Santana-Rios G, Orner GA, Amantana A, Provost C, Wu S-Y, and Dashwood RH. Potent antimutagenic activity of white tea in comparison with green tea in the Salmonella assay. Mutat. Res. 495: 61-74, 2001.

The authors evaluated the antimutagenic properties of constituents of white and green teas using the bacterial Salmonella assay. White tea is the least processed tea—its leaves and buds have been only steamed and dried, whereas the leaves of green tea have been withered, steamed, and dried. White tea had a greater inhibitory effect than green tea on the mutagenesis of Salmonella by heterocyclic amines, also known as cooked-meat mutagens. Both teas have nine major constitutent flavonoids, although white tea contains more of many of them.

Xu M, Orner GA, Bailey GS, Stoner GD, Horio DT, and Dashwood RH. Post-initiation effects of chlorophyllin and indole-3-carbinol in rats given 1,2-dimethylhydrazine or 2-amino-3-methylimidazo[4,5-f]quinoline. Carcinogenesis 22: 309-314, 2001. 

Yu Z, Xu M, Santana-Rios G, Shen R, Izquierdo-Pulido M, Williams DE, and Dashwood RH. A comparison of whole wheat, refined wheat and wheat bran as inhibitors of heterocyclic amines in the Salmonella mutagenicity assay and in the rat colonic aberrant crypt focus assay. Food Chem. Toxicol. 39: 655-665, 2001.

A number of studies have suggested that whole grains reduce the risk of colorectal cancer, while others have found no association between dietary fiber and colorectal cancer. Wheat consists of three components: the endosperm, bran, and germ. Refined wheat flour is made from only the starchy endosperm. In this paper, the authors analyzed the inhibition of mutagenicity in vitro and in vivo by whole wheat, refined wheat, and wheat bran using the bacterial Salmonella assay (in vitro) and the aberrant crypt focus (ACF) assay in rats. Salmonella cultures and rats were exposed to heterocyclic amines implicated in colorectal cancer. In vitro, the water-soluble fraction from refined and unrefined flour, but not bran, inhibited the mutagens. Rats treated with refined wheat had a slight increase in ACF, whereas unrefined wheat had a slight inhibitory effect. The ratio of the wheat to the mutagen may explain the discrepancy of the magnitude of the effects in vitro versus in vivo; i.e. the weight ratio of the grain:mutagens in vitro was about 10,000:1 but only 350:1 in vivo. 

Antioxidants and Oxidative Stress

Carr A and Frei B. The role of natural antioxidants in preserving the biological activity of endothelium-derived nitric oxide. Free Radic. Biol. Med. 28: 1806-1814, 2000.

Endothelial cells line the walls of blood vessels. Nitric oxide (NO), a signaling molecule in the vascular system, is made in endothelial cells from the amino acid L-arginine. NO relaxes the arterial wall, promoting normal blood flow, which may protect against angina pectoris, heart attack, hypertension, and stroke. The antioxidant vitamin E may enhance the activity of NO by preventing lipid oxidation or inhibiting protein kinase C (a marker of inflammation). Vitamin C has been shown to improve NO-mediated vasodilation in numerous clinical studies of patients with heart disease, diabetes, or other coronary risk factors. Possible mechanisms include scavenging superoxide, inhibiting the oxidation of lipids, sparing intracellular thiols (compounds that stabilize NO), and increasing levels of tetrahydrobiopterin, a co-factor in the synthesis of NO. 

Carr AC, McCall MR, and Frei B. Oxidation of LDL by myeloperoxidase and reactive nitrogen species: Reaction pathways and antioxidant protection. Arterioscler. Thromb. Vasc. Biol. 20: 1716-1723, 2000.

Carr AC, Myzak MC, Stocker R, McCall MR, and Frei B. Myeloperoxidase binds to low-density lipoprotein: potential implications for atherosclerosis. FEBS Lett. 487: 176-180, 2000.

Carr AC, Tijerina T, and Frei B. Vitamin C protects against and reverses specific hypochlorous acid- and chloramine-dependent modifications of low-density lipoprotein. Biochem. J. 346: 491-499, 2000.

Chen K, Suh J, Carr AC, Morrow JD, Zeind J, and Frei B. Vitamin C suppresses oxidative lipid damage in vivo, even in the presence of iron overload. Am. J. Physiol. Endocrinol. Metab. 279: E1406-E1412, 2000.

There has been much speculation about whether vitamin C can act as a pro-oxidant in the body, based on its ability to react with iron or copper in the test tube to form reactive oxygen species. In this paper, the authors gave low or high doses of vitamin C to guinea pigs—a species that, like humans, does not synthesize vitamin C—that had been injected with iron to produce iron overload. The amount of isoprostanes, which are sensitive markers of lipid oxidation, was then measured in the guinea pig plasma and livers. The guinea pigs given the high ascorbate dose had significantly lower levels of hepatic isoprostanes than the animals given the low ascorbate dose, indicating that vitamin C acts as an antioxidant even in the case of iron overload. Interestingly, iron loading itself did not cause increased lipid oxidation. It was also observed that iron loading retarded growth and caused tissue damage and that the combination of iron overload and low ascorbate status resulted in increased plasma triglycerides.

Liu, J, Yeo HC, Overvik-Douki E, Hagen TM, Doniger SJ, Chu DW, Brooks GA, and Ames BN. Chronically and acutely exercised rats: biomarkers of oxidative stress and endogenous antioxidants. J. Appl Physiol. 89: 21-28, 2000.

McCall MR and Frei B. Mechanisms of LDL oxidation. In: Oxidative Stress and Vascular Disease (Keaney JF Jr., ed.), Kluwer Academic Publishers, Boston, pp. 75-98, 2000. 

Traber MG, van der Vliet A, Reznick AZ, and Cross CE. Tobacco-related diseases: Is there a role for antioxidant micronutrient supplementation? Clin. Chest Med. 21: 173-187, 2000.

Miranda CL, Stevens JF, Ivanov V, McCall M, Frei B, Deinzer ML, and Buhler DR. Antioxidant and prooxidant actions of prenylated and nonprenylated chalcones and flavanones in vitro. J. Agric. Food Chem. 48: 3876-3884, 2000.

The authors examined the in vitro antioxidant activity of flavonoids found in hops and beer. Using LDL cholesterol isolated from human plasma, they found that xanthohumol, one of the major flavonoids in hops and beer, effectively inhibited lipid oxidation induced by copper. The fate of ingested flavonoids in beer is unknown, i.e. they may or may not be absorbed into the bloodstream or chemically modified after absorption.

Mowri H-O, Frei B, and Keaney JF Jr. Glucose enhancement of LDL oxidation is strictly metal ion dependent. Free Radic. Biol. Med. 29: 814-824, 2000.

Lodge JK, Traber MG, and Sadler PJ. Cu²⁺-induced low density lipoprotein peroxidation is dependent on the initial O₂ concentration: An O₂ consumption study. Lipids 35: 1087-1092, 2000.

Frei B and Traber MG. The new U.S. Dietary Reference Intakes for vitamins C and E. Redox Report 6: 5-9, 2001. 

The authors, both renowned experts on vitamin C or E, offer commentary on the DRIs for these vitamins published by the Food and Nutrition Board (FNB) in 2000. The new RDAs for adults for vitamin C are 90 mg/day for men and 75 mg/day for women. Additionally, the FNB established, for the first time, a tolerable upper intake level (UL) for vitamin C of 2,000 mg/day based on diarrhea and gastrointestinal (GI) disturbances. The authors conclude that an extensive review of over 200 research articles suggests that the epidemiological, biochemical, and clinical evidence strongly supports an RDA for adults for vitamin C of about 120 mg/day. Citing a number of safety reviews on vitamin C, the authors note that diarrhea and GI disturbances are not serious criteria for establishing a UL and that a UL for vitamin C cannot be set based on published, controlled studies. The new RDA for vitamin E for adult men and women was set at 15 mg natural vitamin E (d-alpha- or RRR-alpha-tocopherol)/day. It is based on the prevention of overt deficiency symptoms, such as peripheral neuropathy, and on 30-year old data on the prevention of red blood cell rupture in vitro. The FNB also distinguished between natural and synthetic vitamin E (dl-alpha- or all rac-tocopherol), which is incompletely recognized by the vitamin E transfer protein in the liver. While the results of supplementation studies in humans have been equivocal, the authors contend that the effect of vitamin E on primary prevention of heart disease in healthy humans has not been adequately studied and that vitamin E may be of special benefit to people with certain genetic dispositions. The authors agree with the FNB's UL of 1,000 mg/day of natural vitamin E (based on the risk of hemorrhagic stroke), but argue that the daily intake of 200 mg of natural vitamin E may offer substantial protection against heart disease.

German JB and Traber MG. Nutrients and oxidation: Actions, transport, and metabolism of dietary antioxidants. In: Handbook of Vitamins (Rucker, Suttie, McCormick and Machlin, eds.), Marcel Dekker, Inc., New York, pp. 569-588, 2001.

Decker EA, Ivanov V, Zhu B-Z, and Frei B. Inhibition of low-density lipoprotein oxidation by carnosine and histidine. J. Agric. Food Chem. 49: 511-516, 2001.

Kaushik S, Wander R, Leonard S, German B, and Traber MG. Removal of fat from cow's milk decreases the vitamin E contents of the resulting dairy products. Lipids 36: 73-78, 2001.

Lauridsen C, Leonard S, Griffin DA, Liebler DC, McClure TD, and Traber MG. Quantitative analysis by liquid chromatography-tandem mass spectrometry of deuterium-labeled and unlabeled vitamin E in biological samples. Anal. Biochem. 289: 89-95, 2001.

Duffy SJ, Gokce N, Holbrook M, Huang A, Frei B, Keaney JF Jr, and Vita JA. Treatment of hypertension with ascorbic acid. Lancet 354: 2048-2049, 1999.

The authors conducted a randomized, double-blind, placebo-controlled study to evaluate the effect of vitamin C supplements on blood pressure in hypertensive subjects, most of whom were taking drugs to control high-blood pressure. Mean blood pressure was reduced by about 10% in those subjects taking 500 mg/day of vitamin C for the one-month period of the study.

Frei B. On the role of vitamin C and other antioxidants in atherogenesis and vascular dysfunction. Proc. Soc. Exp. Biol. Med. 222: 196-204, 1999.

Jialal I, Devaraj S, Huet BA, and Traber MG. GISSI-Prevenzione trial. Lancet 354: 1554, 1999.

Duffy SJ, Keaney JF Jr, Holbrook M, Gokce N, Swerdloff PL, Frei B, and Vita JA. Short- and long-term black tea consumption reverses endothelial dysfunction in patients with coronary artery disease. Circulation 104: 151-156, 2001.

Epidemiological evidence suggests that tea decreases the risk of cardiovascular disease. The molecular mechanisms for this protective effect are unknown, but this study offers a possible explanation: tea normalizes vascular function, but does not affect blood pressure or heart rate. Black tea (450 ml) was consumed by study subjects, followed by measurement of brachial artery dilation by ultrasound after 2 hours and again after 4 weeks of daily tea consumption (900 ml/day). Acute and chronic consumption of tea resulted in an increase in plasma polyphenolic flavonoids and significant arterial dilation. The loss of proper arterial function, or endothelial dysfunction, has been associated with the development of atherosclerosis and cardiovascular events like stroke and heart attack.

Jialal I, Traber MG, and Devaraj S. Is there a vitamin E paradox? Curr. Opin. Lipidol. 12: 49-53, 2001.

The authors have critically evaluated the five major clinical trials in which supplementary vitamin E, ranging from 50 to 800 IU/day, was taken by subjects at high risk for cancer or heart disease or who already had heart disease or diabetes. While designed as a cancer prevention study, the ATBC trial found a substantial reduction in the risk for non-fatal second heart attacks in male smokers who took 50 IU/day of vitamin E for 5-8 years, although there was no effect on the first coronary event or the number of coronary events. The British CHAOS trial followed subjects with coronary artery disease for about one and one-half years who were given 400 or 800 IU/day of vitamin E or a placebo. Those who took vitamin E had a 77% reduction in the risk for nonfatal heart attack. The GISSI trial in Italy found a 20% reduction in cardiovascular deaths among the participants who took 330 IU/day of vitamin E for about 3.5 years. The HOPE trial followed men and women in Canada, Europe, USA, and South America who were at high risk for heart attack or stroke because they had heart disease or diabetes. They took 400 IU/day of vitamin E for 4-6 years and were compared to other subjects taking drugs or placebo. There was no difference in the incidence of heart attack, stroke, or death from cardiovascular disease between the placebo and vitamin E groups, although dietary differences among the geographical regions may have confounded the results. Lastly, the SPACE trial in Israel found that the intake of 800 IU/day of vitamin E for over 500 days resulted in over a 50% reduction in primary endpoints (heart attack, stroke, peripheral vascular disease, and unstable angina) in hemodialysis patients with heart disease.

Polidori MC, Mecocci P, and Frei B. Plasma vitamin C levels are decreased and correlated with brain damage in patients with intracranial hemorrhage or head trauma. Stroke 32: 898-902, 2001.

Traber MG. Does vitamin E decrease heart attack risk? Summary and implications with respect to dietary recommendations. J. Nutr. 131: 395S-397S, 2001.

Results of epidemiological studies indicate that supplemental vitamin E may reduce the risk of heart attacks. However, intervention studies in which subjects were given vitamin E supplements and monitored for years have been equivocal. The author of this article points out that potent non-antioxidant activities of vitamin E, such as its inhibition of inflammation, platelet aggregation, and smooth muscle cell proliferation that leads to increased vascular wall thickness, may significantly decrease the risk of heart attacks. The role of vitamin E in normalizing vascular function may also be important. More studies on these functions of vitamin E are needed so that future intake recommendations can be based on the prevention of chronic disease.

Aging

Other LPI Papers

Terasawa Y, Cases SJ, Wong JS, Jamil H, Jothi S, Traber MG, Packer L, Gordon DA, Hamilton RL, and Farese, RV Jr. Apolipoprotein B-related gene expression and ultrastructural characteristics of lipoprotein secretion in mouse yolk sac during embryonic development. J. Lipid Res. 40: 1967-1977, 1999.

Traber MG. The bioavailability bugaboo. Am. J. Clin. Nutr. 71: 1029-1030, 2000.

Traber MG and Jialal I. Measurement of lipid-soluble vitamins—further adjustment needed? Lancet 355: 2013-2014, 2000.

Freedman JE, Parker C III, Li L, Perlman JA, Frei B, Ivanov V, Deak LR, Iafrati MD, and Folts JD. Select flavonoids and whole juice from purple grapes inhibit platelet function and enhance nitric oxide release. Circulation 103: 2792-2798, 2001. 

Red wine consumption has long been associated with a decreased risk for cardiovascular disease, partly due to the presence of polyphenolic flavonoids in wine. These substances are also present in grape juice, and the authors of this study investigated the biochemical effects of purple grape juice in vitro and in vivo. Volunteers drank about 500 ml of purple grape juice daily for two weeks, which produced beneficial effects on blood parameters, including decreased platelet aggregation, increased nitric oxide production, and decreased levels of the superoxide free radical. Similar results were observed in cell cultures treated with purple grape juice. These findings demonstrate that the flavonoids in purple grapes and beverages made from them may help prevent cardiovascular events. 

Krueger SK, Yueh M-F, Martin SR, Pereira CB, and Williams DE. Characterization of expressed full-length and truncated FMO2 from Rhesus monkey. Drug Metabol. Dispos. 29: 693-700, 2001.

Katchamart S and Williams DE. Indole-3-carbinol modulation of hepatic monooxygenases CYP1A1, CYP1A2 and FMO1 in guinea pig, mouse and rabbit. Comp. Biochem. Physiol., Part C, 129: 377-384, 2001.

Last updated November, 2001