Elucidating the Skin Delivery of Aglycone and Glycoside Flavonoids: How the Structures Affect Cutaneous Absorption

Abstract

Flavonoids are bioactive phytochemicals that exhibit protective potential against cutaneous inflammation and photoaging. We selected eight flavonoid aglycones or glycosides to elucidate the chemistry behind their skin absorption capability through experimental and computational approaches. The skin delivery was conducted using nude mouse and pig skins mounted on an in vitro Franz cell assembly. The anti-inflammatory activity was examined using the O2•– and elastase inhibition in activated human neutrophils. In the equivalent dose (6 mM) application on nude mouse skin, the skin deposition of naringenin and kaempferol was 0.37 and 0.11 nM/mg, respectively, which was higher than that of the other flavonoids. Both penetrants were beneficial for targeted cutaneous therapy due to their minimal diffusion across the skin. The absorption was generally greater for topically applied aglycones than glycosides. Although naringenin could be classified as a hydrophilic flavonoid, the flexibility of the chiral center in the C ring of this flavanone could lead to better skin transport than the flavonols and flavones with a planar structure. An optimized hydrophilic and lipophilic balance of the flavonoid structure was important for governing the cutaneous delivery. The hydrogen bond acceptor and stratum corneum lipid docking estimated by molecular modeling showed some relationships with the skin deposition. The interaction with cholesteryl sulfate could be a factor for predicting the cutaneous absorption of aglycone flavonoids (correlation coefficient = 0.97). Baicalin (3 µM) showed the highest activity against oxidative burst with an O2•– inhibition percentage of 77%. Although naringenin displayed an inhibition efficiency of only 20%, this compound still demonstrated an impressive therapeutic index because of the high absorption. Our data are advantageous to providing the information on the structure–permeation relationship for topically applied flavonoids.

Antibacterial Activity of Some Flavonoids and Organic Acids Widely Distributed in Plants

“…For example, many herbal preparations utilized as natural diuretics, and plant extracts with other main pharmacological activities (i.e., drugs against cardiovascular diseases, sedatives, anti-inflammatory agents) exhibit additional beneficial effects by the antimicrobial action [41,42]. Recent data show that flavonoids have protective potential against cutaneous inflammatory reactions and affect wound healing [43,44]. In addition, organic acids (especially citric acid) seem to be of significant importance in the antimicrobial activity and health of the skin [45,46].…”

Phytochemical Analysis, In Vitro Anti-Inflammatory and Antimicrobial Activity of Piliostigma thonningii Leaf Extracts from Benin

“…Thermal treatment during boiling or roasting can lead to the cleavage of the aglycone of flavonoids during ethnomedical practice [16]. Other components in herbal mixtures with β glucosidase activity [17] can also cause this decomposition, as well as enzymatic hydrolysis in skin tissue during topical application [18]. Moreover, the presence of quercetin in P. thonningii leaf extracts has been reported [10,15].…”

Phytochemical Characterization and In Vitro Anti-Inflammatory, Antioxidant and Antimicrobial Activity of Combretum Collinum Fresen Leaves Extracts from Benin

“…During the ethnomedical application, cleavage of the aglycon can be caused by thermal treatment (boiling or roasting) [18], or by other components with β-glucosidase activity in herbal mixtures [19]. During application to skin tissue, flavonoid glycosides may also be susceptible to enzymatic hydrolysis [20]. Therefore, not only myricetin-3-O-rhamnoside was tested, but also myricetin to determine the effect of the aglycone.…”