Flavonoids xanthine oxidase inhibition

It is possible that dietary flavonoids participate in the regulation of cellular function independent of their antioxidant properties. Other non-antioxidant direct effects reported include inhibition of prooxidant enzymes (xanthine oxidase, NAD(P)H oxidase, lipoxygenases), induction of antioxidant enzymes (superoxide dismutase, gluthathione peroxidase, glutathione S-transferase), and inhibition of redox-sensitive transcription factors. 

The ability of flavonoids (quercetin and rutin) to react with superoxide has been shown in both aqueous and aprotic media [59,94]. Then, the inhibitory activity of flavonoids in various enzymatic and nonenzymatic superoxide-producing systems has been studied. It was found that flavonoids may inhibit superoxide production by xanthine oxidase by both the scavenging of superoxide and the inhibition of enzyme activity, with the ratio of these two mechanisms depending on the structures of flavonoids (Table 29.4). As seen from Table 29.4, the data obtained by different authors may significantly differ. For example, in recent work [107] it was found that rutin was ineffective in the inhibition of xanthine oxidase that contradicts the previous results [108,109], The origins of such big differences are unknown. 

In addition to xanthine oxidase, flavonoids are able to inhibit the activity of a wide range of enzymes. These inhibitory effects of flavonoids may depend both on their free radical scavenging and chelating properties. Thus, it has been shown that flavonoids inhibit... 

Numerous studies were dedicated to the effects of flavonoids on microsomal and mitochondrial lipid peroxidation. Kaempferol, quercetin, 7,8-dihydroxyflavone and D-catechin inhibited lipid peroxidation of light mitochondrial fraction from the rat liver initiated by the xanthine oxidase system [126]. Catechin, rutin, and naringin inhibited microsomal lipid peroxidation, xanthine oxidase activity, and DNA cleavage [127]. Myricetin inhibited ferric nitrilotriacetate-induced DNA oxidation and lipid peroxidation in primary rat hepatocyte cultures and activated DNA repair process [128]. 

Sanders et al. [133] found that although quercetin treatment of streptozotocin diabetic rats diminished oxidized glutathione in brain and hepatic glutathione peroxidase activity, this flavonoid enhanced hepatic lipid peroxidation, decreased hepatic glutathione level, and increased renal and cardiac glutathione peroxidase activity. In authors opinion the partial prooxidant effect of quercetin questions the efficacy of quercetin therapy in diabetic patients. (Antioxidant and prooxidant activities of flavonoids are discussed in Chapter 29.) Administration of endothelin antagonist J-104132 to streptozotocin-induced diabetic rats inhibited the enhanced endothelin-1-stimulated superoxide production [134]. Interleukin-10 preserved endothelium-dependent vasorelaxation in streptozotocin-induced diabetic mice probably by reducing superoxide production by xanthine oxidase [135]. 

Values ( mmol I-1) of Flavonoids for the Inhibition of Xanthine Oxidase and Scavenging Superoxide Ion... 

Xanthine oxidase catalyzes the formation of urate and superoxide anion from xanthine. Quercetin and baicalein inhibit both xanthine oxidase and xanthine dehydrogenase. The level of xanthine oxidase is high in patients with hepatitis and brain tumor and select flavonoids might be useful in treating this disorder. 

A wide variety of compounds have been shown to inhibit xanthine oxidase guanidines and some triazines (F7), purine derivatives such as purine 6-aldehyde (G5), 6-mercaptopurine (S20), 2,6-diaminopurine (W8), flavonoids (B13), and Antabuse (R6). Although these compounds and the inhibitions they produce are of interest in understanding the nature of the action of xanthine oxidase, none has been useful clinically in limiting urate production. Antabuse, as a result of its action, produces other effects that (fortunately ) have not been found with allopurinol. 

Table 3. Summnry of the Classification of Flavonoids into Six Categories According to their Inhibition of Xanthine Oxidase (XO) and Superoxide...

The antioxidant activity of alizarin was established in four different assays (1) suppression of light emission in the p-iodophenol enhanced chemiluminescent assay, (2) scavenging of superoxide anion (02 -) in a hypoxanthine-xanthine oxidase system, (3) protection of rat liver microsomes from lipid peroxidation by ADP/iron(II) ions, and (4) protection of bromobenzene-intoxicated mice from liver injury in vivo [141]. Alizarin was compared with Trolox (water soluble vitamin E), the flavonoid baicalin and green tea proanthocyanidins. In assay (1) the activity of alizarin was 76% of that of Trolox. In assay (2) the inhibition of 02 -induced chemiluminescence was 40%, 32%, 23% and 14% for Trolox, alizarin, green tea polyphenols and baicalin respectively. Alizarin was not significantly active in the lipid peroxidation assay but after baicalin the most active compound in the in vivo assay. This shows again the difficulty in the evaluation of antioxidant activity and the differences between in vitro and in vivo assays [141]. 

Lin C-M, Chen C-S, Chen C-T, Liang Y-C, Lin J-K (2002) Molecular modeling of flavonoids that inhibits xanthine oxidase. Biochem Biophys Res Commun 294(1) 167-172. doi 10.1016/S0006-291X(02)00442 ... 

In view of their reduction potential, flavonoids have also been shown to interact with enzymes either unspecifically or specifically and modify their activity through reduction of metals in the active center. Of particular interest, because of their role in inflammatory conditions, is the reductive inactivation of lipoxygenases, cyclo-oxygenases, myeloperoxidase, and xanthine oxidase. In view of prooxidant activity of the enzymes, their inhibition by polyphenols may be regarded as an indirect antioxidation action. The list of enzymatic activities inhibited by flavonoids and other polyphenols also include phospholipase A2, protein kinases, metalloproteinases, drug metabolism enzymes, and telomerase, as reviewed elsewhere (Frade et al, 2005). 

Protection of cells against oxidative damage, with result, inhibition of cell-mediated oxidation of LDL, achieved via the potency of flavonoids to inhibit xanthine oxidase [64], NADPH oxidase [65], or... 

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