Recent Advances on Flavonoids and their Bioavailability

Amber Bates, Amanda Broome, Leah Crosby and Laura Offutt

Texas Tech University

November 9, 2007

Flavonoid Structure

(Liu, 2004)

Structure of Flavonoid Classes

(Liu, 2004)

There is growing evidence from human feeding studies that the absorption and bioavailability of specific flavonoids is much higher than originally

believed (Ross and Kasum, 2002).

Bioavailability• Structure

– Aglycone (aglycone)– Glycoside (aglycone+sugar)– Aglycones are freely absorbed from the gut by passive

diffusion, while glycosides are hydrolyzed by colon microflora before it is absorbed gastro intestinally (Meyer et al., 2006).

• Location– Liver– Colon

• Individual• Food (Preparation)

http://pennhealth.com/health_info/Surgery/abdominalexploration_1.html

Anthocyanidins

Anthocyanidins200g grapes = 150mg anthocyanidins

100g blueberries = 500mg anthocyanidins

300ml red wine = 100mg anthocyanidins

(Manach and Donovan, 2004)

Anthocyanidin Structure6 found in fruits and Vegetables:CyanidinDelphinidinPetunidinPeonidinPelargonidin Malvidin

(Prior and Wu, 2006)

wwwchem.uwimona.edu.jm

Health Benefits• Prevention

– Heart disease– Cancer– Age-related brain

problems

• Mechanisms– Free radical scavenging– Metal chelating– Protein binding– Antioxidants(Wu et al., 2002)

Breakdown

• Present as β-glycosides

• Hydrolyzation

• Deglycosylation due to gut flora

(Aura, 2005)

www.friedli.com

Absorption

• Lactase phloridzin hydrolase (LPH) hydrolyzes most anthocyanidins allowing them to be absorbed by the small intestine (Hollman, 2004).

• Cyanidin-3-glucoside is not hydrolyzed in the small intestine (Aura, 2005).

• Bilitranslocase plays a role in absorption at the gastric level (Passamonti et al, 2003).

• Plasma levels taken after 150mg to 2g anthocyanidin consumption were less than 0.02 mmol/l (Manach and Adonovan, 2004).

• Peak concentration of anthocyanidins after elderberry consumption was reached in after 2 hours (Murkovic et al, 1999).

• Age plays no role in absorption

(Wu et al, 2002).

• pH may play a role in absorption

(Aura et al, 2005).

Excretion

• Rapid excretion in urine (Manach and Adonovan, 2004).

• 60-90% of anthocyanidins are lost within four hours of a meal (Prior and Wu, 2006).

Is More Better?

• Studies have shown maxiumum absorption to be 350µmol (Prior and Wu, 2006).

• A higher maxiumum absorbtion may be possible with strawberry (Carkeet et al., 2007).

Tissue Distribution• Blackberry

anthocyanidins have reached the brain, stomach , liver, and kidney (Prior and Wu, 2006).

Flavanols

Flavanols

• The structure of flavanols is similar to its counter parts except it is lacking an oxygen group at the 4-position of the heterocyclic C-ring (Hollman and Arts, 2000).

http://www.freepatentsonline.com/20040162338-0-large.jpg

Flavanols• Flavanols are found in many foods.

– Green and black tea– Strawberry, apricot, pear, cherry, peach, and

plum

FreeFoto.com

Flavanols• Red wines have been proven to have high

flavanol content (Hollman and Arts, 2000).– Pinot Noir grapes– Grape cultivar is important for flavanol content.

FreeFoto.com

Flavanols

• Tea is considered the most important flavanol source in many countries (Hollman and Arts, 2000).

Flavanols

• Studies have shown the impact of post harvest handling of fruits and vegetables can be detrimental to the flavanol contents.

• As a result, oxidation and polymerization of flavanols can reduce the content of monomeric flavanols by as much as 90%.

(Hollman and Arts, 2000)

Flavanol Bioavailability

• Bioavailability of flavanols has been researched with green tea (GT) and black tea (BT).

• The result of these studies suggest that tea polyphenols can be absorbed by humans.

(Warden et al.2001)

Flavanol Bioavailability

• Metabolism is important in the absorbtion of any food.

• In the metabolism of flavonoids, two compartments are important– First is tissues in the body– Second is the colon (Hollman and Arts, 2000)

Flavonols

Flavonol Fruits and Vegetables

www.viva.org.uk, http://flavo.vtt.fi/flavonols.htm, http://www.onions-usa.org/, http://en.wikipedia.org/wiki/Kale, www.worldcommunitycookbook.org/.../broccoli.jpg, http://en.wikipedia.org/wiki/Camellia_sinensis, http://www.cheapwine.fr/fx/red-wine.jpg

Quercetin

Myricetin

Kaempferol

Flavonol Structure

www.biochemj.org http://www.wilshiretechnologies.com/images/antioxidants/myricetin.gif

Myricetin

OCH3

OH

Isorhamnetin

Flavonol Bioavailability

• Studies assumed the polar flavonoid glucosides could not be absorbed in the small intestine

• Absorption dependent on b-glucoside linkage by the colonic microflora

(Griffiths, and Barrow, 1972)

Quercetin Bioavailability • Pig gastrointestinal system is much like the human system

(Cermak et. al, 2003)

• Quercetin aglycone (a non-sugar molecule) and quercetin-3-O-glucoside (sugar molecule) was enhanced with a higher fat diet compared to a lower fat diet (Lesser et. al, 2004).

• Improved quercetin solubility with an accelerated absorption of the lipophilic quercetin aglycone; this was enhanced by a prolonged circulation of bile from the liver that assisted in digestion of the lipophilic aglycone (Lesser et. al, 2004)

• Glucosides (from onion) were more bioavailable than the glycosides and rutinosides (purest form); the sugar moiety is therefore important in determining the uptake of quercetin in its various forms (Hollman and Arts, 2000)

Pig

Human

Quercetin Bioavailability

Walle et al., 2001(Walle et al., 2001)

Quercetin Bioavailability

(Walle et al., 2001)

Quercetin Bioavailability

• Quercetin measured in plasma after oral consumption of quercetin from red wine was lower than consumption of onions and not different from consumption of black tea (Walle et al., 2001).

Isorhamnetin Bioavailability

• Isorhamnetin were fully metabolized in the intestine because no flavonols were found in the plasma therefore, intestine can methylate flavonols (Cermak et. al, 2003)

• Isorhamnetin was measured as a quercetin metabolite and it was observed that both the quercetin-3-glucoside and the quercetine-49-glucoside was methylated into isorhamnetin after absorption by the body plasma (Olthof et al., 2000),

Kaempferol Bioavailability

“Kaempferol is a efficient scavenger of DPPH radicals and a better inhibitor of xanthine/xanthine oxidase than the two glycosides” (Park et al., 2006).

Flavanones

Flavanones• Major dietary sources are citrus fruits.• Most common are hesperidin and

naringenin (Ross and Kasum, 2002).

http://giniann.wordpress.com/category/quick-meals/, http://www.news-medical.net/?id=10213

Flavanones Bioavailability

• Intestinal microflora, which is responsible for breaking down naringenin and hesperidin, is different for each individual; thus varying degrees of absorption occur (Erlund et al., 2002).

Hesperidin Bioavailability• The structure of hesperidin is an aglycone, glucose, and

a rhamnose sugar, of which the latter decreases absorption.

(Nielson et al., 2006)

Flavones

Flavones• Major dietary sources: parsley, thyme, and celery.

• The most abundant flavones in plants are luteolin (5,7,3’,4’-tetrahydroxyflavone) and apigenin (5,7,4’-trihydroxyflavone) (Hollman and Arts, 2000).

http://www.bigoven.com/whatis.aspx?id=Parsley, http://whatscookingamerica.net/thyme.htm, http://www.assuredproduce.co.uk/ap/consumers/producelibrary.aspx?id=145559

Flavones Bioavailability• Bioavailability of flavones low due to low solubility or the high

degree of first pass metabolism (Siu et al., 2005).• Apigenin is the least soluble while luteolin is the most soluble

(Siu et al., 2005).

Stomach

Mouth

Small intestine

common bile duct

Liver

bilebile

food

food

Diagram of First-Pass Metabolismhttp://www.nara-wu.ac.jp/life/food/foodchem/inoue_top.html, http://www.food-info.net/uk/qa/qa-fp120.htm

Luteolin

Apigenin Bioavailability• After consumption

of parsley, apigenin is detected in plasma (Meyer et al., 2006).

• Maximum concentrations ranged from 28.75 to 337.46 nmol/l (Meyer et al., 2006).

http://www.esa.int/esaHS/SEMQRH7LURE_iss_3.html

ConclusionsBioavailability of flavonoids is dependent on:

Structure Location

Individual Food (Preparation)

The physiological interest of dietary polyphenols depends on their intestinal absorption and their

subsequent interactions with target tissues; however the mechanisms of gastrointestinal absorption of polyphenols are not completely

understood (Silberberg et al., 2006).

Literature CitedAura, A., P. Martin-Lopez, K. O’Leary, G. Williamson, K. Oksman-Caldentey, K. Poutanen, C. Santos-

Buelga. 2005. In Vitro Metabolism of Anthocyanins by Human Gut Microflora. Eur. J. Nutr. 44:133-142.

Carkeet, Colleen, Beverly Clevidence, and Janet Novotny. 2007. Absorption and metabolism of pelargonidin-3-glucoside with increasing strawberry dose. FASEB Journal 21:5: A120-A120.Griffiths, L. A. & Barrow, A. 1972 Metabolism of flavonoid compoundsin germ-free rats. Biochem. Journal 130: 1161–1162.

Cermak, R., S. Landgraf, and S. Wolffram. 2003. The bioavailability of quercetin in pigs depnds on the glycoside moiety and on dietary factors. American Society for Nutritional Sciences. 2802.

Erlund, I., Silaste, M.L., Alfthan, G., Rantala, M., Kesaniemi, Y.A. and A. Aro. 2002. Plasma concentrations of the flavonoids hesperitin, naringenin and quercetin in human subjects following their habitual diets, and diets high or low in fruit and vegetables. European Journal of Clinical Nutrition. 56: 891-898.

Hollman, P.C.H. and I.C.W. Arts. 2000. Flavonols, flavones and flavanols- nature, occurrence and dietary burden. Journal of the Sciences of Food and Agriculture. 80: 1081-1093.

Hollman, P. Absorption, Bioavailability, and Metabolism of Flavonoids. 2004. Pharmaceutical Biology 42: 74-83.

Liu, H.R. 2004. Potential Synergy of Phytochemicals in Cancer Prevention: Mechanisms of Action. Journal of Nutrition. 3479S-3485S

Lesser, S., R. Cermak, S. Wolffram. 2004. Bioavailability of quercetin in pigs is influenced by the dietary fat content. Journal of Nutrition 134: 1508-1511.Meyer, H., A. Bolarinwa, G. Wolfram, and J. Linseisen. 2006. Bioavailability of Apigenin from Apiin-Rich Parsley in Humans. 50: 167-172.

Murkovic, M., H. Toplak, U. Adam, and W. Pfannhauser. Analysis of Anthocyanins in Plasma for Determination of Their Bioavailability. Journal of Food Composition and Analysis 13: 291-296.

Manach, C. and J. Donovan. 2004. Pharmacokinetics and Metabolism of Dietary Flavonoids in Humans. Free Radical Research 38: 77-785.

Literature Cited (continued)Nielson, L.F., Chee, W.S.S., Poulsen, L., Offord-Cavin, E., Rasmussen, S.E., Frederiksen, H., Enslen, M.,

Barron, D., Horcajada, M-N. and G. Williamson. 2006. Bioavailability is improved by enzymatic modification of the citrus flavonoid Hesperidin in humans: A randomized, double-blind, crossover trail. Journal of Nutrition. 136: 404-408.

Olthof, M.R., P.C.H. Hollman, T.B. Vree, and M.B. Katan. 2000. Glucoside and Quercetin-4-Glucoside do not differ in humans. Human Nutrition and Metabolism – Research Communication 130 (5): 1200 – 1204.

Park, J.S., H.S.Rho, D.H. Kim, and IH.S. Chang. 2006. Enzymatic Preparation of Kaempferol from Green Tea Seed and Its Antioxidant Activity. J. Agric. Food Chem. 54, 2951-2956.

Passamonti S., U. Vrhovsek, A. Vanzo, F. Mattivi. 2003. The Stomach as a Site for Anthocyanins Absorption from Food. FEBS Letters 544: 210-213.

Prior, R. and X. Wu. 2006. Anthocyanins: Structural Characteristics that Result in Unique Metabolic Patterns and Biological Activities. Free Radical Research 40: 1014-1028.

Ross, J.A., and C.M. Kasum. 2002. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu. Rev. Nutr. 22:19-34.

Siu, P.N., Wong, K.Y., Zhang, L. and Z. Zuo. 2005. Evaluation of the first-pass glucuronidation of selected flavones in gut by Caco-2 monolayer model. J Pharmaceutical Sci 8:1-9.

Silberberg, M., C., Morand, T., Mathevon, C., Besson, C., Manach, A., Scalbert and C. Remesy. 2006. The bioavailability of polyphenols is highly governed by the capacity of the intestine and the liver to secrete conjugated metabolites. Eur. J. Nutr. 45:88-96.

Walle, T., K. Walle, P.V. Halushka. 2001. Carbon Dioxide is the Major Metabolite of Quercetin. Human Nutrition and Metabolism 131 (10): 2648.

Warden, Beverly A., Lametta S. Smith, Gary R. Beecher, Douglas A. Balentine and Beverly A. Clevidence. Catechins Are Bioavailable in Men and Women Drinking Black Tea throughout the Day. Journal of Nutrition 131: 1731 – 1737, 2001.

Wu, X., G. Cao, and R. Prior. 2002. Absorption and Metabolism of Anthocyanins in Elderly Women After Consumption of Elderberry or Blueberry. J. Nutr. 132: 1865-1871.

QUESTIONS?