Phloretin

Last updated
Phloretin
Phloretin.svg
Names
Preferred IUPAC name
3-(4-Hydroxyphenyl)-1-(2,4,6-trihydroxyphenyl)propan-1-one
Other names
Dihydronaringenin
Phloretol
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.000.444 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C15H14O5/c16-10-4-1-9(2-5-10)3-6-12(18)15-13(19)7-11(17)8-14(15)20/h1-2,4-5,7-8,16-17,19-20H,3,6H2 X mark.svgN
    Key: VGEREEWJJVICBM-UHFFFAOYSA-N X mark.svgN
  • InChI=1/C15H14O5/c16-10-4-1-9(2-5-10)3-6-12(18)15-13(19)7-11(17)8-14(15)20/h1-2,4-5,7-8,16-17,19-20H,3,6H2
    Key: VGEREEWJJVICBM-UHFFFAOYAB
  • C1=CC(=CC=C1CCC(=O)C2=C(C=C(C=C2O)O)O)O
Properties
C15H14O5
Molar mass 274.272 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Phloretin is a dihydrochalcone, a type of natural phenol. It can be found in apple tree leaves [1] and the Manchurian apricot. [2]

Contents

Metabolism

In rats, ingested phlorizin is converted into phloretin by hydrolytic enzymes in the small intestine. [3] [4] Phloretin hydrolase hydrolyses phloretin into phloretic acid and phloroglucinol.

Pharmacological research

In an animal model, phloretin inhibited active transport of glucose into cells by SGLT1 and SGLT2, though the inhibition is weaker than by its glycoside phlorizin. [5] An important effect of this is the inhibition of glucose absorption by the small intestine [4] and the inhibition of renal glucose reabsorption. [3] Phloretin also inhibits a variety of urea transporters. [6] [7] It induces urea loss and diuresis when coupled with high protein diets. Phloretin has been found to inhibit weight gain and improve metabolic homeostasis in mice fed with high-fat diet. [8] Phloretin inhibits aquaporin 9 (AQP9) on mouse hepatocytes. [9]

Nanoparticle Synthesis

Phloretin functionalized gold-nanoparticles (Pht-GNPs) were synthesized using a single-step synthesis method and tested for its anticancer activity. Pht-GNPs showed significant cancer cell toxicities compared to free phloretin. [10]

Glycosides

See also

Related Research Articles

In cellular biology, active transport is the movement of molecules across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that uses an electrochemical gradient.

Collecting duct system Kidney system

The collecting duct system of the kidney consists of a series of tubules and ducts that physically connect nephrons to a minor calyx or directly to the renal pelvis. The collecting duct system is the last part of nephron and participates in electrolyte and fluid balance through reabsorption and excretion, processes regulated by the hormones aldosterone and vasopressin.

Cotransporter

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

Diabetic nephropathy Chronic loss of kidney function

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. The triad of protein leaking into the urine, rising blood pressure with hypertension and then falling renal function is common to many forms of CKD. Protein loss in the urine due to damage of the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) so called nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacyglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenes in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.

Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle. The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.

Sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron. They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron. If the plasma glucose concentration is too high (hyperglycemia), glucose passes into the urine (glucosuria) because SGLT are saturated with the filtered glucose.

AM404

AM404, also known as N-arachidonoylaminophenol, is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action and anticonvulsant effects. Chemically, it is the amide formed from 4-aminophenol and arachidonic acid.

The Randle cycle, also known as the glucose fatty-acid cycle, is a metabolic process involving the competition of glucose and fatty acids for substrates. It is theorized to play a role in explaining type 2 diabetes and insulin resistance.

Sodium/glucose cotransporter 1

Sodium/glucose cotransporter 1 (SGLT1) also known as solute carrier family 5 member 1 is a protein in humans that is encoded by the SLC5A1 gene which encodes the production of the SGLT1 protein to line the absorptive cells in the small intestine and the epithelial cells of the kidney tubules of the nephron for the purpose of glucose uptake into cells. Through the use of the sodium glucose cotransporter 1 protein, cells are able to obtain glucose which is further utilized to make and store energy for the cell.

Sodium/glucose cotransporter 2

The sodium/glucose cotransporter 2 (SGLT2) is a protein that in humans is encoded by the SLC5A2 gene.

A urea transporter is a membrane transport protein, transporting urea. Humans and other mammals have two types of urea transport proteins, UT-A and UT-B. The UT-A proteins are important for renal urea handling and are produced by alternative splicing of the SLC14A2 gene. Urea transport in the kidney is regulated by vasopressin.

Renal glucose reabsorption is the part of kidney (renal) physiology that deals with the retrieval of filtered glucose, preventing it from disappearing from the body through the urine.

Sergliflozin etabonate

Sergliflozin etabonate is an investigational anti-diabetic drug being developed by GlaxoSmithKline. It did not undergo further development after phase II.

Phlorizin Chemical compound

Phlorizin is a glucoside of phloretin, a dihydrochalcone. A white solid, samples often appear yellow owing to impurities. It is of sweet taste and contains four molecules of water in the crystal. Above 200 °C, it decomposes to give rufin. It is poorly soluble in ether and cold water, but soluble in ethanol and hot water. Upon prolonged exposure to aqueous solutions phlorizin hydrolyzes to phloretin and glucose.

SLC5A4

The low affinity sodium-glucose cotransporter also known as the sodium/glucose cotransporter 3 (SGLT3) or solute carrier family 5 member 4 (SLC5A4) is a protein that in humans is encoded by the SLC5A4 gene. It functions as a sugar sensor.

Empagliflozin, sold under the brand name Jardiance among others, is an antidiabetic medication used to improve glucose control in people with type 2 diabetes, used to reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease, used to reduce the risk of death and hospitalization in people with heart failure and low ejection fraction, and used to reduce the risk of cardiovascular death and hospitalization for heart failure in adults. It can be prescribed instead of metformin and has benefits over sulfonylureas. It may be used together with other medications such as metformin or insulin. It is not recommended for type 1 diabetes. It is taken by mouth.

Tofogliflozin

Tofogliflozin is an experimental drug for the treatment of diabetes mellitus and is being developed by Chugai Pharma in collaboration with Kowa and Sanofi. It is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. As of September 2012, the drug is in Phase III clinical trials.

Gliflozins are a class of drugs in the treatment of type 2 diabetes (T2D). They act by inhibiting sodium/glucose cotransporter 2 (SGLT-2), and are therefore also called SGLT-2 inhibitors. The efficacy of the drug is dependent on renal excretion and prevents glucose from going into blood circulation by promoting glucosuria. The mechanism of action is insulin independent.

SGLT2 inhibitors, also called gliflozins, are a class of medications that alter essential physiology of the nephron; unlike SGLT1 inhibitors that modulate sodium/glucose channels in the intestinal mucosa. The foremost metabolic effect appears to show that this pharmaceutical class inhibits reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type II diabetes mellitus (T2DM). Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in T2DM patients. Several medications of this class have been approved or are currently under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.

References

  1. Picinelli A.; Dapena E.; Mangas J. J. (1995). "Polyphenolic pattern in apple tree leaves in relation to scab resistance. A preliminary study". Journal of Agricultural and Food Chemistry. 43 (8): 2273–2278. doi:10.1021/jf00056a057.
  2. "Manchurian Apricot (Prunus armeniaca var. mandshurica)" (PDF). North Dakota State University. Retrieved January 30, 2014.
  3. 1 2 Idris, I.; Donnelly, R. (2009). "Sodium-glucose co-transporter-2 inhibitors: An emerging new class of oral antidiabetic drug". Diabetes, Obesity and Metabolism. 11 (2): 79–88. doi: 10.1111/j.1463-1326.2008.00982.x . PMID   19125776.
  4. 1 2 Crespy, V.; Aprikian, O.; Morand, C.; Besson, C.; Manach, C.; Demigné, C.; Rémésy, C. (2001). "Bioavailability of phloretin and phloridzin in rats". The Journal of Nutrition. 131 (12): 3227–3230. doi: 10.1093/jn/131.12.3227 . PMID   11739871.
  5. Chan, Stephen S.; William D. Lotspeich (1962-12-01). "Comparative effects of phlorizin and phloretin on glucose transport in the cat kidney". American Journal of Physiology. Legacy Content. 203 (6): 975–979. doi:10.1152/ajplegacy.1962.203.6.975. ISSN   0002-9513. PMID   14019989 . Retrieved 2012-10-21.
  6. Fenton, Robert A.; Chung-Lin Chou; Gavin S. Stewart; Craig P. Smith; Mark A. Knepper (2004-05-11). "Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct". Proceedings of the National Academy of Sciences of the United States of America. 101 (19): 7469–7474. Bibcode:2004PNAS..101.7469F. doi: 10.1073/pnas.0401704101 . ISSN   0027-8424. PMC   409942 . PMID   15123796.
  7. Shayakul, Chairat; Hiroyasu Tsukaguchi; Urs V. Berger; Matthias A. Hediger (2001-03-01). "Molecular characterization of a novel urea transporter from kidney inner medullary collecting ducts". American Journal of Physiology. Renal Physiology. 280 (3): F487–F494. doi:10.1152/ajprenal.2001.280.3.f487. ISSN   1931-857X. PMID   11181411. Archived from the original on 2016-03-04. Retrieved 2012-10-21.
  8. Alsanea, Sary; Gao, Mingming; Liu, Dexi (May 2017). "Phloretin Prevents High-Fat Diet-Induced Obesity and Improves Metabolic Homeostasis". The AAPS Journal. 19 (3): 797–805. doi:10.1208/s12248-017-0053-0. ISSN   1550-7416. PMID   28197827. S2CID   3638970.
  9. Fenton, Robert A.; Chou, Chung-Lin; Stewart, Gavin S.; Smith, Craig P.; Knepper, Mark A. (2004-05-11). "Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct". Proceedings of the National Academy of Sciences of the United States of America. 101 (19): 7469–7474. Bibcode:2004PNAS..101.7469F. doi: 10.1073/pnas.0401704101 . ISSN   0027-8424. PMC   409942 . PMID   15123796.
  10. Payne NJ, Badwaik VD, Waghwani HK, Moolani HV, Tockstein S, Thompson DH, Dakshinamurthy R (March 2018). "Development of dihydrochalcone-functionalized gold nanoparticles for augmented antineoplastic activity". International Journal of Nanomedicine. 13: 1917–1926. doi: 10.2147/IJN.S143506 . PMID   29636609.