The Molecular Pharmacology of Phloretin: Anti-Inflammatory Mechanisms of Action

Abstract

The isolation of phlorizin from the bark of an apple tree in 1835 led to a flurry of research on its inhibitory effect on glucose transporters in the intestine and kidney. Using phlorizin as a prototype drug, antidiabetic agents with more selective inhibitory activity towards glucose transport at the kidney have subsequently been developed. In contrast, its hydrolysis product in the body, phloretin, which is also found in the apple plant, has weak antidiabetic properties. Phloretin, however, displays a range of pharmacological effects including antibacterial, anticancer, and cellular and organ protective properties both in vitro and in vivo. In this communication, the molecular basis of its anti-inflammatory mechanisms that attribute to its pharmacological effects is scrutinised. These include inhibiting the signalling pathways of inflammatory mediators' expression that support its suppressive effect in immune cells overactivation, obesity-induced inflammation, arthritis, endothelial, myocardial, hepatic, renal and lung injury, and inflammation in the gut, skin, and nervous system, among others.

Keywords: COX; NF-κB; Nrf2; apple flavonoids; cytokines; iNOS; inflammation; phloretin; phlorizin.

Figure 1

Structures of phlorizin, phloretin, and some selective SGLT2 inhibitors.

Figure 2

Anti-inflammatory effect of phloretin through inhibition of phosphorylation of MAPKs and IκBα. Most of the studies on the activation of inflammatory mediators from immune cells employed LPS which interacts with its receptor, TLR4. While a direct effect on TLR1/2 has been suggested, most of the data indicate an inhibitory effect on NF-κB mobilization to the nucleus. The LPS response shown by blue arrows includes the degradation of the NF-κB inhibitory protein, IκBα, via promoting its phosphorylation. This frees the p65/p50 to mobilise to the nucleus and activate inflammatory target genes such as COX, iNOS, and cytokines including TNF-α, IL-1β, and IL-6. Phloretin has been shown the suppress the NF-κB activity by inhibiting IκBα degradation (see red lines). The exact mechanism of how the MAPK activity leads to the activation of proinflammatory genes has not yet been fully established but the key steps after induction by inflammatory agents such as LPS is the phosphorylation of p38, ERK, and JNK which have been shown to be targeted by phloretin (see red lines). Note that other pro-inflammatory agents such as TNF-α, IL-1β, and IL-6 can also activate the MAPK and NF-κB pathways by interacting with their cell-surface receptors.

Figure 3

The crosstalk between AMPK, Nrf2, and SIRT1 pathways in the anti-inflammatory effect of phloretin. The activation of AMPK and SIRT1 are closely related in the regulation of metabolism and pathologies such as oxidative stress and inflammation. Activation of AMPK by phloretin via its phosphorylation as well as increased expression of SERT1 have been associated with its anti-inflammatory effect and modulation of lipid metabolism such as inhibition of lipid accumulation. This activity was further shown to be related to the induction of Nrf2 that suppresses both the oxidative stress and inflammatory pathways induced by a variety of agents including LPS. Increased SERT3 activity by phloretin is also reported. The red line shows the inhibitory response.