FLAVONOID

Flavonoid (hoặc bioflavonoid) (bắt nguồn từ Latin flavus nghĩa là màu vàng, màu của flavonoid trong tự nhiên) là 1 loại chất chuyển hóa trung gian của thực vật. Tuy nhiên một số flavonoid có màu xanh, tím đỏ và cũng có một số khác lại không có màu. Trong thực vật cũng có một số nhóm hợp chất khác không thuộc flavonoid nhưng lại có màu vàng như carotenoid, anthranoid, xanthon có thể gây nhầm lẫn.

Flavonoid được gọi là vitamin P (do tác dụng thẩm thấu vào thành mạch máu) từ giữa những năm 1930 đến những năm 50 đầu, nhưng thuật ngữ này đã lỗi thời và không còn được sử dụng.^[1]

Theo danh pháp IUPAC,^[2][3], flavonoid có thể được chia thành:

• flavonoids hoặc bioflavonoids.
• isoflavonoids, bắt nguồn từ cấu trúc của 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone)
• neoflavonoids, bắt nguồn từ cấu trúc của 4-phenylcoumarine (4-phenyl-1,2-benzopyrone).

Thuật ngữ flavonoid và bioflavonoid do mô tả các hợp chất polyhydroxy polyphenol không chứa ketone không sát nghĩa nên được gọi một cách chuyên biệt hơn là flavanoids.

Chức năng của flavonoid trong thực vật

Flavonoid phổ biến ở nhiều loại thực vật và có nhiều chức năng.

Flavonoid là một sắc tố sinh học, sắc tố thực vật quan trọng tạo ra màu sắc của hoa, cụ thể giúp sản xuất sắc tố vàng, đỏ, xanh cho cánh hoa để thu hút nhiều động vật đến thụ phấn.

Trong thực vật bậc cao, flavonoids tham gia vào lọc tia cực tím (UV), cộng sinh cố định đạm và sắc tố hoa.

Flavonoids có thể hoạt động như một chất chuyển giao hóa học hoặc điều chỉnh sinh lý. Flavonoids cũng có thể hoạt động như các chất ức chế chu kỳ tế bào.

Flavonoids được tiết ra bởi rễ các cây chủ để giúp vi khuẩn Rhizobia trong giai đoạn lây nhiễm của mối quan hệ cộng sinh với các cây họ đậu (legumes) như đậu cô ve, đậu hà lan, cỏ ba lá (clover), và đậu nành. Rhizobia sống trong đất có thể cảm nhận được chất flavonoid và tiết ra các chất tiếp nhận. Các chất này lần lượt được các cây chủ nhận biết và có thể dẫn đến sự biến dạng các rễ cũng như một số phản ứng của tế bào chẳng hạn như chất khử tạp chất ion và sự hình thành nốt sần ở rễ (root nodule).

Ngoài ra, một số chất flavonoid có hoạt tính ức chế chống lại các sinh vật gây ra như bệnh ở thực vật như Fusarium oxysporum.^[4]

Phân nhóm

Hơn 5000 flavonoid tự nhiên được đặc trưng bởi nhiều loại thực vật khác nhau và được phân loại theo cấu trúc hóa học, và thường được chia thành các phân nhóm sau đây (tham khảo thêm ^[5]):

Anthoxanthins

Anthoxanthins được chia ra thành hai nhóm:^[6]

Nhóm	Khung (skeleton)				Các ví dụ
	Mô tả	Nhóm chức năng		Công thức cấu tạo
		3-hydroxyl	2,3-dihydro
Flavone	2-phenylchromen-4-one	✗	✗		Luteolin, Apigenin, Tangeritin
Flavonol or 3-hydroxyflavone	3-hydroxy-2-phenylchromen-4-one	✓	✗		Quercetin, Kaempferol, Myricetin, Fisetin, Isorhamnetin, Pachypodol, Rhamnazin,Pyranoflavonols, Furanoflavonols

Flavanones

Flavanones

Nhóm	Khung (skeleton)				Các ví dụ
	Mô tả	Nhóm chức năng		Công thức cấu tạo
		3-hydroxyl	2,3-dihydro
Flavanone	2,3-dihydro-2-phenylchromen-4-one	✗	✓		Hesperetin, Naringenin, Eriodictyol, Homoeriodictyol

Flavanonols

Flavanonols

Nhóm	Khung (skeleton)				Các ví dụ
	Mô tả	Nhóm chức năng		Công thức cấu tạo
		3-hydroxyl	2,3-dihydro
Flavanonol or 3-Hydroxyflavanone or 2,3-dihydroflavonol	3-hydroxy-2,3-dihydro-2-phenylchromen-4-one	✓	✓		Taxifolin (hoặc Dihydroquercetin), Dihydrokaempferol

Flavans

Cấu tạo Flavan

Gồm flavan-3-ols (flavanols), flavan-4-ols và flavan-3,4-diols.

Khung	Tên
	Flavan-3-ol (flavanol)
	Flavan-4-ol
	Flavan-3,4-diol (leucoanthocyanidin)

• Flavan-3-ols (flavanols)
  • Flavan-3-ols sử dụng khung 2-phenyl-3,4-dihydro-2H-chromen-3-ol.
    • Catechin (C), Gallocatechin (GC), Catechin 3-gallate (Cg), Gallocatechin 3-gallate (GCg)), Epicatechins (Epicatechin (EC)), Epigallocatechin (EGC), Epicatechin 3-gallate (ECg), Epigallocatechin 3-gallate (EGCg).
  • Theaflavin
  • Theaflavin-3-gallate; Theaflavin-3'-gallate; Theaflavin-3,3'-digallate.
  • Thearubigins.
  • Proanthocyanidins là các dimer, trimer, oligomer, hoặc polymer của các flavanol.

Anthocyanidins

Khung Flavylium của anthocyanidins

• Anthocyanidins

Anthocyanidins là aglycones của anthocyanins. Anthocyanidins sử dụng khung ion flavylium (2-phenylchromenylium).

Các ví dụ: Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin

Isoflavonoids

• Isoflavonoids

• Isoflavones sử dụng khung 3-phenylchromen-4-one (không có sự thay thế nhóm hydroxyl ở carbon vị trí số 2). Ví dụ: Genistein, Daidzein, Glycitein
• Isoflavanes.
• Isoflavandiols.
• Isoflavenes.
• Coumestans.
• Pterocarpans.

Research

In vitro

Flavonoids have been shown to have a wide range of biological and pharmacological activities in in vitro studies. Examples include anti-allergic,^[12] anti-inflammatory,^[12][13] antioxidant,^[13] anti-microbial (antibacterial,^[14][15] antifungal,^[16][17] and antiviral^[16][17]), anti-cancer,^[18][13] and anti-diarrheal activities.^[19] Flavonoids have also been shown to inhibit topoisomerase enzymes^[20][21] and to induce DNA mutations in the mixed-lineage leukemia (MLL) gene in in vitro studies.^[22] However, in most of the above cases no follow up in vivo or clinical research has been performed, leaving it impossible to say if these activities have any beneficial or detrimental effect on human health. Biological and pharmacological activities which have been investigated in greater depth are described below.

In vivo

Flavonoid-rich grape-seed extract has been shown to have antioxidant activity in in vivo studies with rats, protecting their gastrointestinal mucosa against the reactive oxygen species generated by acute and chronic stress.^[23] In the absence of any additional in vivo data, it is impossible to say if these findings are generalizable to all flavonoids. Also, without any clinical studies, it is impossible to say if the antioxidant activity of grape-seed flavonoids offers any protection against oxidative stress in the human gastrointestinal tract.

Research at the Linus Pauling Institute and the European Food Safety Authority shows that flavonoids are poorly absorbed in the human body (less than 5%), with most of what is absorbed being quickly metabolized and excreted.^[24][25][26] These findings suggest that flavonoids have negligible systemic antioxidant activity, and that the increase in antioxidant capacity of blood seen after consumption of flavonoid-rich foods is not caused directly by flavonoids, but due to increased production of uric acid resulting from excretion of flavonoids from the body.^[27]

Inflammation

Inflammation has been implicated as a possible origin of numerous local and systemic diseases, such as cancer,^[28] cardiovascular disorders,^[29] diabetes mellitus^[30] and celiac disease.^[31]

Preliminary studies indicate that flavonoids may affect anti-inflammatory mechanisms via their ability to inhibit reactive oxygen or nitrogen compounds.^[32] Flavonoids have also been proposed to inhibit the pro-inflammatory activity of enzymes involved in free radical production, such as cyclooxygenase, lipoxygenase or inducible nitric oxide synthase,^[32][33] and to modify intracellular signaling pathways in immune cells.^[32]

Procyanidins, a class of flavonoids, have been shown in preliminary research to have anti-inflammatory mechanisms including modulation of the arachidonic acid pathway, inhibition of gene transcription, protein expression and activity of inflammatory enzymes, as well as secretion of anti-inflammatory mediators.^[34]

Cancer

While some clinical studies have suggested flavonoids have a role in cancer prevention,^[35][36] others have been inconclusive or suggested they may be harmful.^[37][36][38] Such conflicting findings have been attributed, in part, to the fact that many of the studies are retrospective in design and use a small sample size. A call has been made for more prospective clinical studies with larger sample sizes.^[36]

In 2012, researchers from the European Prospective Investigation into Cancer and Nutrition (EPIC) reported the findings of one such prospective study. After comparing dietary flavonoid and lignan intake with the incidence of gastric carcinoma in ~475,000 people from 10 European countries, they concluded that dietary flavonoid intake is associated with reduced gastric carcinoma risk in women but not men.^[39] Further research is needed to understand the nature of this association, and determine whether or not the association exists in women from non-European countries.

Cardiovascular diseases

Among the most intensively studied of general human disorders possibly affected by dietary flavonoids, preliminary cardiovascular disease research has revealed the following mechanisms under investigation in patients or normal subjects^{[40][41][42][43]}

• inhibit coagulation, thrombus formation or platelet aggregation
• reduce risk of atherosclerosis
• reduce arterial blood pressure and risk of hypertension
• reduce oxidative stress and related signaling pathways in blood vessel cells
• modify vascular inflammatory mechanisms
• improve endothelial and capillary function
• modify blood lipid levels
• regulate carbohydrate and glucose metabolism
• modify mechanisms of aging

Listed on the clinical trial registry of the US National Institutes of Health (November 2013) are 36 human studies completed or underway to study the dietary effects of plant flavonoids on cardiovascular diseases.^[44]

Antibacterial

Flavonoids have been shown to have (a) direct antibacterial activity, (b) synergistic activity with antibiotics, and (c) the ability to suppress bacterial virulence factors in numerous in vitro and a limited number of in vivo studies.^[14][45] Noteworthy among the in vivo studies^[46][47][48] is the finding that oral quercetin protects guinea pigs against the Group 1 carcinogen Helicobacter pylori.^[48] Researchers from the European Prospective Investigation into Cancer and Nutrition have speculated this may be one reason why dietary flavonoid intake is associated with reduced gastric carcinoma risk in European women.^[39] Additional in vivo and clinical research is needed to determine if flavonoids could be used as pharmaceutical drugs for the treatment of bacterial infection, or whether dietary flavonoid intake offers any protection against infection.

Dietary sources

Flavonoids (specifically flavanoids such as the catechins) are "the most common group of polyphenolic compounds in the human diet and are found ubiquitously in plants".^[49] Flavonols, the original bioflavonoids such as quercetin, are also found ubiquitously, but in lesser quantities. The widespread distribution of flavonoids, their variety and their relatively low toxicity compared to other active plant compounds (for instance alkaloids) mean that many animals, including humans, ingest significant quantities in their diet. Foods with a high flavonoid content include parsley,^[50] onions,^[50] blueberries and other berries,^[50] black tea,^[50] green tea and oolong tea,^[50] bananas, all citrus fruits, Ginkgo biloba, red wine, sea-buckthorns, and dark chocolate (with a cocoa content of 70% or greater). Further information on dietary sources of flavonoids can be obtained from the US Department of Agriculture flavonoid database.^[50]

Parsley

Parsley, both fresh and dried, contains flavones.^[50]

Blueberries

Blueberries are a dietary source of anthocyanidins.^[50]

Black tea

Black tea is a rich source of dietary flavan-3-ols.^[50]

Citrus

The citrus flavonoids include hesperidin (a glycoside of the flavanone hesperetin), quercitrin, rutin (two glycosides of the flavonol quercetin), and the flavone tangeritin.

Wine

Main article: Polyphenols in wine

Dark Chocolate

Main article: Health effects of chocolate

Flavonoids exist naturally in cacao, but because they can be bitter, they are often removed from chocolate, even dark chocolate.^[51] Although flavonoids are present in milk chocolate, milk may interfere with their absorption.^[52][53]

Subgroups

Over 5000 naturally occurring flavonoids have been characterized from various plants. They have been classified according to their chemical structure, and are usually subdivided into the following subgroups (for further reading see ^[54]):

Anthoxanthins

Anthoxanthins are divided into two groups:^[55]

Group		Skeleton				Examples
		Description	Functional groups		Structural formula
			3-hydroxyl	2,3-dihydro
Flavone		2-phenylchromen-4-one	✗	✗		Luteolin, Apigenin, Tangeritin
Flavonol or 3-hydroxyflavone		3-hydroxy-2-phenylchromen-4-one	✓	✗		Quercetin, Kaempferol, Myricetin, Fisetin, Galangin, Isorhamnetin, Pachypodol, Rhamnazin,Pyranoflavonols, Furanoflavonols,

Flavan

Flavanones

Flavanones

Group	Skeleton				Examples
	Description	Functional groups		Structural formula
		3-hydroxyl	2,3-dihydro
Flavanone	2,3-dihydro-2-phenylchromen-4-one	✗	✓		Hesperetin, Naringenin, Eriodictyol, Homoeriodictyol

Flavanonols

Flavanonols

Group	Skeleton				Examples
	Description	Functional groups		Structural formula
		3-hydroxyl	2,3-dihydro
Flavanonol or 3-Hydroxyflavanone or 2,3-dihydroflavonol	3-hydroxy-2,3-dihydro-2-phenylchromen-4-one	✓	✓		Taxifolin (or Dihydroquercetin), Dihydrokaempferol

Flavans

Flavan structure

Include flavan-3-ols (flavanols), flavan-4-ols and flavan-3,4-diols.

Skeleton	Name
	Flavan-3-ol (flavanol)
	Flavan-4-ol
	Flavan-3,4-diol (leucoanthocyanidin)

• Flavan-3-ols (flavanols)
  • Flavan-3-ols use the 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton.
    • Catechin (C), Gallocatechin (GC), Catechin 3-gallate (Cg), Gallocatechin 3-gallate (GCg)), Epicatechins (Epicatechin (EC)), Epigallocatechin (EGC), Epicatechin 3-gallate (ECg), Epigallocatechin 3-gallate (EGCg)
  • Theaflavin.
  • Theaflavin-3-gallate; Theaflavin-3'-gallate; Theaflavin-3,3'-digallate.
  • Thearubigins.
  • Proanthocyanidins are dimers, trimers, oligomers, or polymers of the flavanols.

Anthocyanidins

Flavylium skeleton of anthocyanidins

• Anthocyanidins

Anthocyanidins are the aglycones of anthocyanins. Anthocyanidins use the flavylium (2-phenylchromenylium) ion skeleton

Examples: Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin

Isoflavonoids

• Isoflavonoids
  • Isoflavones use the 3-phenylchromen-4-one skeleton (with no hydroxyl group substitution on carbon at position 2). Examples: Genistein, Daidzein, Glycitein
  • Isoflavanes.
  • Isoflavandiols.
  • Isoflavenes.
  • Coumestans.
  • Pterocarpans.