Pharmacologic Comparison of High-Dose Hesperetin and Quercetin on MDCK II Cell Viability, Tight Junction Integrity, and Cell Shape

Abstract

The modulation of tight junction (TJ) integrity with small molecules is important for drug delivery. High-dose baicalin (BLI), baicalein (BLE), quercetin (QUE), and hesperetin (HST) have been shown to open TJs in Madin-Darby canine kidney (MDCK) II cells, but the mechanisms for HST and QUE remain unclear. In this study, we compared the effects of HST and QUE on cell proliferation, morphological changes, and TJ integrity. HST and QUE were found to have opposing effects on the MDCK II cell viability, promotion, and suppression, respectively. Only QUE, but not HST, induced a morphological change in MDCK II into a slenderer cell shape. Both HST and QUE downregulated the subcellular localization of claudin (CLD)-2. However, only QUE, but not HST, downregulated CLD-2 expression. Conversely, only HST was shown to directly bind to the first PDZ domain of ZO-1, a key molecule to promote TJ biogenesis. The TGFβ pathway partially contributed to the HST-induced cell proliferation, since SB431541 ameliorated the effect. In contrast, the MEK pathway was not involved by both the flavonoids, since U0126 did not revert their TJ-opening effect. The results offer insight for using HST or QUE as naturally occurring absorption enhancers through the paracellular route.

Antioxidant Compounds and Health Benefits of Citrus Fruits

“…Moreover, the Yuja peel fractions induced the production of proteins relating to skin hydration, and they decreased melanin content, thus promoting advances in the understanding of the skin benefits provided by Yuja peel fractions, which may contribute to the development of novel pharmaceuticals and cosmetics [ 25 ]. In the in vitro study of Nakashima et al [ 26 ], new pharmacological insights into the ways in which high doses of flavonoids quercetin (C 15 H 10 O 7 ) and hesperidin (C 28 H 34 O 15 ) differentially modulate cell viability, tight junction integrity, and cell shape are provided. Considering that the barrier function of tight junctions may block the absorption of some molecules, the identification of reversible modifiers of its integrity are desirable as drug absorption enhancers [ 27 ].…”

“…Considering that the barrier function of tight junctions may block the absorption of some molecules, the identification of reversible modifiers of its integrity are desirable as drug absorption enhancers [ 27 ]. They conclude by suggesting both quercetin and hesperidin are promising compounds for developing a naturally occurring drug absorption enhancer for the paracellular route, with hesperidin being the most attractive for such a technology [ 26 ]. Finally, García-Nicolás et al [ 28 ] conducted a spatial metabolomic analysis for the characterization of phenolic compounds in juices and fruit tissue extracts of lemons, limes, and mandarins.…”