FLAVONOIDS: BIOCHEMISTRY, BIOPHYSICS, MEDICINE - Tarakhovsky Yu. S. - 2013

PART 1. MAJOR FLAVONOIDS

1.6. Flavanonols (Dihydroflavonols)

Flavanonols (Fig. 13) are quite widely distributed in nature. They are found in ferns, gymnosperms, and angiosperms. The highest number of species containing flavanonols belongs to the families Fabaceae, Asteraceae, Pinaceae, Moraceae, and Rutaceae. They are predominantly localized in the wood, bark, leaves, or roots of plants.

Class="center">Fig. 13. Most prominent flavanonols

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1.6.1. Taxifolin (Dihydroquercetin)

Taxifolin is present in lemons, grapes, tomatoes, apples, and red onion varieties. It is found in the widely distributed herbaceous plant milk thistle (Silybum marianum). Taxifolin has also been detected in the fruits of the Amazonian acai palm (Euterpe oleracea) and in the conifer sometimes referred to as the Japanese cypress (Chamaecyparis obtusa). Additionally, taxifolin can be produced from (+)-catechin using Burkholderia sp. KTC-1 Bacteria, recently isolated from peat. The taxifolin glycoside astilbin has been found in the bark of the Brazilian tree Hymenaea martiana and the Brazilian shrubs Dimorphandra mollis and Erythroxylum gonocladum. Astilbin is present in red wine varieties such as Merlot and Cabernet Sauvignon. The rhizomes of Smilax glabra, a plant used in traditional Chinese medicine, serve as a good source for obtaining astilbin. In Russia, the commercial sources of taxifolin are the wood of Siberian larch (Larix sibirica), Gmelin larch (Larix gmelinii), and Dahurian larch (Larix dahurica).

Flavanonols possess two chiral centers at carbon positions 2 and 3, enabling them to form four diastereoisomers, as demonstrated by the taxifolin molecule (Fig. 14). Commercially available taxifolin, typically extracted from larch wood, exists in the 2R,3R-form. Taxifolin derived from lemons, tomatoes, and grapes contains (+)-2S,3R-epitaxifolin. However, taxifolin preparations obtained from other natural sources, such as apples or the traditional Chinese medicinal plant tu-fu-ling (Smilax glabra), may contain a mixture of several chiral isomers. Furthermore, the racemization of flavonoids (the loss of optical activity due to The formation of a chiral isomer mixture) can be promoted by elevated temperatures, storage at high humidity, pH fluctuations, and other factors. Although the pharmacological properties of these stereoisomers may differ—an aspect that is currently understudied—data regarding pharmacokinetic differences among taxifolin stereoisomers do exist.

Fig. 14. Diastereoisomers of taxifolin. Similar to catechins, the isomerization of these molecules is possible due to the absence of a double bond between carbon atoms 2 and 3.

The bioavailability of taxifolin is relatively low. Animal studies in rats have shown that 0.17% of the taxifolin present in the intestine enters the bloodstream. Experiments on Caco-2 intestinal epithelial Cell monolayers indicate that ATP-binding cassette (ABC) transporters—specifically P-glycoprotein and multidrug resistance-associated protein 2, which restrict xenobiotic penetration into the body—play a significant role in limiting taxifolin bioavailability. It is hypothesized that substances capable of inhibiting ABC transporter activity or downregulating their expression could enhance taxifolin bioavailability. Agents that improve taxifolin solubility in Water, such as cyclodextrins, may similarly increase its bioavailability. Dissolving taxifolin in a lipid medium can raise its bioavailability up to 36%.

The mutagenic potential of quercetin and taxifolin has been investigated using Salmonella typhimurium and Escherichia coli bacterial assays. Quercetin was found to induce mutagenesis, although its activity decreased in the presence of ferrous iron.

The cellular effects of taxifolin are highly diverse. This agent is capable of activating the ARE (antioxidant response element) enzymatic antioxidant defense system, inhibiting cytochrome P450 and fatty acid synthase, modulating TNF-α and NF-kB METABOLISM/31.html">Transcription, influencing Cholesterol Metabolism, and regulating nitric oxide levels in the Blood.

Taxifolin acts as an inhibitor of free radical generation during Lipid Peroxidation, as demonstrated using a cytochrome c-cardiolipin complex in the presence of hydrogen peroxide. The Antioxidant Properties of astilbin are likewise linked to its ability to inhibit peroxidase activity. A novel therapeutic approach involves the combined administration of taxifolin and Lipoic Acid for the Treatment of thrombosis. Antioxidants are known to help prevent The Development of deep vein thrombosis. Lipoic acid is a potent antioxidant capable of boosting the efficacy

of other antioxidants, which is why it is sometimes referred to as the "antioxidant of antioxidants." Animal studies have demonstrated that a mixture of lipoic acid and taxifolin (marketed as lipovertin) can exhibit high efficacy in treating venous thrombosis.

Animal and cell culture experiments indicate that taxifolin (dihydroquercetin) and its glycoside astilbin possess significant therapeutic potential across a wide range of pathologies. The cardiovascular benefits of dihydroquercetin are well established. Dihydroquercetin-containing preparations improve blood rheology and inhibit platelet aggregation. They have also been utilized in the treatment of patients suffering from ischemic Heart disease. Animal models have shown that at a blood concentration of 1 µg/L, taxifolin can mitigate cerebral ischemia owing to its antioxidant activity, which suppresses the infiltration of reactive oxygen species-producing leukocytes. This is accompanied by the normalization of nuclear transcription factor NF-kB activity, alongside the inhibition of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, ultimately leading to reduced prostaglandin production and the suppression of inflammatory pathways. Investigations into the effects of astilbin on hepatic and renal ischemia have revealed decreased blood concentrations of nitric oxide and creatinine, indicating a restoration of renal function. A reduction in The production of the monocyte chemoattractant MCP-3 was also observed, resulting in attenuated monocyte infiltration.

Animal studies have demonstrated that astilbin at a concentration of 10 µM can normalize blood pressure in hypertensive subjects through the inhibition of angiotensin-converting enzyme (ACE), which produces angiotensin—a peptide hormone responsible for vasoconstriction and elevated blood pressure. Furthermore, astilbin is hypothesized to prevent atherosclerosis by suppressing aortic smooth Muscle proliferation and blocking the infiltration of immune Cells driving inflammatory processes and atherosclerotic plaque formation. Moreover, astilbin functions as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme in Cholesterol Biosynthesis and the pharmacological target of cholesterol-lowering statin drugs. Investigations into taxifolin's effects on hepatic function reveal that, much like statins, this flavonoid suppresses the secretion of apolipoprotein B and low-density lipoprotein (LDL)—implicated in cholesterol Transport from the Liver to peripheral Tissues, which promotes atherosclerosis (often called "bad cholesterol"). Concurrently, it upregulates the secretion of apolipoprotein A1 and high-density lipoprotein (HDL)—involved in reverse cholesterol transport from peripheral tissues back to the liver for subsequent excretion (often called "good cholesterol"). It is anticipated that in the future, taxifolin, astilbin, or their derivatives may serve as effective, safe alternatives to modern statins in the management of atherosclerosis.

Taxifolin and astilbin are also believed to be effective therapeutic agents for immune-mediated disorders. For instance, studies on a T-lymphocyte cell line (Jurkat cells) revealed that astilbin can induce apoptosis in T cells whose proliferation was previously triggered by phytohemagglutinin. Treatment of these activated cells with the immunosuppressant cyclosporin A attenuated The Effect of astilbin. Conversely, supplementing the cells with the growth factor interleukin-2 significantly heightened their sensitivity to astilbin-induced apoptosis. Thus, astilbin demonstrated a selective ability to neutralize aberrant T-lymphocyte proliferation driven by Hormones or toxins, while leaving normal cell proliferation unaffected. Furthermore, astilbin prevented the adhesion of Jurkat T cells to endothelial cell monolayers induced by toxins such as concanavalin A or phorbol esters, without interfering with baseline T-Cell Adhesion in the absence of toxins. This adhesion-blocking effect did not compromise cell viability, as astilbin simultaneously inhibited tumor necrosis factor-alpha (TNF-α) production by T lymphocytes. This mechanism likely plays a crucial role in protecting the liver from toxin-induced injury.