Beyond Radical Scavenging

20.3.1 Direct Protection against DNA Damage

Studies investigating hydrogen peroxide-induced toxicity in cell culture determined that the anthocyanins delphinidin and cyanidin (aglycones and glycosides) were protective against DNA strand breaks in human colon cells.6970 Furthermore, glycosides of cyanidin, petunidin, peonidin, and malvidin were observed to decrease the formation of oxidized DNA bases and lipid hydroperoxides in vitamin E-deficient rats.71 Although the mechanisms mediating these effects have not been determined, pulse radiolysis studies utilizing in vitro plasmid environments have indicated that flavonoids may be protective against free radical-induced DNA damage through mechanisms independent of their antioxidant capabilities.72 Additionally, an investigation by Sarma and Sharma73 found cya-nidin to complex with DNA, forming an anthocyanin-DNA co-pigment, which appeared to protect the DNA from oxidation when exposed to hydroxyl radicals. Unfortunately, the biological implications of such an interaction are at present unknown.

20.3.2 Enzymatic Antioxidant Defense

Anthocyanins, and other flavonoids such as quercetin, have been observed to have beneficial effects on endogenous enzymes associated with oxidative stress. In established models of oxidative stress, such as ischemia-reperfusion and hyper-oxia, anthocyanins have been observed to inhibit xanthine oxidase, and complement superoxide dismutase, catalase, and glutathione peroxidase.15 74 Ischemia-reperfusion is associated with the excessive production of reactive oxygen species and subsequent oxidative injury. During ischemia, the catabolism of the available ATP leads to an increased concentration of the purine metabolites xanthine and hypoxanthine. The conversion of xanthine-dehydrogenase to the free radical generating form, xanthine oxidase, occurs under the ischemic condition. Upon reperfusion, when oxygen is reintroduced suddenly, a massive "burst" of free radical generation results from the xanthine oxidase-catalyzed formation of superoxide. The ensuing free radical-mediated chain reaction results in extensive tissue injury at the site of reperfusion as a consequence of the increased leakage of superoxide from dysfunctional mitochondria, the accumulation of leukocytes, the accumulation of reduced catecholamines, flavines and quinines, and the release of iron from heme proteins. Ischemia-reperfusion injury is a major concern during organ transplantation and as result of vascular occlusion. Anthocyanins have been observed to have an inhibitory effect on xanthine oxidase and xanthine dehydrogenase activity under experimentally induced ischemic conditions.1574 Additionally, the chronic feeding of cyanidin 3-glucoside to rats resulted in a significant reduction in reactive oxygen radical production and prevented glu-tathione decline in a hepatic ischemia-reperfusion model of oxidative stress in rats. The resistance imposed by cyanidin-3-glucoside occurred without affecting levels of endogenous serum antioxidant enzymes.33 75 76

Hyperoxia is the result of an excess of oxygen in tissues or organs. Although hyperoxia is generally not experienced under normal/basal circumstances, it can be induced experimentally by increasing the level of atmospheric oxygen. Hyper-oxia is an excepted model of oxidative stress and generally results in a significant increase in oxygen radical production followed by the induction of vast quantities of endogenous antioxidant defense enzymes including superoxide dismutase, catalase, and glutathione peroxidase. Supplementation of an anthocyanin-rich extract from blueberries was reported to impose resistance to hyperoxia-induced oxidative stress in rats without affecting endogenous serum antioxidant enzymes.77

20.3.3 Cell Cycle and Tumor Development

Anthocyanins isolated from various fruits have been observed to reduce the frequency of induced mutation and to display general inhibitory activity against carcinogenesis in numerous tissues and cancer cell lines. They have been shown to reduce hydrogen peroxide-induced DNA damage in primary human colon cells isolated from biopsies,27 reduce the frequency of induced mutation by benzo(a)pyrene,46 suppress lesion development and tumor promotion in human and animal models of colon carcinogenesis,33,78,79 directly inhibit cell growth of human malignant carcinoma and lymphoma cultured cells,80 impair angiogene-sis,68 and induce apoptosis in human leukemia cells (cell line HL-60; 33). Many of these reported activities appear to occur through mechanisms other than radical scavenging. By using cell culture models, many flavonoids, including antho-cyanins, have been shown to reduce tumor development, inhibit proliferation, and prevent in vitro angiogenesis through nonradical scavenging mechanisms.68,79,81 Some of the suggested properties of anthocyanins that mediate their action against tumor promotion and development include inhibition of the release of superoxide from stimulated human granulocytes,46 direct cytostatic activity effecting cell proliferation and differentiation,80 inhibition of epidermal growth factor receptor and vascular endothelial growth factor,68,78 and direct inhibition of the kinase signaling pathways.33,81

Mechanistic studies using mouse epidermal cells suggest that the ortho-dihydroxyl phenyl (B-ring) portion of the anthocyanin is the component responsible for effects on lesion development. Researchers based this assumption on structure-activity relationship studies that have shown cyanidin, delphinidin, and petunidin to have significant antitumor promoting effects while, in this model, malvidin, peonidin, and pelargonidin had no effect.33 Anthocyanins and their respective aglycones have also been observed to significantly reduce tumor development in cultured cells.7879 Researchers reported the aglycones to have a significantly higher activity over that of their respective glycosides; however, the glycosides were still active. Because anthocyanin aglycones have not been detected in the circulation, the effects of anthocyanin aglycones on the suppression of tumor development would presumably be achieved primarily in the colon while glycoside interactions may include systemic effects.

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