Eye Lens in Aging and Diabetes: Effect of Quercetin

Abstract

Old age is accompanied by a number of pathological eye conditions. Cataract is the most common age-related eye complication. Because the lens becomes naturally more opaque over time, aging is the most important risk factor for developing cataract, which is a major cause of blindness in the world. Cataractogenesis is also one of the earliest secondary complications of diabetes mellitus. The lens is a closed system with limited capability to repair or regenerate itself. Current evidence supports the view that cataractogenesis is a multifactorial process. Oxidative stress and its sequelae are clearly involved in the etiology of senile cataract, whereas mechanisms related to glucose toxicity, namely oxidative stress, processes of nonenzymatic glycation, and enhanced polyol pathway contribute significantly to the development of the eye complications under conditions of diabetes. There is an urgent need for inexpensive, nonsurgical approaches to the treatment of cataract. Recently, considerable attention has been devoted to the search for phytochemical therapeutics. Several pharmacological actions of natural flavonoids may operate in preventing cataract because flavonoids are capable of affecting multiple mechanisms or etiological factors responsible for the development of sight-threatening ocular diseases. The flavonol quercetin is the most widely consumed flavonoid in the human diet. In this article, quercetin is reviewed as an agent that could reduce the risk of cataract formation via affecting multiple pathways pertinent to eye lens opacification, including oxidative stress, nonenzymatic glycation, the polyol pathway, lens calpain proteases, and epithelial cell signaling. In addition, the bioavailability of quercetin to the lens is considered.

Introduction

The young lens has substantial reserves of antioxidants and antioxidant enzymes that may prevent damage. Proteolytic enzymes may selectively remove obsolete proteins and provide a second level of defense. Compromises of lens function upon aging are associated with, and may be causally related to, depleted or diminished primary antioxidant reserves, antioxidant enzyme capabilities, and diminished secondary defenses such as proteases. Environmental stress such as smoking and excessive ultraviolet (UV)-light exposure, appear to provide an additional oxidative challenge associated with the depletion of antioxidants as well as with enhanced risk for cataract. Other risk factors for cataract formation include diabetes, galactosemia, radiation, life-threatening diarrhea, renal failure, and many drugs.^{1,3,4,8

–14} Etiologically, the most common types of cataract are those associated with aging and diabetes.^15,16 Cataractogenesis is one of the earliest secondary complications of diabetes mellitus. Diabetic patients are about 60% more likely to develop these eye conditions.¹⁷

People with diabetes also tend to get cataract at a younger age with a faster progression. The association between diabetes and cataract formation has been shown in clinical epidemiological and basic research studies. Because extracellular glucose diffuses into the lens uncontrolled by the hormone insulin, the lens is one of the most affected body parts in diabetes mellitus. The proteins of the lens are extremely long-lived, and there is virtually no protein turnover, which provides great opportunities for posttranslational modification to occur.¹⁸ Multiple mechanisms have been implicated in the development of cataract in diabetes. To date, the exact sequence of events leading to opacification has not been clearly defined. Thus, the relationship of the opacity to the initiating event may be obscure. What are the molecular changes that are responsible for the increasing level of lens turbidity? How can these changes be arrested? A further problem is that the appearance of opacity in model systems rarely duplicates the cataracts observed in humans.^4,5,19

The lens is a closed system with limited capability to repair or regenerate itself. Oxidative stress and its sequelae are clearly involved in the etiology of age-related cataract whereas mechanisms related to glucose toxicity, namely oxidative stress, processes of nonenzymatic glycation, and enhanced polyol patway, contribute significantly to the development of the eye complications under conditions of diabetes.^{4,5,20

–25}

Treatment recommendations for the general aging population emphasize the use of antioxidant micronutrients. Several clinical studies have pointed to a diminution of human senile cataract incidence after an adequate supply of antioxidants in food.^4
–6,16,26 In the case of diabetic patients, the need for tight blood glucose control is a key prerequisite to reduce the incidence, progression, and severity of cataract. Yet periods of hyperglycemia in the daily regimen of a diabetic patient cannot be avoided, with the all aforementioned deleterious consequences of glucose toxicity. Therefore, additional adjunct therapy, e.g., including antioxidants, antiglycation agents, and aldose reductase inhibitors, is needed to attenuate the noxious effects of glucose.

Recently, considerable attention has been devoted to the search for phytochemical therapeutics. There is epidemiologic evidence that a sufficient intake of fruit and vegetables can lower the risk of cataract in humans.⁶ A variety of constituents, like vitamins, minerals, fiber, and numerous phytochemicals, including flavonoids, may contribute to the protective effect of fruits and vegetables. Indeed, several pharmacological actions of flavonoids may operate in the prevention of both age-related and diabetic cataract, as flavonoids are capable of affecting multiple mechanisms or etiological factors responsible for the development of sight-threatening ocular diseases.^27
–29

The flavonol quercetin (Fig. 1) is the most widely consumed flavonoid in the human diet.^30,31 Quercetin and other flavonoids have been shown to have protective effects against eye lens opacification. In plants, quercetin is present mainly in the form of O-glycosides with a sugar group, such as glucose, galactose, rhamnose, rutinose, or xylose. The glycosidic structure has a large impact on quercetin bioavailability.

FIG. 1.

Molecular structure of quercetin [2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one].

In this article, quercetin is reviewed as an agent that could reduce the risk of cataract formation by affecting multiple pathways pertinent to eye lens opacification, including oxidative stress, nonenzymatic glycation, polyol pathway, lens calpain proteases, and epithelial cell signaling. In addition, the bioavailability of quercetin to the lens is considered.

Anticataract Action of Quercetin

Models in vitro

Under in vitro conditions, using the rat lens organ culture endowed with hydrogen peroxide (H₂O₂), it was demonstrated that low micromolar levels of quercetin inhibited oxidation-induced sodium and calcium influx and loss of lens transparency.³² As shown later by Cornish et al.,³³ quercetin was rapidly lost from the medium and readily entered the lens, where it was methylated to 3′-O-methyl quercetin. Both quercetin and its metabolite were active in inhibiting oxidative damage in the lens.

The addition of quercetin (20 μg/mL) to rat lens organ culture supplemented with selenite prevented the formation of opacity as a result of selenite toxic effects.³⁴ The glucoside of isorhamnetin (methylated quercetin), isolated as a bioactive flavonoid from the leaves of Cochlospermum religiosum (silk-cotton tree),³⁵ and flavonoid fraction isolated from fresh leaves of Vitex negundo (chastetree)³⁴ protected enucleated rat eye lenses against selenite-induced cataract in an in vitro culture model.

The flavonoid venoruton, a mixture of mono-, di-, tri-, and tetrahydroxyethylrutosides, significantly reduced the degree of opacification and the leakage of lactate dehydrogenase in rat lens organ culture simulating diabetic conditions.³⁶

Animal models in vivo

As early as in 1977, Varma et al.³⁷ studied the effect of quercetin rhamnoside (quercitrin) on the development of cataract in the rodent Octodon degus (brush-tailed rat or degu) made diabetic by a single intraperitoneal dose of streptozotocin. The control diabetic animals not receiving quercitrin developed a nuclear opacity by about the tenth day after the onset of hyperglycemia. In contrast, the diabetic animals treated with quercitrin (70 mg/day) did not develop cataracts, even 25 days after the onset of diabetes, although they had a blood glucose concentration similar to that of the control diabetic group. In a similar study performed by Lu et al.³⁸ in streptozotocin diabetic rats, high-isoflavone soy protein markedly decreased the death rate and incidence of cataracts in the diabetic animals. At the same time, reduced serum glucose and methylglyoxal were recorded in the treated rats. Nakano et al.³⁹ reported lower incidence of cataract in streptozotocin diabetic rats treated with flavangenol, a complex mixture of bioflavaonoids with oligomeric proanthocyanidin as main constituents.

Topical administration of quercetin (10 μM) to the orbital pouch of the galactosemic neonatal rat diminished cataractogenesis in the corresponding lens. Comparison with the contralateral lens indicates that quercetin reduced intracellular edema, prevented extracellular fluid accumulation, and maintained cellular interdigitation of the superficial anterior cortical fiber. In addition to preserving fiber integrity, topical application of quercetin maintained lens growth, as evidenced by radius and dry weight measurements.⁴⁰ Analogously, in the same galactosemic rat model, Mohan et al.⁴¹ recorded anticataract action of quercetin and structurally related myricetin after topical administration. In galactosemic rats, oral treatment with quercetin (400 mg/100 grams of diet) resulted in a significant correction of eye lens electrolyte disturbances and normalization of lens protein levels.⁴² The results imply that inclusion of quercetin contributes to lens transparency through the maintenance of characteristic osmotic ion equilibrium and protein levels of the lens. The isoflavone genistein delayed the progression of cataracts induced in rats by dietary galactose.⁴³

The rat selenite cataract model^19,44,45 was used extensively to study the anticataract action of flavonoids, including free quercetin aglycone as well as its natural glycosides. In a number of these studies,^46

–49 quercetin was used as a reference flavonoid; uniformly, its intraperitoneal administration was reported to retard progression of lens opacity.

Rutin (quercetin rutinoside) was reported⁵⁰ to prevent selenite-induced cataractogenesis in rat pups. At the end of the 30-day study period, all of the rat pups that had received only selenite were found to have developed a dense nuclear opacity in the lens of each eye, whereas only 33.3% of pups that had received selenite and been treated with an intraperitoneal dose (175 mg/kg of body weight) of rutin hydrate were found to have mild lenticular opacification in each eye. The other 66.7% of pups in that group had clear lenses in both eyes, as in normal pups. The mean activities of catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione transferase (GST), and glutathione reductase (GSR) were found to be significantly lower in the lenses of cataract-untreated rat pups than in normal control rat lenses. However, in lenses treated with rutin hydrate, the mean activities of antioxidant enzymes were significantly higher than the values in rat pups with untreated cataracts.

Onion is a flavonoid-rich food, and the major flavonoids have been identified as quercetin, quercetin-4′-glucoside and quercetin-3,4′-diglucoside.^51,52 In the study of Javadzadeh et al.,⁵³ the instillation of fresh juice of crude onion into the rat eyes was found to prevent selenite-induced cataract formation by 75%. This effect was associated with a higher mean total antioxidant level as well as higher mean activities of SOD and GPx in the lenses of rats receiving fresh juice of crude onion and subcutaneous injection of sodium-selenite compared with those rats which received only sodium-selenite injection. The onion juice, as a flavonoid-rich source, was postulated to provide an additional support to the antioxidant agents, leading to the elevation of total antioxidant levels and SOD and GPx activities in the rat lens, in spite of exposure to sodium-selenite.

Flavonoid fractions isolated from natural sources including green and black tea,^54,55 Ginkgo biloba,⁵⁶ grape seeds,⁵⁷ Emilia sonchifolia (lilac tasselflower), ⁵⁸ Vitex negundo (chastetree),⁴⁸ and broccoli⁴⁹ were shown to have anticataract activity in the selenite-induced experimental cataract in rats. In addition, Ginkgo biloba extracts were found to protect rats against radiation-induced cataract.⁵⁹

Among others, damage to the lens epithelium is considered a major cause of cataract formation.⁶⁰ Catechin was found to inhibit apoptotic cell death in the lens epithelium of rats after cataract induction with N-methyl-N-nitrosourea.⁶¹ Grape seed extract rich in flavonoids reduced H₂O₂-induced apoptosis of human lens epithelial cells and depressed H₂O₂-induced activation and translocation of the nuclear factor kappa-B (NF-κB).⁶² Similarly, the flavonoid fisetin was found to protect human lens epithelial cells from UVB-induced oxidative stress by inhibiting the generation of reactive oxygen species and modulating the activation of NF-κB and the mitogen-activated protein kinase (MAPK) pathways.⁶³

Quercetin As a Multifunctional Agent

Innovative strategies in the treatment of disorders of multifactorial origin, including both senile and diabetic cataract, are focused on rational design of chemical entities able to affect multiple key mechanisms simultaneously. This approach increases the chance of successful therapeutic intervention, decreases the risk of side effects, and is economical. Considering that quercetin could prevent cataract formation, it is plausible to assume that it could act via multiple pathways.

Indeed, qeuercetin is one of the most frequently studied flavonoids, and it is endowed with a broad spectrum of biological activities. As reviewed below, quercetin efficiently affects the multiple key molecular mechanisms involved in the etiology of both age-related and diabetic cataract, namely oxidative stress, nonenzymatic glycation, polyol pathway, calpain protease action, and lens epithelial cell signaling.

Antioxidant action of quercetin

The antioxidant action of flavonoids, the best-described biological activity of this group of natural polyphenolic substances, is covered by a number of excellent reviews.^{31,64

–74} Flavonoids may exert antioxidant effects due to their ability to act as free-radical scavengers, hydrogen-donating compounds, singlet-oxygen quenchers, and metal ion chelators. Within the flavonoid family, quercetin is the most potent scavenger of reactive oxygen species, including superoxide, peroxyl, alkoxyl and hydroxyl radicals, and reactive nitrogen species like nitric oxide (NO^•) and peroxynitrite (ONOO).^31,64,74,75 It is beyond the scope of this review to give a thorough survey of the abundant literature covering numerous studies of the antioxidant action of quercetin. Nevertheless, key structural features responsible for the high antioxidant efficacy of quercetin, also with relevance to the eye lens, are highlighted.

The high antioxidant activity of quercetin stems from the fact that quercetin complies with the general structural requirements for effective radical scavenging and/or the antioxidant potential of flavonoids known as Bors' criteria,^68,74 namely: (1) The presence of a catechol group in ring B, capable of readily donating hydrogen (electron) to stabilize a radical species, (2) the presence of 2,3-unsaturation in conjugation with a 4-oxo-function in the C-ring, which is responsible for electron delocalization, and (3) the presence of a 3-hydroxyl group in the heterocyclic ring which increases the radical-scavenging activity. The catechol moiety may also ascribe an ability to chelate transition metal ions such as copper and iron.

Quercetin was found also to scavenge efficiently the model free radicals of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and α, γ-bisdiphenylene-β-phenylallyl (BDPA).⁷⁵ Circulating plasma metabolites of quercetin, such as glucuronides and O-methylated forms, and intracellular metabolites may participate directly in antioxidant reactions, yet their effectiveness is reduced relative to the parent aglycones.⁴⁶ Quercetin chelating activity for transition metal ions is well documented.^64,66,72 Quercetin inhibits xanthine oxidase, the enzyme responsible for superoxide anion production.⁷⁶ Interestingly, regarding xanthine oxidase inhibition, isorhamnetin (3-methylquercetin) was found to be even more active than the aglycone form of quercetin.⁷⁷

As reviewed below, the high antioxidant efficacy of quercetin is accompanied by its ability to inhibit aldose reductase and nonenzymatic glycation—activities of high relevance to the development of diabetic cataract.

Aldose reductase inhibition by quercetin

The accumulation of polyol sorbitol within the lens is a primary contributing factor to the formation of diabetic cataract^5,20,21,78 and is a mechanism different from senile cataract. In diabetes, glucose is in a high concentration in the aqueous humor and can diffuse passively into the lens. The enzyme aldose reductase within the lens converts glucose to sorbitol. This polyol cannot diffuse passively out of the lens and accumulates or is converted to fructose.

Aldose reductase inhibitors represent a potential therapeutic strategy for preventing the onset or progression of diabetic cataract.^{5,20,79
–81} Pharmacophoric requirements for aldose reductase inhibitors are determined by the structural features of the inhibitor binding site of aldose reductase, which was shown to be formed by a large hydrophobic pocket.⁸² This pocket is mainly composed of two regions: (1) A hydrophilic anionic binding site which accommodates acidic functionalities and (2) a region of hydrophobic residues that binds the hydrophobic aromatic ring system of the inhibitors. Inhibitor binding is therefore a consequence of polar and nonpolar interactions between the inhibitor and the complementary residues that line the enzyme-binding pocket. It has been proposed that the specificity for the inhibitor was mainly due to inhibitor–enzyme interactions at the nonpolar domain.⁸³

To date, two main classes of active aldose reductase inhibitors have been reported and classified on the basis of the ionizable group, which allows them to anchor to the catalytic site: (1) Carboxylic acids (substitution derivatives of acetic acid) and (2) spirohydantoins, with epalrestat and sorbinil being the most representative members of each respective family.^20,79

–82 They are generally referred to as carboxylate-type and hydantoin-type inhibitors. A third class of aldose reductase inhibitors represents flavonoids. Since the mid-1970s, a number of studies have been reported on the inhibition of aldose reductase by flavonoids^{84

–92}; of them, quercetin was found a potent inhibitor of aldose reductase. The efficacy of quercetin, characterized by the corresponding half-maximal inhibitory concentration (IC₅₀) values in the low micromolar range, is due to the fact that it possesses most of the right structural features required for a firm anchoring to the catalytic site of the aldose reductase enzyme, as summarized by Matsuda et al.⁸⁹: (1) The presence of a 7-hydroxyl group and catechol moiety at the B ring guarantees the strong activity; (2) the 5-hydroxyl moiety does not affect the activity; (3) the 3-hydroxyl and 7-O-glucosyl moieties reduce the activity; (4) the 2–3 double bond enhances the activity; (5) the flavonols having the catechol moiety (the 3′,4′-dihydroxyl moiety) at the B ring exhibit stronger activity than those with the pyrogallol moiety (the 3′,4′,5′-trihydroxyl moiety). Quercetin has often been used as a positive control in comparing the inhibitory activity of active components isolated from natural products against rat lens or human recombinant aldose reductase.^{89,91,93

–101}

As a member of the flavonoid class of aldose reductase inhibitors, in comparison with the aldose reductase inhibitors of the carboxylate type, whose acidic nature results in their poor biological availability, quercetin possesses a higher pK_a value, which is a prerequisite for its better pharmacokinetics.

In the light of the above-mentioned biological activities of quercetin, this flavonol serves as an example of a bifunctional agent for the "multitarget" approach to the treatment of diabetic cataract by combining the aldose reductase inhibitory activity with its antioxidant action. Considering the physiological detoxification role of aldose reductase against the toxic carbonyl products of oxidative stress, a concurrent administration of antioxidants is required to counterbalance its inhibition. In addition, starting from quercetin as a lead structure, a series of 4H-1-benzopyran-4-one derivatives was designed and developed as semisynthetic agents, structurally related to quercetin, with dual antioxidant/ aldose reductase inhibition activity.¹⁰²

In seeking more efficient bifunctional flavonoids combining antioxidant and aldose reductase inhibitory activity, with a potential of possible pharmacological prevention of diabetic cataract and other long-term diabetic complications, both sets of the aforementioned criteria should be applied in screening available databases of flavonoid structures.

Advanced glycation inhibition by quercetin

The process of nonenzymatic glycation is well known to be one of the key mechanisms leading to diabetic cataract.^{23,24,103

–106} In compliance with the glycation theory of aging,¹⁰⁷ accumulation of advanced glycation end products in the aging lens, yet to a lesser extent in comparison with the diabetic eye, may contribute to age-related lens opacity. In seeking potential anticataract drugs, clinically useful antiglycation agents are a reasonable option. As reviewed below, a number of naturally occurring flavonoids, including quercetin, were reported to exhibit inhibitory effects on advanced glycation end products formation.

Quercetin, both as a free aglycone and in the form of glycosides, was reported to inhibit efficiently nonenzymatic glycation of bovine serum albumin,^109

–112 collagen,^113,114 histones,¹¹⁵ and tissue proteins¹¹⁶ in glucose-based protein glycation models under in vitro conditions. Under in vivo conditions, the glucose adduct of rutin (G-rutin) was found to inhibit glycation reactions in muscle, kidney, and plasma proteins of streptozotocin-induced diabetic rats.¹⁰⁸ In their study based on 62 flavonoids, Matsuda et al.¹¹⁷ formulated structural requirements of flavonoids for inhibition of protein nonenzymatic glycation, yet these principles should be corroborated further.

Calpain inhibition by quercetin

Activation of calpain, a cytosolic cysteine protease dependent on calcium, may contribute to cataract development.¹¹⁸ Therefore, calpain inhibitors can be candidates for anticataract drugs. In the course of searching for calpain inhibitors, quercetin and several other natural flavonoids showed significant calpain inhibitory activities, characterized by the IC₅₀ values of 210.9 μM and 48.1 μM for quercetin and quercetin 3-O-β-D-glucopyranoside, respectively.^119,120

Quercetin and eye lens epithelial cell signaling

Accumulating evidence suggests that the cellular effects of flavonoids may also be mediated by their interactions with specific proteins central to intracellular signaling cascades. For example, according to the challenging hypothesis of Williams et al.,⁶⁶ flavonoids are unlikely to express beneficial action in vivo through outcompeting physiological antioxidants such as ascorbate or α-tocopherol present at much higher concentrations. Considering the eye, a single layer of epithelial cells covers the anterior surface of the lens. Damage to the lens epithelium has been one of a major foci in the identification of causes of cataract formation.^60,121,122

Flavonoids in general^{62,63,123,124} and quercetin specifically^125
–127 were reported to interfere with particular signaling pathways in lens epithelium with consequences relevant to cataract progression. Quercetin, at a low concentration (0.1 μM), protected human lens epithelial cell cultures and reversed the toxic effects of dimethyl sulfoxide (1% vol/vol). However, at higher concentrations, quercetin induced apoptosis and upregulated apoptotic genes in a dose-dependent manner and was found to be toxic to human lens epithelial cells with a median lethal dose (LD₅₀) of 90.85 μM.¹²⁵ Radreau et al.¹²⁶ demonstrated stimulation of the hypoxia-inducible factor-1 (HIF-1) pathway in lens epithelial cells by quercetin accompanied by the activation and synthesis of downstream effectors, including vascular endothelial growth factor and erythropoietin. On studying the cellular-signaling pathways potentially involved in the UV- and H₂O₂-induced cataractogenesis, Jiang et al.¹²⁷ found that UV radiation and H₂O₂ induced a decrease of collagen in cultured human lens epithelial cells. Quercetin attenuated the observed changes. On the basis of mechanistic studies using specific inhibitors, they inferred involvement of c-Jun N-terminal kinase (JNK).

Bioavailability of Quercetin

The biological activity of flavonoids is often assessed by using in vitro models; in almost all such studies, cells are treated with aglycones and data are reported at concentrations that elicit a response. However, plasma and tissues are not exposed in vivo to flavonoids in these forms. The forms reaching the blood and tissues are, in general, neither aglycones nor the same as the dietary source glycosides. In blood, flavonoids are present as conjugates of glucuronate or sulfate, with or without methylation of the catechol functional group. As a consequence, the flavonoid conjugates are likely to possess different biological properties and distribution patterns within tissues and cells than have flavonoid aglycones. Although deconjugation can potentially occur in vivo to produce aglycone, it occurs only at certain sites. Thus, to what extent can in vitro effects produced by the aglycones be extrapolated to the in vivo situation, in particular in humans, is poorly understood.

To date, only a few studies have investigated delivery of flavonoids to the eye. Drug delivery to the ocular tissues is a challenging task. It depends on the physicochemical and biopharmaceutical characteristics of the selected flavonoids and very importantly on the route of administration. Topical application is the most favored mode for ocular conditions. Systemic or oral administration is another option for delivering therapeutic agents to the ocular tissues. However, these routes are challenged by several physiological barriers and involve unnecessary systemic exposure to the drug. The topical route is mainly used to deliver drugs to the anterior segment of the eye. Local administration may yield much higher and effective concentrations of the parent flavonoids in the ocular tissues and at much lower doses, contrary to the oral route.

Quercetin occurs in plants mainly in the form of O-glycoside conjugates linked to sugars like glucose, galactose, arabinose, or rhamnose.^128,129 The bioavailability is primarily determined by the type of the sugar moiety.^129,130

In the case of quercetin monoglucosides, quercetin aglycone can be enzymatically released in the small intestine by the brush border lactase phlorizin hydrolase¹³¹ or by β-glucosidase activity.¹³² The enzyme of lactase phlorizin hydrolase exhibits broad substrate specificity for flavonoid-monoglucosides, and the released aglycone may then enter the small intestine epithelial cells by passive diffusion.¹³³ Alternatively, cytosolic β-glucosidase functions within the epithelial cells after the quercetin glucosides entered via the sodium-dependent glucose transporter 1.¹³⁴

On the other hand quercetin-3-rutinoside (rutin) is not a substrate of lactase phlorizin hydrolase. The quercetin aglycone is released hydrolytically by bacterial α-rhamnosidases and β-glucosidases in the lower gastrointestinal tract. Thus, absorption of quercetin from rutin is delayed, and quercetin bioavailability is much smaller in comparison with that of quercetin-glucosides.^{130,135
–137}

Prior to passage into the bloodstream, the aglycones undergo metabolism, forming sulfate, glucuronide, and/or methylated metabolites. In humans, plasma quercetin exists largely in these conjugated forms, reaching micromolar concentrations following ingestion of quercetin rich foods.^138
–140

In relation to cataract, it is important to consider the bioavailability of quercetin and its metabolites to the lens. In the anterior chamber of the eye, the aqueous humor bathes the anterior surface of the lens, providing all oxygen and nutrient requirements. Therefore, it is this route through which dietary flavonoids would reach the lens. In the in vitro experiments performed by Cornish et al.³³ in a lens organ culture, quercetin was shown to enter the lens from surrounding artificial aqueous humor. In the lens, enzymes that metabolized the quercetin to 3′-O-methyl quercetin were identified. Metabolism reduced the efficacy but did not terminate the protective action of quercetin because 3′-O-methyl quercetin was also found to be effective in reducing opacification. In analogy with the ability of fluorescein glucuronides to enter the anterior chamber of the eye following oral administration,¹⁴¹ it was hypothesized that quercetin glucuronides would also be transported into the aqueous humor if present in plasma, where deglucuronidation could occur via endogenous β-glucuronidase activity. β-Glucuronidase is present in many tissues and body fluids in humans,¹⁴² and its activity has been demonstrated in the normal human lens¹⁴³ and aqueous humor.¹⁴⁴ Following uptake of glucuronides into the aqueous humor, the lens could therefore be exposed to the circulating conjugates and/or to aglycone following deglucuronidation in the aqueous humor.

Medical Aspects of Cataract

Cataracts constitute an immense public health burden, and it would be very useful to identify dietary supplements or pharmacological interventions that could delay the onset of these pathological eye conditions. It is important to study relationships between risk for the age-related eye disorders and nutrition or drug supplementation, because surgical resources are insufficient to provide economical and safe treatment for cataract. It is likely that the same nutritional practices or pharmacological therapies that are associated with prolonged eye function will also be associated with delayed age-related disorders of other organs, and perhaps with aging in general.

Although growing evidence suggests that cataractogenesis in general can be prevented through nutrition, antioxidant supplementation, and lifestyle changes, no specific recommendations for management of cataract are currently available. Presently, surgical extraction remains the only cataract cure. Cataract surgery has become the most frequent surgical procedure in people aged 65 years or older in the Western world, causing a considerable financial burden to the health-care system.^14,145,146

Hence, there is an urgent need for inexpensive, nonsurgical approaches to the treatment of cataract,¹⁴⁷ because a delay of 10 years for the onset of cataract by any means would be expected to halve the number of cataract extractions.¹⁴⁸ This calls for the search of alternative pharmacological measures to treat this disorder.

Conclusions

A better understanding of mechanisms of ocular complications, along with identification of the right nutrient(s) and supplement(s) for their treatment, establishment of their useful levels, and development of intraocular drug delivery systems remain the highest priority for future research.

Despite the fact that there is a variety of agents that have the potential of preventing age-related cataract in animals, a clear-cut recommendation for future interventions in humans to slow down the development of age-related vision impairment is not available as yet. Proper nutrition, possibly including the use of antioxidant supplements, started early in life (a time yet to be defined) and maintained throughout maturity for those at risk, along with healthy lifestyles, may provide the least costly and most practical option. In addition to proper nutrition, epidemiologic data suggest that avoiding oxidative stress (i.e., smoking and excess sunlight exposure) may also be protective. The elucidation of pathological mechanisms involved in the development of age-related disorders of the eye lens remains a challenge. In diabetic patients, tight control of hyperglycemia is the first prerequisite to attenuate the risk of cataract. In addition, adjunct therapy is needed to help preserve vision in diabetic patients, aimed at correcting biochemical and metabolic abnormalities in the hyperglycemic milieu of the diabetic individual.

The current data for quercetin and other polyphenol phytochemicals in relation to cataract, along with epidemiological knowledge regarding diet and lens opacity, demonstrate that flavonoids may play a role in prevention of cataract. Future clinical trials are expected to assess the benefits of flavonoid pharmacological interventions in lowering the risk of both age-related and diabetic eye complications.

Footnotes

Acknowledgments

The work was supported by The Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic for the Structural Funds of European Union, OP R&D of ERDF by realization of the Project Evaluation of natural substances and their selection for prevention and treatment of lifestyle diseases (ITMS 26240220040). It was also supported by the Joint Research Project between the Scientific and Technical Research Council of Turkey (TÜBİTAK) and the Slovak Academy of Sciences 2010-2012 (SBAG 108S239) and VEGA 2/0067/11.

Author Disclosure Statement

There are no commercial associations that might create a conflict of interest in connection with this article. No competing financial interests exist concerning any of the authors of this investigation.

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