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      Orange Juice and Hesperetin Supplementation to Hyperuricemic Rats Alter Oxidative Stress Markers and Xanthine Oxidoreductase Activity

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          Abstract

          Our objective was to examine the effect of orange juice and hesperetin on serum total antioxidant capacity (TAC), lipid peroxidation (MDA), uric acid and hepatic xanthine oxidase (XO) and xanthine dehydrogenase (XDH) activity in hyperuricemic rats. Experimentally hyperuricemia in rats was induced by intraperitoneal injection of potassium oxonate (250 mg/kg). Orange juice (5 ml/kg) and hesperetin (5 mg/kg) was given by oral gavage to rats for 2 weeks and biochemical data was measured. Data showed that orange juice supplementation increased serum TAC and decreased MDA concentration ( p≤0.05). Orange juice also inhibited hepatic XO and XDH activity and decreased serum uric acid levels. Hesperetin, which is the main flavanone constituent in orange juice, also exhibited antioxidative and antihyperuricemic properties, but its effect was weaker than that of orange juice. Although the hypouricemic effect of allopurinol (5 mg/kg), as a positive control, was much higher than that of orange juice and hesperetin, it could not significantly change biomarkers of oxidative stress. These features of orange juice and hesperetin make them an attractive candidate for the prophylactic treatment of hyperuricaemia, particularly if these compounds are to be taken on a long-term basis.

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          Dietary flavonoids: effects on xenobiotic and carcinogen metabolism.

          Flavonoids are present in fruits, vegetables and beverages derived from plants (tea, red wine), and in many dietary supplements or herbal remedies including Ginkgo Biloba, Soy Isoflavones, and Milk Thistle. Flavonoids have been described as health-promoting, disease-preventing dietary supplements, and have activity as cancer preventive agents. Additionally, they are extremely safe and associated with low toxicity, making them excellent candidates for chemopreventive agents. The cancer protective effects of flavonoids have been attributed to a wide variety of mechanisms, including modulating enzyme activities resulting in the decreased carcinogenicity of xenobiotics. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzymes involved in the activation of procarcinogens and phase II enzymes, largely responsible for the detoxification of carcinogens. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction of specific CYP isozymes, and the activation or inhibition of these enzymes. Some flavonoids alter CYPs through binding to the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, acting as either AhR agonists or antagonists. Inhibition of CYP enzymes, including CYP 1A1, 1A2, 2E1 and 3A4 by competitive or mechanism-based mechanisms also occurs. Flavones (chrysin, baicalein, and galangin), flavanones (naringenin) and isoflavones (genistein, biochanin A) inhibit the activity of aromatase (CYP19), thus decreasing estrogen biosynthesis and producing antiestrogenic effects, important in breast and prostate cancers. Activation of phase II detoxifying enzymes, such as UDP-glucuronyl transferase, glutathione S-transferase, and quinone reductase by flavonoids results in the detoxification of carcinogens and represents one mechanism of their anticarcinogenic effects. A number of flavonoids including fisetin, galangin, quercetin, kaempferol, and genistein represent potent non-competitive inhibitors of sulfotransferase 1A1 (or P-PST); this may represent an important mechanism for the chemoprevention of sulfation-induced carcinogenesis. Importantly, the effects of flavonoids on enzymes are generally dependent on the concentrations of flavonoids present, and the different flavonoids ingested. Due to the low oral bioavailability of many flavonoids, the concentrations achieved in vivo following dietary administration tend to be low, and may not reflect the concentrations tested under in vitro conditions; however, this may not be true following the ingestion of herbal preparations when much higher plasma concentrations may be obtained. Effects will also vary with the tissue distribution of enzymes, and with the species used in testing since differences between species in enzyme activities also can be substantial. Additionally, in humans, marked interindividual variability in drug-metabolizing enzymes occurs as a result of genetic and environmental factors. This variability in xenobiotic metabolizing enzymes and the effect of flavonoid ingestion on enzyme expression and activity can contribute to the varying susceptibility different individuals have to diseases such as cancer. As well, flavonoids may also interact with chemotherapeutic drugs used in cancer treatment through the induction or inhibition of their metabolism.
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            Lipid peroxidation in maternal and cord blood and protective mechanism against activated-oxygen toxicity in the blood.

            Concentrations of a peroxidation product (malondialdehyde), fluorescent chromophores, lipofuscin-like fluorescent products, superoxide dismutase, catalase, glutathione peroxidase, and vitamin E in the maternal blood and the cord blood were determined and the results obtained were related to the estimation of lipid peroxidation and protective mechanism against uncontrolled oxidative processes in late pregnancy. Serum levels of fluorescent products were higher in the maternal blood than in the cord blood, indicating less frequent lipid peroxidation in the fetus than in the mother. In support of this assumption, the three protective enzymes and vitamin E were present in relatively lower concentrations in the cord blood. Sudden exposure of the newborn infant to a normobaric atmosphere after beginning breathing seems, therefore, to cause oxidation of red blood cell membrane, denaturation of the membrane, inducing hemoglobin breakdown, and consequently hemolysis.
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              Uric acid and oxidative stress: relative impact on cardiovascular risk?

              Post-hoc analyses of the GREACE and the LIFE trials have renewed the interest in elevated serum uric acid (SUA) as a factor contributing to atherosclerotic cardiovascular disease (CVD) and in the possible benefit derived from its pharmacological reduction. The results of these trials are consistent with reports indicating favourable effects of SUA lowering treatment with allopurinol on the rate of cardiovascular complications in patients with coronary heart disease, congestive heart failure and dilated cardiomyopathy. Two recent overviews have concluded that, while in population samples at relatively low risk of CVD, SUA is at best a very weak predictor of CVD, by contrast it is a significant independent predictor among subjects at high or very high risk. This raises the question of a different meaning of excess SUA levels under different circumstances. Whereas in uncomplicated obese, insulin-resistant and hypertensive patients SUA levels increase mainly as a consequence of impaired renal excretion, in conditions of local ischemia an increased production of uric acid occurs in parallel with that of reactive oxygen species (ROS). Thus, although clinical and experimental evidence suggest that uric acid has actually antioxidant properties, it is conceivable that under these conditions its antioxidant activity is overcome by the pro-oxidant and pro-inflammatory effects of ROS accumulation. At present, there is no solid evidence to recommend treatment of the mild asymptomatic hyperuricemia associated with obesity, diabetes and/or hypertension (up to 10mg/dL). By contrast, similar SUA elevations in patients at higher cardiovascular risk should be taken more seriously. A controlled trial to investigate the effects of SUA reduction in these patients, while monitoring concomitant changes in parameters of oxidative stress and inflammation, is warranted.
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                Author and article information

                Journal
                J Clin Biochem Nutr
                JCBN
                Journal of Clinical Biochemistry and Nutrition
                the Society for Free Radical Research Japan (Kyoto, Japan )
                0912-0009
                1880-5086
                November 2009
                28 October 2009
                : 45
                : 3
                : 285-291
                Affiliations
                [1 ]Nutrition Department of Para-Medical School, Ahvaz Jondishapur University of Medical Sciences, Ahvaz 61357-15794, Iran
                [2 ]Schools of Health and Institute of Public Health, Tehran University of Medical Science, Tehran 14176-14411, Iran
                [3 ]Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz 51664-14766, Iran
                Author notes
                *To whom correspondence should be addressed. Tel: +98-611-3367550 Fax: +98-611-3367550 E-mail: haidari58@ 123456gmail.com
                Article
                jcbn09-15
                10.3164/jcbn.09-15
                2771249
                19902018
                277f3463-325f-4c5e-b874-0afa437b6f7e
                Copyright © 2009 JCBN

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 February 2009
                : 20 March 2009
                Categories
                Original Article

                Biochemistry
                xanthine oxidase,antioxidant,flavonoids,uric acid
                Biochemistry
                xanthine oxidase, antioxidant, flavonoids, uric acid

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