Stephen Lawson

Recent Publications in Orthomolecular Nutrition and Medicine by LPI Scientists


Selected summaries by Stephen Lawson
LPI Administrative Officer

(LPI scientist identified in bold face)

Cancer

Breinholt V, Arbogast D, Loveland P, Pereira C, Dashwood R, Hendricks J, and Bailey G. Chlorophyllin chemoprevention in trout initiated by aflatoxin B1 bath treatment: An evaluation of reduced bioavailability vs. target organ protective mechanisms. Tox. Appl. Pharmacol. 158: 141-151, 1999.


Dashwood RH. Early detection and prevention of colorectal cancer (Review). Oncol. Rep. 6: 277-281, 1999.

The author reviews the value of early screening of colorectal cancer, which is the second leading cause of cancer mortality in the U. S. In addition to the conventional detection methods, including fecal blood tests, sigmoidoscopy, colonoscopy, and digital exams, screening for intermediate biomarkers, such as aberrant crypt foci (ACF) in the colon, may prove valuable. In rats, exposure to heterocyclic amines formed in meat, fish, and poultry by high-temperature cooking causes the formation of ACF, which are biomarkers for the earliest changes associated with the development of frank tumors. Exercise, avoidance of charred food and excessive fat, and the consumption of ample cereal and vegetables lower the risk of colorectal cancer. 


Santana-Rios G and Dashwood RH. Time to discontinue antigenotoxicity studies of dietary fiber? Mutat. Res. 429: 269-271, 1999.


Xu M and Dashwood RH. Chemoprevention studies of heterocyclic amine-induced colon carcinogenesis. Cancer Lett. 143: 179-183, 1999.

In rats, the exposure to mutagenic heterocyclic amines formed in meat, fish, and poultry by high-temperature cooking produces colon cancer. An early morphological lesion in the development of colon tumors are aberrant crypt foci (ACF). In this study, the authors used ACF and tumors as endpoints and found that several dietary constituents, including chlorophyllin (a derivative of chlorophyll, the green pigment in plants), catechins in green and black tea, indole-3-carbinol from cruciferous vegetables like broccoli and brussels sprouts, and conjugated linoleic acids effectively inhibit heterocyclic amine-induced carcinogenesis.


Xu M, Chen R, and Dashwood RH. Effect of carcinogen dose fractionation, diet and source of F344 rat on the induction of colonic aberrant crypts by 2-amino-3-methylimidazo[4,5-f]quinoline. Carcinogenesis 20: 2293-2298, 1999.

Scott Leonard in the lab Dashwood RH. Modulation of mutagenicity and carcinogenicity. In: Food Borne Carcinogens (Nagao M. and Sugimura T., eds.), J. Wiley & Sons, Ltd., Sussex, England, Chapter 9, pp. 285-312, 2000.

Magnuson BA, South EH, Exon JH, Dashwood RH, Xu M, Hendrix K, and Hubele S. Increased susceptibility of adult rats to azoxymethane-induced aberrant crypt foci. Cancer Lett. 161: 185-193, 2000.

Miranda CL, Yang Y-H, Henderson MC, Stevens JF, Santana-Rios G, Deinzer ML, and Buhler DR. Prenylflavonoids from hops inhibit the metabolic activation of the carcinogenic heterocyclic amine 2-amino-3-methylim-idazo[4,5-f]quinoline, mediated by CDNA-expressed human CYP1A2. Drug Metabolism and Disposition 28: 1297-1302, 2000.

Blum CA, Xu M, Orner GA, Fong AT, Bailey GS, Stoner GD, Horio DT, and Dashwood RH. Beta-Catenin mutation in rat colon tumors initiated by 1,2-dimethylhydrazine and 2-amino-3-methylimidazo[4,5-f]quinoline, and the effect of post-initiation treatment with chlorophyllin and indole-3-carbinol. Carcinogenesis 22: 315-320, 2001.

Carlson DB, Williams DE, Spitsbergen JM, Ross PF, Bacon CW, Meredith FI, and Riley RT. Fumonisin B1 promotes aflatoxin B1 and N-methyl-N'-nitro-nitrosoguanidine-initiated liver tumors in rainbow trout. Toxicol. Appl. Pharmacol. 172: 29-36, 2001.

Dashwood RH, Xu M, Orner GA, and Horio DT. Colonic cell proliferation, apoptosis and aberrant crypt foci development in rats given 2-amino-3-methylimidazo[4,5-f]quinoline and treated post-initiation with chlorophyllin. Eur. J. Cancer Prev. 10: 139-145, 2001.

Riley RT, Enongene E, Voss KA, Norred WP, Meredith FI, Sharma RP, Spitsbergen J, Williams DE, Carlson DB, and Merrill AH Jr. Sphingolipid perturbations as mechanisms for fumonisin carcinogenesis. Environm. Hlth. Perspect. 109: 301-308, 2001.


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

Ivanov V and Roomi MW. Decreased expression of transforming growth factor b1 in blood plasma of guinea pigs fed vitamin C deficient diet. Clin. Chim. Acta 269: 219-221, 1998.

Ivanov VO, Rabovsky AB, Ivanova SV, and Niedzwiecki A. Transforming growth factor-beta 1 and ascorbate regulate proliferation of cultured smooth muscle cells by independent mechanisms. Atherosclerosis 140: 25-34, 1998.

Shwaery GT, Mowri H-O, Keaney JF Jr, and Frei B. Preparation of lipid hydroperoxide-free low-density lipoproteins. Methods Enzymol. 300: 17-23, 1999.

Terry Tijerina in the lab Shwaery GT, Samii JM, Frei B, and Keaney JF Jr. Determination of phospholipid oxidation in cultured cells. Methods Enzymol. 300: 51-57, 1999.

Cross CE, Traber M, Eiserich J, and van der Vliet A. Micronutrient antioxidants and smoking. Brit. Med. Bull. 55: 691-704, 1999.

Frei B. Molecular and biological mechanisms of antioxidant action. FASEB J. 13: 963-964, 1999.

Traber MG. Utilization of vitamin E. BioFactors 10: 115-120, 1999.


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.


O'Byrne D, Grundy S, Packer L, Devaraj S, Baldenius K, Hoppe PP, Kraemer K, Jialal I, and Traber MG. Studies of LDL oxidation following a-, g- or d-tocotrienyl acetate supplementation of hypercholesterolemic humans. Free Radic. Biol. Med. 29: 834-845, 2000.

In this randomized, placebo-controlled, double-blind study, groups of patients with elevated plasma cholesterol levels were given a daily placebo or 250 mg supplements of alpha-, gamma-, or delta-tocotrienyl acetate for 8 weeks. Tocotrienols are members of the natural vitamin E family that have potent in vitro antioxidant activity. The authors found that the tocotrienols were absorbed and present in plasma but did not lower cholesterol levels in patients. After supplementation, the plasma levels of alpha-tocotrienol were only one-twentieth those of alpha-tocopherol. Alpha-tocotrienol supplementation inhibited the oxidation of LDL cholesterol in blood taken from patients, but much less than the magnitude of the antioxidant effect of alpha-tocopherol. The retention of alpha-tocotrienol in the blood is limited. 


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.

Parks EJ, Dare D, Frazier KB, Hellerstein MK, Neese RA, Hughes E, and Traber MG. Dependence of plasma a-tocopherol flux on very low-density triglyceride clearance in humans. Free Radic. Biol. Med. 29: 1151-1159, 2000.

Parks E and Traber MG. Mechanisms of vitamin E regulation: Research over the past decade and focus on the future. Antiox. Redox Signal. 2: 405-412, 2000.

Lodge JK, Traber MG, Elsner A, and Brigelius-Flohe R. A rapid method for the extraction and determination of vitamin E metabolites in human urine. J. Lipid Res. 41: 148-154, 2000.

Traber MG. Vitamin E. In: Handbook of Oxidants and Antioxidants in Exercise. (Sen CK, Packer L, and Hanninen O, eds.), Elsevier, pp. 359-371, 2000.

Frei B and McCall MR. Antioxidant vitamins: Evidence from biomarkers in humans. In: Functions of Vitamins beyond Recommended Dietary Allowances (Walter P, Hornig D, Moser U, eds.), Karger, Basel, Bibl. Nutr. Dieta. no. 55, pp. 46-67, 2001.


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.


Jung Suh in the lab 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.

Lodge JK, Ridlington J, Leonard S, Vaule H, and Traber MG. a- and g-Tocotrienols are metabolized to carboxyethyl-hydroxychroman derivatives and excreted in human urine. Lipids 36: 43-48, 2001.

McCall M, Carr AC, Forte TM, and Frei B. LDL modified by hypochlorous acid is a potent inhibitor of lecithin-cholesterol acyltransferase activity. Arterioscler. Thromb. Vasc. Biol. 21: 1040-1045, 2001.

Traber MG. Vitamin E: too much or not enough? Am. J. Clin. Nutr. 73: 997-998, 2001.

Carr AC, Decker EA, Park YJ, and Frei B. Comparison of low-density lipoprotein modification by myeloperoxidase-derived hypochlorous and hypobromous acids. Free Radic. Biol. Med. 31: 62-72, 2001.

Carr AC and Frei B. The nitric oxide congener nitrite inhibits myeloperoxidase/H2O2/Cl--mediated modification of low-density lipoprotein. J. Biol. Chem. 276: 1822-1828, 2001.

Carr AC, Hawkins CL, Thomas SR, Stocker R, and Frei B. Relative reactivities of N-chloramines and hypochlorous acid with human plasma constituents. Free Radic. Biol. Med. 30: 526-536, 2001.

Heart Disease


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.

Carr AC, Zhu B-Z, and Frei B. Potential antiatherogenic mechanisms of ascorbate (vitamin C) and a-tocopherol (vitamin E). Circ. Res. 87: 349-354, 2000.

Fang JC, Kinlay S, Hikita H, Suh JH, Piana RN, Selwyn AP, Frei B, Morrow JD, and Ganz P. Relation of preservation of nitric oxide-dependent coronary vasomotor function to plasma vitamin C concentrations in cardiac transplant recipients. Am. J. Cardiol. 86: 460-462, 2000.


Terasawa Y, Ladha Z, Leonard SW, Morrow JD, Newland D, Sanan D, Packer L, Traber MG, and Farese RV Jr. Increased atherosclerosis in hyperlipidemic mice deficient in a-tocopherol transfer protein and vitamin E. Proc. Natl. Acad. Sci. USA 97: 13830-13834, 2000.

In this study, a special hyperlipidemic mouse strain was used to assess the role of vitamin E in inhibiting atherosclerosis. These mice do not have the alpha-tocopherol (natural vitamin E) transfer protein gene that codes for the synthesis of the liver protein that helps distribute alpha-tocopherol to tissues. Therefore, they have elevated lipid levels and are deficient in vitamin E, which increased the severity of atherosclerotic lesions. Isoprostanes—sensitive markers of lipid oxidation—were found to be increased in aortic tissues, thereby providing more support for the hypothesis that oxidative stress promotes atherosclerosis.


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

Hagen TM. Increased mitochondrial decay and oxidative stress in the aging rat heart: Improvement by dietary supplementation with (R)-a-lipoic acid. In: Free Radicals in Chemistry, Biology and Medicine (Yoshikawa T, Toyokuni S, Yamamoto Y, and Naito Y, eds.), OICA Int., London, chapter 27, pp. 262-271, 2000.


Du Heath in the lab Hagen TM, Vinarsky V, Wehr CM, and Ames BN. (R)-a-Lipoic acid reverses the age-associated increase in susceptibility of hepatocytes to tert-butylhydroperoxide both in vitro and in vivo. Antiox. Redox Signaling 2: 473-483, 2000.

The toxin tert-butylhydroperoxide (t-BuOOH) causes lipid oxidation, mitochondrial damage, and the loss of glutathione, an important intracellular antioxidant. Liver cells from old rats are much more sensitive than cells from young rats to t-BuOOH toxicity. However, treatment of cells from old rats with R-alpha-lipoic acid, an antioxidant found in green leafy vegetables and meat, significantly protected the cells from t-BuOOH toxicity. To assess the physiological relevance of this result, old rats were dietarily supplemented with R-alpha-lipoic acid for two weeks, which provided protection against t-BuOOH toxicity and increased glutathione levels in liver cells. Supplementation of young rats with R-alpha-lipoic acid did not enhance the resistance to t-BuOOH toxicity, indicating that the antioxidant defense system of young rats was already functioning well.


Suh JH, Shigeno ET, Morrow JD, Cox B, Rocha AE, Frei B, and Hagen TM. Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-a-lipoic acid. FASEB J. 15: 700-706, 2001.

When oxidant production exceeds the antioxidant defense, oxidative stress is generated. Oxidative stress has been implicated in many chronic diseases as well as in aging. In this study, the authors investigated age-related changes in heart muscle cells known as myocytes. Myocytes from old rats showed increased oxidant production, decreased vitamin C levels, and increased oxidative DNA damage, all of which impair optimal function. When old rats were dietarily supplemented with R-alpha-lipoic acid, the level of oxidant production in myocytes fell to that observed in young rats, vitamin C levels increased, and the amount of oxidative DNA damage decreased.


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


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