Flavanones(Naringenin)

Julia Patterson, Danielle Selden, Erin Prasad, Yulia McDonald

Naringenin

C15 H12 O5

What is a Flavanone? A type of flavonoids. They are generally glycosylated by a

disaccharide at position seven to give flavanone glycosides.

The enzyme chalcone isomeraase uses a chalcone-like compound to produce a flavanone.

The flavonoid existing in highest concentration in grapefruit juice is naringin, which in humans is metabolized to naringenin (Bioactive form).

Naringenin The predominant flavanone in

grapefruit

Grapefruit A subtropical citrus tree known for its bitter fruit.

When it was first discovered in Barbados, it was named the “forbidden fruit.”

Evergreen tree’s produce grapefruit, usually grow to be around 16-20ft tall. Leaves are dark green, long, and thin. It produces 2 in white flowers, and the fruits skin is a yellow-orange.

The flesh is highly acidic and the pulp varies in color depending on where its cultivated, which includes white, pink, and red pulps with varying sweetness.

The fruit is grown in the U.S in Florida, Texas, Arizona, and California.

Grapefruits contain a number of polyphenolic compounds, including flavanone naringin, alongside the two furanocoumarins bergamottin and dihydroxyberamottin.

Naringenin Health benefits

Anti-microbial properties enhances immunity (immune system modulator)

Preserves youthfulness of skin Regulates antioxidant capacity of catalase and

superoxide dismutase (free radical scavengers) Protects plasma vitamin E Regulates CYP450 Reduction of plasma cholesterol via reduction of

Apo B secretion of LDL to cells This helps lower chances for athlerosclerosis and

heart disease

Case study- Metabolic Syndrome and Naringenin

Naringenin enhances insulin-stimulated tyrosine phosphorylation and improves the cellular actions of

insulin in a dietary model of metabolic syndrome Study explores the effects of naringenin (understood

as an insulin sensitizer) in a high fructose induced model of insulin resistance.

Adult male wistar rats were divided up into two groups and were fed either a starch-based control diet or a high fructose diet (60 g/100 g) for 60 days. From the 16th day, rats in each group were further

divided into two, one of which was administered naringenin (50 mg/kg b.w) and the other was untreated for the next 45 days.

Oral glucose tolerance tests were done on day 59. On day 60, the levels of glucose, insulin, TG, free fatty acids in the blood and the activities of insulin-inducible and suppressible enzymes in cytosolic and mitochondrial fractions of liver and skeletal muscle were assayed.

PTK & PTP Protein tyrosine kinases (PTK) are the

cellular enzymes that phosphorylate the tyrosine residues in proteins while protein tyrosine phosphatases (PTP) selectively dephosphor- ylate the tyrosine residues. The extent of tyrosine phosphorylation on a given protein is controlled by the reciprocal actions of PTP and PTK. Agents which enhance tyrosine phosphorylation could act as effective insulin sensitizers. (Kannappan)

Case Study Results The extent of protein tyrosine phosphorylation in response

to insulin was determined by assaying protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) in the liver.

Results- fructose administration increased the plasma levels of glucose, insulin, TG, and FFA as compared to control rats. Insulin resistance was indicated by alterations in insulin

sensitivity indices. Alterations in enzyme activites and reduced glycogen content were obseved in fructose fed rats. PTP activity was high, while PTK was lower suggesting reduced tyrosine phosphorylation status.

Administration of naringenin improved insulin sensitivity and enhanced tyrosine phosphorylation in fructose-fed animals, while it did not affect the parameters in control diet-fed rats.

Conclusion- Naringenin improves insulin signaling and sensitivity and thereby promotes the cellular actions of insulin in this model.

Kannappan S, Anuradha C V. Naringenin enchances insulin-stimulated tyrosine phosphorylation and improves the cellular actions of insulin in a dietary model of metabolic syndrome. Eur J Nutr. 2010:49:101-109

Naringenin compound in

Grapefruit Grapefruit has a mean 53.00 mg/100 g FW

Minimum of 53.00 mg/100 g FW Max of 53.00 mg/100 g FW

Phenol- Explorer

http://www.phenol-explorer.eu/contents/total?utf8=✓&options%5Bexperimental_method_group_id%5D=1&compound_id=201&commit=Go

Naringenin Polyphenol content

found in foods Values determined by Chromatography Red wine- 0.05 mg/100ml

Grapefruit juice, pure juice- 1.56 mg/ml

Mexican oregano, dried- 372.00 mg/100 g FW Almond- 0.09 mg/100 g FW Pistachio, dehulled- 1.00e-02 mg/100 g FE http://www.phenol-explorer.eu/contents/total?

compound_id=201

Naringenin Polyphenol content

found in foods Values Determined by Chromatography after hydroylsis Orange (Blond)- 11.22 mg/100 g FW Grapefruit- 53.00 mg/100 g FW Lemon- .55 mg/100 g FW Lime- 3.40 mg/100 g FW Orange (Blond), pure juice- 0.80 mg/100ml Tomato, whole, raw- 0.96 mg/100g FW Tomato (Cherry), whole, raw- 3.84 mg/100 g FW

http://www.phenol-explorer.eu/contents/total?utf8=✓&options%5Bexperimental_method_group_id%5D=1&compound_id=201&commit=Go

Grapefruit Health Importance

½ of a grapefruit provides 80% of daily vitamin C Pectin fiber In the fruit helps lower cholesterol Grapefruit seeds have antioxidant properties. Vitamin B6 source, potassium, thiamin, niacin The pink and red hues contain the beneficial

antioxidant lycopene. Grapefruit is very low in calories- just 42 calories

per 100g. The famous “Grapefruit Diet” is based on the

theory being the fruit has a low glycemic index and is able to help the body’s metabolism burn fat.

Grapefruit Health Importance cont.

Grapefruit seed extract has been shown to have strong antimicrobal properties against fungi and bacteria- however there are no studies in humans to document this efficacy.

Studies have hypothesized that grapefruit juice may play a direct role in the development of hormone dependent cancers

A 2007 study found a correlation between eating a quarter of grapefruit daily and a 30% increase in risk for breast cancer in post-menopausal women. The study points to the inhibition of CYP3A4 enzyme by grapefruit, which metabolizes estrogen.

A 2008 study, showed that grapfruit consumption does not increase breat cancer risk and found a significant decrease in breast cancer risk with greater intake of grapefruit in women who never used hormone therapy.

Drug Nutrient Interactions

Grapefruits can have a number of interactions with drugs, often increasing the effective potency of compounds.

The polyphenolic compounds in grapefruits inhibit the drug-metabolizing enzyme isoform CYP3A4 predominately in the small intestine, but at higher doses also inhibits hepatic CYP3A4.

The effect of 4 oz. grapefruit juice can contain enough naringin to inhibit the metabolism of substrates of CYP3A4 in as short as 72 hours, which is why this is problematic.

This inhibition of this enzyme also increases the effects of a variety of drugs by increasing their bioavailability causing drug levels leading to adverse effects and/ or toxicity.

Grapefruits are the first drug-interacting fruit juice documented, highly with statins.

Bioavailability Naringenin is found in grapefruits,

oranges, lemons, limes and tomato skin, but grapefruit provides the highest plasma concentration.

Absorption: 15% of ingested naringenin will be absorbed in the GI tract with the glycosilated form is less bioavailable than the aglycol form

Grapefruit juice can provide much higher plasma concentrations of naringenin than orange juice.

Availability in the market

Production in 4 U.S. sates, counting for 1/2 of the world’s grapefruit output since 1990

Florida (75% of U.S. grapefruit), California, Texas, Arizona

Florida and Texas grapefruit is available from November- June

California and Arizona’s fruit availiable from July-October

Florida’s warm weather allows grapefruit to reach maturity faster, allowing for an early

market.

Ripeness and Storage

Choose a grapefruit that feels solid and weighty. Look for a shiny, smooth skin to be sure of freshness. Reject those with soft areas, large brown spots, or dull dry looking skin.

For optimal bioavailability, keep grapefruits at 65F for a week, and 2-3 weeks in the fruit/veg compartment of the fridge. You may store grapefruit up to 6-8 weeks in the fridge.

The first sign of a grapefruit going bad is the dehydration and collapse of the stem end

Grapefruit Nutritional

Information 100g of grapefruit contains- according to the USDA

Calories: 42 Fat: 0.10 CHO: 8.08 Fibers: 1.1 Protein: 0.68 Cholesterol: 0

Grapefruit recipe Pink Grapefruit Sandwich Cookies

Cookie recipe: Yields 15 sandwich cookies

Ingredients: Grated zest of 1 Ruby Red grapefruit, plus ¼ c freshly squeezed juice 1 c sugar 1 ½ cu all purpose flour, plus more for work surface ¾ c. cake flour (not self-rising) 1 tsp baking powder ½ tsp salt ½ c (1 stick) unsalted butter, softened 2 large egg yolks.Directions: Preheat oven to 350 degrees. Line a baking sheet with parchment paper;

set aside. In a small bowl, combine zest with 1 tbl sugar; set aside. In a medium bowl, whisk together both flours, baking powder, and salt; set aside. In the bowl of an electric mixer fitted with the paddle attachment, beat butter and remaining sugar on med-high speed until light and fluffy, about 2 min., scraping down sides of bowl as needed. Add egg yolks, and beat until combined, scraping down sides of bowl as needed Beat in reserved zest-sugar mixture. Add the flour mixture in two batches, alternating with the juice, and beat to combine.

Grapefruit Recipe, cont.

Turn our dough onto a piece of plastic wrap, and shape into a 1-in thick disk, Wrap in plastic, and refrigerate until firm, about 30 min. On a lightly floured work surface, roll out disk to 1/8 in thick using a lightly floured rolling pin. Using a lightly floured 2 in round cookie cutter, cut out rounds and place about 1 in apart on prepared sheet. Bake, rotating sheet halfway through, until edges are golden: 8-10 min. Transfer to a wire rack to cool completely.

Using an offset spatula, spread 1 tbl filling onto flat sides of half the cookies. Sandwich with remaining cookies, keeping flat sides down. Once filled, cookies can be kept in an airtight container in the refrigerator for up to 3 days.

Grapefruit Recipe, cont.

Cream filling: Yield enough to fill 15 cookies

Ingredients: ½ c. unsalted butter, softened 2 c. confectioners’ sugar 1 tbl honey 3 tbl. Freshly squeezed Ruby Red grapefruit juice 2 tbl grapefruit zest. Directions: In the bowl of an electric mixer fitted with the paddle attachment,

beat butter and sugar until light and fluffy, about 4 minutes. Beat in honey. Add juice 1 tbl at a time, until filling holds together and is smooth and creamy, about 2 min. Add zest. Transfer to a small bowl, cover, and set aside until ready to use.

Grapefruit Recipe, cont.

Adapted from Martha Stewart’s Pink grapefruit sandwich cookies.

http://www.marthastewart.com/286439/grapefruit-recipes/@center/276955/seasonal-produce-recipe-guide#/199922

Fun Facts Grapefruit was first discovered

in the forests of the island of Barbados

Grapefruit got its name from the way it grows on trees, in clusters like grapes

Botanists theorize that the grapefruit is a hybrid of the pomelo and the orange

http://www.youtube.com/watch?v=-le4BhypxR0

What do you think? What is your opinion on giving the

elderly grapefruit if they absolutely love it but their medications suggest to not eat it due to DNI? (not medical opinion, personal)

Would you suggest eating grapefruit as a cholesterol lowering mechanism for your patients?

References Bhagwat S, Haytowitz D B, Holden J M. USDA Database

for the Flavonoid Content of Selected Foods. Nutrient Data Laboratory-Beltsville Human Nutrition Research Center- U.S. Department of Agriculture. 9:2011

Erlund I, Meririnne E, Alfthan G, Aro A. Plasma Kinetics and Urinary Excretion of the Flavanones Naringenin and Hesperetin in Humans after Ingestion of Orange Juice and Grapefruit Juice. Human Nutrition and Metabolism. J. Nutr. 2001:131:235-241

Foreign Agriculture Service Horticultural and Tropical Products Division. Handling charts. http://www.fas.usda.gov/htp . 2005

Grunz G, Haas K, Soukup S et al. Structural features and bioavailability of four flavonids and their implications for lifespan-extending and antioxidant action in C. elegans. Mechanisms of Aging and Development. 2012:133:1-10

References Cont. Kannappan S, Anuradha C V. Naringenin enchances insulin-

stimulated tyrosine phosphorylation and improves the cellular actions of insulin in a dietary model of metabolic syndrome. Eur J Nutr. 2010:49:101-109

Kim E H, Hankinson S E, Eliassen A H, Willet W C. A prospective study of grapefruit and grapefruit juice intake and breast cancer risk. BJC. 1998:1:240-241

Nutrition and You- grapefruit nutrition facts. www.nutrition-and-you.com Last updated December 2009. Accessed May 23, 2012.

Monroe K R, Murphy S P, Kolonel L N, Pike M C. Prospective study of grapefruit intake and the risk of breast cancer in postmenopausal wome: the Multiethnic Cohort Study. BJC. 1997:3:440-445

Phenol-Explorer, Naringenin. Phenol-Explore the database on polyphenol content in foods. http://www.phenol-explorer.eu/ Last updated on October 12, 2011. Accessed on May 23, 2012.

References Cont. Peterson J J, Beecher G R, Bhagwat S A et al. Flavones in grapefruit,

lemons, and limes: A complication and review of the data from the analytical literature. Journal of Food Composition and Analysis. 2005: 19:574-580

Producepedia, Grapefruit. www.producepedia.com Accessed May 23, 2012.

Shulman M, Cohen M, Soto-Gutierrez A et al. Enhancement of Naringenin Bioavailability by complexion with Hydroxypropoyl-B-Cyclodextrin. Plos One. 2011: 6(4). E18033.doi10.1371/journal.pone.0018033

Wikipedia, Flavanone. Wikipedia the Free Encyclopedia. www.wikipedia.org Last revised February 11, 2012. Accessed May 23, 2012.

Wikipedia, grapefruit. Wikipedia The Free Encyclopedia. www.wikipedia.org. Last revised May 12, 2012. Accessed May 23, 2012.

Wikipedia, Naringenin. Wikipedia The Free Encyclopedia. www.wikipedia.org . Last revised