Mechanism between Dietary Dihydrochalcone Intake and Lipid Peroxidation Product Acrolein Reduction

Abstract

Scope Acrolein (ACR), a lipid peroxidation product, pathologically participates in various chronic diseases. In vitro evidence suggestes that dietary dihydrochalcones (DHCs) potentiate safe and alternative therapeutics to synthetic pharmaceuticals for ACR scavenging. Here, to investigate whether ingested DHCs could trap ACR and thereof result in reductions in endogenous ACR in mice is aimed. Methods and results Three doses of phloretin (25, 100, and 400 mg kg−1), a major dietary DHC, are orally administrated to mice and 24 h urine and fecal samples are collected, respectively. High‐resolution MS‐based targeted metabolomics reveal for the first time that phloretin and its oxidized metabolite are able to trap endogenous ACR via formation of ACR conjugates. Quantification further demonstrate that a) more than 13% of ingested phloretin can dose‐dependently trap 0.77−9.92 nmol of ACR within 24 h; b) phloretin ingestion leads to marked reductions in both free ACR and ACR metabolites in mouse urine compared to control; and c) trapping reactions by phloretin can account for up to 20.1% of the total decreases in endogenous ACR, depending on the administration doses. Conclusion Findings from this study indicate that regular consumption of DHCs‐rich diets holds great promise to alleviate the development of ACR‐associated chronic diseases.

Effects of hesperidin combined with synephrine on the capture of acrolein in a mouse model, or in humans by citrus consumption

“…Numerous studies have reported that natural polyphenols or flavonoids, such as phloretin, 12 epigallocatechin gallate, genistein, 13 cyanidin-3- O -glucoside, 14 cardamomin, and alpinetin, 15 can effectively scavenge ACR in vitro and in vivo , in both mice and humans. Additionally, our previous study demonstrated that curcumin in combination with quercetin synergistically inhibited ACR formation in roasted chicken wings.…”

Detoxification of the Lipid Peroxidation Aldehyde, 4-Hydroxynonenal, by Apple Phloretin In Vitro and in Mice

“…Appearance of an extra oxygenated tertiary methine group [δ H 4.79 (1H, m, H-1″) and δ C 80.6 (C-1″)] in the 4-HNE residue (Table ), compared to 4-HNE (see Section ), indicated that the reactive aldehyde group in 4-HNE was attacked by phloretin moiety during the incubation. The observation of one singlet aromatic proton at δ H 5.88 (1H, s, H-5) in ring A of phloretin moiety (Table ) suggested that ring A in phloretin moiety is the active site for the attachment of 4-HNE residue, which is similar to our previous finding on the acrolein conjugation of phloretin . Key HMBC correlations between δ H 4.79 (1H, m, H-1″) and δ C 158.7 (C-2), as well as between δ H 5.55 (1H, dd, J = 17.2, 2.8 Hz, H-2″) and δ C 104.4 (C-3) (Figure B), further confirmed that the aldehyde group of 4-HNE residue attached at the C-3 position in ring A of the phloretin moiety via the formation of a secondary hydroxyl group in P1 .…”

“…The formed HNE–GSH subsequently undergoes reduction and oxidation to produce less toxic 1,4-dihydroxy-2-nonene (DHN) and 4-hydroxy-2-nonenoic acid (HNA) . 4-HNE could also be directly metabolized into DNH by antidiuretic hormone (ADH), which is a member of the aldo-keto reductase (AKR) superfamily. − However, under stress conditions, free radicals in the body increase, resulting in the overproduction of 4-HNE, which may contribute to the development of oxidative stress conditions. , Elevated 4-HNE has been observed in subjects with various chronic diseases. − Zhu and team studied phloretin and hesperetin dihydrochalcone (all with open C-ring) and indicated that the two were better trapping agents of acrolein than their counterpart with closed C-ring. The observation points to the fact that phloretin could be a better trapping agent of cytotoxic 4-HNE.…”

“…35,36 Elevated 4-HNE has been observed in subjects with various chronic diseases. 6−11 Zhu and team 27 studied phloretin and hesperetin dihydrochalcone (all with open C-ring) and indicated that the two were better trapping agents of acrolein than their counterpart with closed C-ring. The observation points to the fact that phloretin could be a better trapping agent of cytotoxic 4-HNE.…”

“…The observation of one singlet aromatic proton at δ H 5.88 (1H, s, H-5) in ring A of phloretin moiety (Table 1) suggested that ring A in phloretin moiety is the active site for the attachment of 4-HNE residue, which is similar to our previous finding on the acrolein conjugation of phloretin. 27 Key HMBC correlations between δ H 4.79 (1H, m, H-1″) and δ C 158.7 (C-2), as well as between δ H 5.55 (1H, dd, J = 17.2, 2.8 Hz, H-2″) and δ C 104.4 (C-3) (Figure 3B), further confirmed that the aldehyde group of 4-HNE residue attached at the C-3 position in ring A of the phloretin moiety via the formation of a secondary hydroxyl group in P1. The characteristic fragment at m/z 305.1395 in MS 2 spectra of P1, producing from dehydration and subsequent C α −C β cleavage (Figure 4B), 2E,4Z)-1-hydroxynona-2,4-dien-1-yl)phenyl)propan-1-one (Figure 3), which is a new compound.…”