10.3 Flavonoids

Flavonoids are a diverse group of plant compounds with powerful health benefits. Found in fruits, vegetables, and herbs, they act as antioxidants and anti-inflammatories in the body. Their unique chemical structure allows them to combat oxidative stress and modulate various biological processes.

From biosynthesis to absorption, flavonoids undergo complex pathways in plants and humans. Understanding their structure-activity relationships is key to harnessing their therapeutic potential for conditions like cancer, heart disease, and neurodegeneration. Ongoing research aims to optimize their bioavailability and efficacy.

Structure of flavonoids

• Flavonoids are a diverse class of polyphenolic compounds widely distributed in plants and play crucial roles in plant physiology and human health
• The basic structure of flavonoids consists of a 15-carbon skeleton with two phenyl rings (A and B) connected by a heterocyclic pyran ring (C)
• Variations in the oxidation state, hydroxylation pattern, and substitution of the C-ring give rise to different subclasses of flavonoids

Common flavonoid subclasses

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• Flavonols (quercetin, kaempferol) have a 3-hydroxyflavone backbone and are the most abundant flavonoids in fruits and vegetables
• Flavones (apigenin, luteolin) have a 2-phenylchromen-4-one backbone and are found in parsley, celery, and chamomile tea
• Flavanones (hesperetin, naringenin) have a 2,3-dihydro-2-phenylchromen-4-one structure and are present in citrus fruits
• Flavan-3-ols (catechins, epicatechins) have a 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton and are found in tea, cocoa, and red wine
• Anthocyanidins (cyanidin, delphinidin) have a flavylium cation structure and are responsible for the red, blue, and purple colors of fruits and flowers
• Isoflavones (genistein, daidzein) have a 3-phenylchromen-4-one backbone and are predominantly found in legumes, especially soybeans

Functional groups in flavonoids

• Hydroxyl (-OH) groups are the most common substituents in flavonoids and contribute to their antioxidant and metal-chelating properties
• Methoxy (-OCH3) groups can replace hydroxyl groups through methylation, altering the solubility and biological activity of flavonoids
• Glycosidic bonds connect sugar moieties (glucose, rhamnose, galactose) to the flavonoid aglycone, affecting their absorption and bioavailability
• Acylation with aromatic or aliphatic acids can modify the stability and solubility of flavonoids
• The presence or absence of a C2-C3 double bond in the C-ring influences the planarity and conjugation of the flavonoid structure

Biosynthesis of flavonoids

• Flavonoids are synthesized through the phenylpropanoid pathway, which starts with the amino acid phenylalanine
• The biosynthesis of flavonoids involves the sequential action of enzymes located in the cytoplasm and endoplasmic reticulum of plant cells
• The diversity of flavonoids arises from the various modifications and substitutions that occur during their biosynthesis

Key enzymes for flavonoid synthesis

• Phenylalanine ammonia-lyase (PAL) catalyzes the deamination of phenylalanine to cinnamic acid, the first step in the phenylpropanoid pathway
• Cinnamate 4-hydroxylase (C4H) and 4-coumaroyl CoA ligase (4CL) convert cinnamic acid to p-coumaroyl CoA, a precursor for flavonoid biosynthesis
• Chalcone synthase (CHS) condenses p-coumaroyl CoA with three molecules of malonyl CoA to form chalcone, the backbone of flavonoids
• Chalcone isomerase (CHI) isomerizes chalcone to form flavanone, which serves as a precursor for various flavonoid subclasses
• Flavanone 3-hydroxylase (F3H) and flavonol synthase (FLS) catalyze the formation of flavonols from flavanones
• Dihydroflavonol 4-reductase (DFR) and anthocyanidin synthase (ANS) are involved in the biosynthesis of anthocyanidins from dihydroflavonols

Regulation of flavonoid biosynthesis

• Flavonoid biosynthesis is regulated by various environmental factors, such as light, temperature, and nutrient availability
• UV-B radiation induces the expression of flavonoid biosynthetic genes, leading to increased accumulation of photoprotective flavonoids in plants
• Transcription factors, such as MYB, bHLH, and WD40 proteins, form complexes that regulate the expression of flavonoid biosynthetic genes
• Hormones, such as jasmonic acid and abscisic acid, can modulate the expression of flavonoid biosynthetic genes in response to biotic and abiotic stresses
• Genetic engineering approaches, such as overexpression or silencing of key biosynthetic genes, can be used to manipulate flavonoid content in plants

Pharmacological activities of flavonoids

• Flavonoids exhibit a wide range of pharmacological activities, making them attractive candidates for the prevention and treatment of various diseases
• The health benefits of flavonoids are attributed to their antioxidant, anti-inflammatory, anticancer, cardiovascular, neuroprotective, and antimicrobial properties
• The structure-activity relationships of flavonoids play a crucial role in determining their biological activities and potential therapeutic applications

Antioxidant properties of flavonoids

• Flavonoids act as potent antioxidants by scavenging reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are involved in oxidative stress and cellular damage
• The hydroxyl groups of flavonoids can donate hydrogen atoms to neutralize free radicals, such as superoxide anion (O2•-), hydroxyl radical (•OH), and peroxyl radical (ROO•)
• Flavonoids can chelate metal ions, such as iron and copper, preventing them from catalyzing the formation of ROS through Fenton reactions
• The antioxidant activity of flavonoids depends on their structure, with the presence of a catechol group in the B-ring and a 2,3-double bond in conjugation with a 4-oxo group in the C-ring being important for optimal radical scavenging
• Examples of flavonoids with strong antioxidant activity include quercetin, catechin, and cyanidin

Anti-inflammatory effects of flavonoids

• Flavonoids exhibit anti-inflammatory properties by modulating the production and activity of inflammatory mediators, such as cytokines, chemokines, and eicosanoids
• Flavonoids can inhibit the expression and activity of pro-inflammatory enzymes, such as cyclooxygenase (COX), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS)
• Certain flavonoids, such as quercetin and kaempferol, can suppress the activation of nuclear factor-kappa B (NF-κB), a transcription factor that regulates the expression of pro-inflammatory genes
• Flavonoids can reduce the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6)
• Examples of flavonoids with anti-inflammatory activity include apigenin, luteolin, and hesperetin

Anticancer potential of flavonoids

• Flavonoids have been shown to possess anticancer properties through various mechanisms, including cell cycle arrest, apoptosis induction, and inhibition of angiogenesis and metastasis
• Flavonoids can modulate the activity of signaling pathways involved in cancer cell proliferation and survival, such as the PI3K/Akt, MAPK, and Wnt/β-catenin pathways
• Certain flavonoids, such as genistein and epigallocatechin gallate (EGCG), can inhibit the activity of oncogenic proteins, such as tyrosine kinases and topoisomerases
• Flavonoids can induce apoptosis in cancer cells by activating caspases and regulating the expression of pro-apoptotic and anti-apoptotic proteins, such as Bax and Bcl-2
• Examples of flavonoids with anticancer activity include fisetin, baicalein, and daidzein

Cardiovascular benefits of flavonoids

• Flavonoids have been associated with a reduced risk of cardiovascular diseases, such as atherosclerosis, hypertension, and coronary heart disease
• Flavonoids can improve endothelial function by increasing the production and bioavailability of nitric oxide (NO), a vasodilator that regulates blood pressure and vascular tone
• Certain flavonoids, such as quercetin and catechin, can inhibit the oxidation of low-density lipoprotein (LDL) cholesterol, a key step in the development of atherosclerosis
• Flavonoids can reduce platelet aggregation and thrombus formation by inhibiting the activity of cyclooxygenase-1 (COX-1) and thromboxane A2 (TXA2)
• Examples of flavonoids with cardiovascular benefits include hesperidin, naringenin, and epicatechin

Neuroprotective roles of flavonoids

• Flavonoids have been shown to exert neuroprotective effects, making them potential candidates for the prevention and treatment of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases
• Flavonoids can reduce oxidative stress and inflammation in the brain, which are implicated in the pathogenesis of neurodegenerative diseases
• Certain flavonoids, such as quercetin and rutin, can inhibit the formation and aggregation of amyloid-beta (Aβ) peptides, a hallmark of Alzheimer's disease
• Flavonoids can modulate the activity of neurotransmitter systems, such as the cholinergic, dopaminergic, and serotonergic systems, which are affected in neurodegenerative disorders
• Examples of flavonoids with neuroprotective activity include epigallocatechin gallate (EGCG), baicalein, and nobiletin

Antimicrobial activity of flavonoids

• Flavonoids have been shown to possess antimicrobial properties against a wide range of bacteria, viruses, and fungi
• Flavonoids can disrupt the integrity of the microbial cell membrane, leading to the leakage of intracellular components and cell death
• Certain flavonoids, such as quercetin and kaempferol, can inhibit the activity of bacterial enzymes involved in cell wall synthesis and nucleic acid replication
• Flavonoids can interfere with the viral replication cycle by inhibiting the activity of viral enzymes, such as reverse transcriptase and protease
• Examples of flavonoids with antimicrobial activity include galangin, myricetin, and chrysin

Structure-activity relationships of flavonoids

• The biological activities of flavonoids are strongly influenced by their chemical structure, including the number and position of functional groups, the presence of double bonds, and the degree of polymerization
• Understanding the structure-activity relationships (SARs) of flavonoids is crucial for the design and development of flavonoid-based therapeutics with enhanced efficacy and selectivity
• Variations in the hydroxylation, glycosylation, methoxylation, and saturation of flavonoids can significantly impact their pharmacological properties and bioavailability

Hydroxylation patterns vs bioactivity

• The number and position of hydroxyl groups on the flavonoid skeleton play a critical role in determining their antioxidant, anti-inflammatory, and anticancer activities
• Flavonoids with a catechol group (3',4'-dihydroxy) in the B-ring, such as quercetin and catechin, exhibit higher antioxidant activity compared to those with a single hydroxyl group
• The presence of a 3-hydroxyl group in the C-ring enhances the ability of flavonoids to chelate metal ions and scavenge free radicals
• Hydroxylation at the 5 and 7 positions of the A-ring is important for the anti-inflammatory activity of flavonoids, as exemplified by apigenin and luteolin
• Increasing the number of hydroxyl groups can improve the water solubility of flavonoids but may reduce their lipophilicity and cellular uptake

Glycosylation vs aglycone forms

• Flavonoids can exist in their aglycone (without sugar) or glycosidic (with sugar) forms, which significantly affects their absorption, metabolism, and biological activity
• Glycosylation increases the water solubility and stability of flavonoids but can hinder their absorption in the small intestine
• Flavonoid glycosides are typically hydrolyzed by intestinal enzymes or gut microbiota before being absorbed as aglycones
• Aglycones are generally more lipophilic and can passively diffuse across cell membranes, leading to higher cellular uptake and bioavailability
• The position and type of sugar moiety attached to the flavonoid skeleton can influence their biological activities, such as the anti-inflammatory effects of hesperidin and naringin

Methoxylation vs hydroxylation

• Methoxylation involves the replacement of a hydroxyl group with a methoxy group, which can alter the physical, chemical, and biological properties of flavonoids
• Methoxylated flavonoids, such as tangeretin and nobiletin, are more lipophilic and can penetrate cell membranes more easily than their hydroxylated counterparts
• Methoxylation can enhance the metabolic stability of flavonoids by protecting them from rapid conjugation and elimination
• However, methoxylation can also reduce the antioxidant activity of flavonoids by blocking the hydroxyl groups involved in radical scavenging
• The balance between methoxylation and hydroxylation can be fine-tuned to optimize the bioavailability and biological activity of flavonoids

Double bond vs single bond in C-ring

• The presence or absence of a C2-C3 double bond in the C-ring of flavonoids can significantly impact their structural and biological properties
• Flavonoids with a C2-C3 double bond, such as flavones and flavonols, have a planar structure that allows for extended conjugation and electron delocalization
• The C2-C3 double bond enhances the stability and antioxidant activity of flavonoids by facilitating electron transfer and resonance stabilization of the radical species
• Flavonoids lacking the C2-C3 double bond, such as flavanones and flavan-3-ols, have a non-planar structure and exhibit lower antioxidant activity
• The saturation of the C2-C3 double bond can increase the flexibility of the flavonoid skeleton, which may influence their binding to target proteins and receptors

Absorption and metabolism of flavonoids

• The absorption and metabolism of flavonoids are complex processes that involve various enzymes, transporters, and microbiota in the gastrointestinal tract and liver
• Understanding the bioavailability and biotransformation of flavonoids is essential for predicting their in vivo effects and potential drug interactions
• Factors such as the flavonoid structure, food matrix, and individual variations in gut microbiota can significantly influence the absorption and metabolism of flavonoids

Bioavailability of flavonoids

• Bioavailability refers to the fraction of an ingested flavonoid that reaches the systemic circulation and is available for biological activity
• Flavonoids generally have low to moderate bioavailability due to their limited absorption, extensive metabolism, and rapid elimination
• The bioavailability of flavonoids is influenced by their chemical structure, with aglycones being more readily absorbed than glycosides
• The presence of food matrix components, such as dietary fiber and proteins, can affect the release and solubilization of flavonoids in the gastrointestinal tract
• Flavonoids with higher lipophilicity, such as isoflavones and flavanones, tend to have higher bioavailability compared to more hydrophilic flavonoids, such as flavonols and anthocyanins

Intestinal absorption of flavonoids

• Flavonoids are primarily absorbed in the small intestine, with the colon playing a minor role in the absorption of some flavonoid metabolites
• Flavonoid glycosides are typically hydrolyzed by lactase-phlorizin hydrolase (LPH) in the brush border of the small intestine, releasing the aglycone for absorption
• Aglycones can passively diffuse across the intestinal epithelium or be actively transported by carriers, such as the sodium-dependent glucose transporter 1 (SGLT1) and the monocarboxylate transporter 1 (MCT1)
• Some flavonoid glycosides, such as quercetin-3-glucoside, can be directly absorbed by the sodium-dependent glucose transporter 1 (SGLT1) without prior hydrolysis
• Efflux transporters, such as P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs), can limit the absorption of flavonoids by pumping them back into the intestinal lumen

Hepatic metabolism of flavonoids

• After absorption, flavonoids undergo extensive first-pass metabolism in the liver, which can significantly reduce their bioavailability and alter their biological activity
• Flavonoids are