What is the Difference between Phloretin and Phlorizin?

In the study of bioactive substances derived from apples, Phloretin and Phlorizin, as representatives of dihydrochalcone compounds, have received widespread attention from the scientific community in recent years. Although these two substances have the same source and similar structure, they exhibit significant differences in biological activity and application value.

1.1 Molecular structural characteristics
Phloretin and Phlorizin are closely related in chemical structure but have key differences. Phloretin is a dihydrochalcone flavonoid compound with a relatively simple molecular structure. Phlorizin is the glucoside of phloretin, which is linked to a glucose group at the C2 'site of the phloretin molecule (the exact structure is phloretin 6'-O-glucoside)._[1] This structural difference determines their differences in physical and chemical properties: phlorizin has better water solubility due to the presence of sugar groups, while resveratrol exhibits stronger lipid solubility.
The introduction of glucose molecules significantly changed the physicochemical properties of the compound: the molecular weight increased from 274.27 to 436.41, the log P value decreased from 3.5 to 0.45, and the water solubility increased by nearly three orders of magnitude.

1.2 Comparison of Physical and Chemical Properties

In recent years, significant progress has been made in the field of biosynthesis research. The team from the Cotton Research Institute of the Chinese Academy of Agricultural Sciences has identified the key gene GhUGT88F3, which regulates the biosynthesis of phlorizin in upland cotton, and elucidated its molecular mechanism of converting phlorizin through glycosylation reactions. Research has identified phloretin-2′-O-glycosyltransferase (P2'GT) in apples as the rate-limiting enzyme for phlorizin biosynthesis. In the presence of uridine diphosphate glucose, it can specifically catalyze the glycosylation reaction at the C2 ′ position of phloretin to produce phlorizin._[2]

2.1 Absorption and Metabolic Dynamics
Phlorizin is absorbed via the sodium-dependent glucose transporter protein (SGLT1) on small intestinal epithelial cells, a process dependent on its glucose moieties. This characteristic later directly led to the development of the SGLT2 inhibitor class hypoglycemic drugs. The absorption mechanism of phloretin is completely different. As a hydrophobic glycoside, it can passively diffuse across cell membranes, resulting in high oral bioavailability. However, it undergoes extensive phase II metabolism in the body, mainly forming glucuronidation and sulfation products.

2.2 Pharmacological activity comparison
(1) Antioxidant activity
Both phloretin and phlorizin show significant antioxidant activity, though they differ in their mechanisms and potency. A study comparing the antioxidant activities of five natural polyphenols found that phloretin showed strong performance in DPPH radical scavenging, ABTS radical scavenging, and iron ion reduction assays. In contrast, the direct antioxidant capacity of resveratrol was relatively weak._[3] Although resveratrol itself has limited direct antioxidant activity, it can be hydrolyzed by gut microbiota into active metabolites that indirectly exert antioxidant and anti-inflammatory effects.
Both compounds activate the cellular Nrf2/HO-1 antioxidant pathway, significantly lowering intracellular reactive oxygen species (ROS), elevating glutathione (GSH) levels, and enhancing antioxidant enzyme activity._[4]  However, molecular docking experiments revealed that phloretin binds to the transcription factor Nrf2 with lower conformational energy and greater structural stability than phlorizin, suggesting a stronger antioxidant effect.

(2) Hypoglycemic activity
Both phloretin and phlorizin exhibit hypoglycemic effects, though through distinct mechanisms. Phlorizin acts as a potent non-selective competitive SGLT inhibitor, with Ki values of 300 nM for hSGLT1 and 39 nM for hSGLT2. It competes with D-glucose for binding to SGLT1 and SGLT2 transporters, thereby reducing renal glucose reabsorption and lowering blood glucose levels. Although phloretin also demonstrates a moderate hypoglycemic effect, its mechanism is more multifactorial, involving improved insulin sensitivity and protection of pancreatic beta cells.

(3) Skin whitening activity
Phloretin is widely recognized as an effective tyrosinase inhibitor, promoting the shedding of melanocytes, fading spots, and brightening skin tone. Its inhibitory strength on tyrosinase is more than 50 times that of phlorizin. The mechanism of action includes: direct inhibition of tyrosinase activity, inhibition of tyrosinase gene expression, and inhibition of superoxide free radical production.
The weak whitening effect of phlorizin may be related to its larger molecular size and poorer skin permeability. However, due to its better water solubility and stability, it is often used as a prodrug in cosmetics, releasing active root bark extract through skin microbiota or enzymatic hydrolysis.

3.1 Pharmaceutical field
Phlorizin was initially investigated as a potential treatment for type 2 diabetes; however, it was later superseded by more selective synthetic analogues such as canagliflozin and dapagliflozin, due to its low bioavailability and non-selective inhibition of SGLT transporters. However, it remains an important lead compound for the development of new hypoglycemic drugs. Phloretin, due to its stronger biological activity and diverse mechanisms of action, has shown broad prospects in the prevention and treatment of metabolic diseases

3.2 Cosmetics industry
In the field of cosmetics, phloretin has become a star ingredient in high-end whitening products. Its addition amount of 0.1-0.5% can significantly inhibit melanin production and has a synergistic effect with traditional whitening agents such as vitamin C and arbutin. Phlorizin is commonly used as a precursor for phloretin in water-based formulations due to its better stability and water solubility. Recent studies indicate that phlorizin exhibits anti-glycation properties by inhibiting the formation of advanced glycation end products (AGEs).

3.3 Food industry
Both are used as functional food ingredients. Phlorizin has been approved as a FOSHU (Specific Health Food) ingredient in Japan for use in blood glucose management products. Phloretin is employed as a natural food preservative owing to its antibacterial properties, particularly its notable inhibitory effect against Gram-positive bacteria. However, attention should be paid to its bioavailability. Phlorizin needs to be hydrolyzed by intestinal enzymes into phloretin before it can be absorbed and utilized.

As naturally derived bioactive compounds, phlorizin and phloretin are structurally related yet exhibit distinct chemical and biological characteristics. Phlorizin demonstrates greater water solubility and functions as a potent SGLT inhibitor with high specificity. Phloretin displays stronger lipid solubility and a broader spectrum of biological activity-particularly notable for its antioxidant, skin-whitening, and anti-inflammatory properties. For more details about Phloretin and Phlorizin, connect with Serrisha from APPCHEM. (Email: cwj@appchem.cn; +86-138-0919-0407)

Reference：

[1]Bai Huirong. Flavonoids from Malus Rockii Rehder[D]. Dali University, 2023. DOI:10.27811/d.cnki.gdixy.2023.000004.
[2]Zhang Tingjing. ENZYMATIC CHARACTERISTICS AND CATALYTIC MECHANISM OF APPLEPHLORETIN-2'-0-GLYCOSYLTRANSFERASE[D]. Northwest A & F University, 2017. DOI:10.27409/d.cnki.gxbnu.2017.000235.
[3]Fan Jinbo, Cai Xitong, Feng Xuqiao, et al. The comparison of five natural phenolic compounds on antioxidant activity in vitro[J]. Food and Fermentation Industries, 2014, 40(07):77-83. DOI:10.13995/j.cnki.11-1802/ts.2014.07.002.
[4]Yang Shengnan. Comparison of Oxidative Stress Damage of HepG2 Cells between Phlorizin and Phloretin[D]. Tianjin University of Science&Technology, 2019. DOI:10.27359/d.cnki.gtqgu.2019.000199.