Recent Publications in Orthomolecular Nutrition and Medicine by LPI Scientists

Selected summaries by Stephen Lawson
LPI Adminstrative Officer

Photo of Stephen Lawson

(LPI scientist identified in bold face)


Traber, Maret; Elsner, Angelika; and Brigelius-Flohé, Regina. Synthetic as compared with natural vitamin E is preferentially excreted as alpha-CEHC in human urine: Studies using deuterated alpha-tocopheryl acetates. FEBS Letters, volume 437, pp. 145-148 (1998)

Using synthetic or natural vitamin E given to human subjects, the authors found that synthetic vitamin E is converted to a metabolite and excreted in the urine, whereas more of the natural vitamin E is retained in the body. Natural vitamin E (RRR-alpha-tocopherol) is usually identified on supplement products as d-alpha tocopherol; synthetic vitamin E (all rac-alpha-tocopherol) is commonly called dl-alpha tocopherol.

Traber, Maret. Recent advances of vitamin E pathophysiology. Asia Pacific Journal of Clinical Nutrition, volume 7, number 3/4, pp. 262-269 (1998)

In this review, Dr. Traber examines the role of vitamin E, including the tocopherols and tocotrienols (four of the eight natural compounds that have vitamin E activity; found in palm oil), in human physiology and disease. She notes that fat malabsorption syndromes can lead to vitamin E deficiency and that vitamin E deficiency can impair immune function. Vitamin E protects LDL cholesterol (the "bad" cholesterol) from oxidation, and tocotrienols inhibit cholesterol synthesis—functions that may help protect against heart disease. Some cell culture experiments suggest that tocotrienols may also inhibit cancer cell proliferation. Vitamin E has been shown to reduce oxidative stress in diabetics, thereby enhancing immune response. Additionally, vitamin E may play an important role in neurological diseases—some evidence shows that vitamin E protects nerve cells from oxidative stress or protein toxicity and may slow the progression of Alzheimer's disease. Lastly, Dr. Traber points out that the skin is quickly depleted of vitamin E by exposure to ultraviolet light and ozone.

Traber, Maret and Arai, Hiroyuki. Molecular mechanisms of vitamin E transport. Annual Reviews of Nutrition, volume 19, pp. 343-355 (1999)

This overview describes the research that led to the recognition of the tocopherol transfer protein, which preferentially binds the alpha-tocopherol form of vitamin E, as being responsible for the higher biological activity of natural vitamin E (d-alpha-tocopherol, or RRR-alpha-tocopherol) compared to synthetic vitamin E (dl-alpha-tocopherol, or all rac-alpha-tocopherol).

Traber, Maret; Serbinova, Elena; and Packer, Lester. Biological activities of tocotrienols and tocopherols. In: Antioxidant Food Supplements in Human Health, New York: Academic Press, pp. 55-71 (1999)

The natural vitamin E family consists of four tocopherols and four tocotrienols. Of these, alpha-tocopherol has the highest biological activity (e.g. ten times the activity of gamma-tocopherol and three times that of alpha-tocotrienol), but alpha-tocotrienol possesses superior antioxidant activity. The tocopherols and tocotrienols have different affinities for different tissues—brain contains only alpha-tocopherol, but the skin contains several tocopherols and tocotrienols.

Brigelius-Flohé, Regina and Traber, Maret. Vitamin E: Function and metabolism. The FASEB Journal, volume 13, pp. 1145-1155 (1999)

Since the various forms of natural vitamin E and synthetic vitamin E possess different metabolic functions and antioxidant potential, the authors find that it is not surprising that experimental, epidemiological, and clinical studies on vitamin E have given sometimes confusing results. For instance, the American diet contains much larger amounts of gamma-tocopherol than the European diet, which contains more alpha-tocopherol.

Burton, Graham; Ingold, Keith; Traber, Maret; and Kayden, Herbert. Reply to W. Cohn. The American Journal of Clinical Nutrition, volume 69, pp. 157-158 (1999)

McCall, Mark and Frei, Balz. Can antioxidant vitamins materially reduce oxidative damage in humans? Free Radical Biology & Medicine, volume 26, number 7/8, pp. 1034-1053 (1999)

In this comprehensive review, Drs. McCall and Frei examine the evidence that supplementation with the antioxidants vitamin C, vitamin E, or beta-carotene reduces oxidative damage to lipids, proteins, and DNA in humans. There is not enough data to assess the effect of these antioxidants on protein damage, and the results of studies that investigated the effects of antioxidant supplementation on DNA damage have been inconclusive. The authors conclude that the evidence does not support an important role for beta-carotene in reducing oxidative damage, but that vitamins E and C reduce the oxidation of lipids, which may have an impact on heart disease.

Wiseman, Sheila; Balentine, Douglas; and Frei, Balz. Antioxidants in tea. Critical Reviews in Food Science and Nutrition, vol. 37, number 8, pp. 705-718 (1997)

Dr. Frei and his colleagues review the antioxidant potential of various compounds in tea. In test-tube (in vitro) experiments, catechins and theaflavins from tea are substantially more potent free radical scavengers than vitamins C or E and protect LDL cholesterol from oxidation. Tea constituents have been shown to protect against oxidative stress in animals and in humans, and the beverage, studied in vitro, has a greater antioxidant capacity than most fruits and vegetables.

Cherubini, Antonio; Beal, M. Flint; and Frei, Balz. Black tea increases the resistance of human plasma to lipid peroxidation in vitro, but not ex vivo. Free Radical Biology & Medicine, volume 27, number 3/4, pp. 381-387 (1999)

Dr. Frei and his colleagues investigated the antioxidant effect of black tea in vitro and in human plasma obtained from subjects who drank black tea. While the black tea extracts containing polyphenols very effectively inhibited lipid oxidation in the test tube, lipid oxidation in blood taken from subjects who consumed the beverage was not decreased. The authors suggest that this may be due to insufficient bioavailability of tea polyphenols in humans; i.e. the polyphenols are not readily absorbed into the bloodstream during digestion.

photo of Anitra Carr
Dr. Anitra Carr in the lab

Carr, Anitra and Frei, Balz. Does vitamin C act as a pro-oxidant under physiological conditions? The FASEB Journal, volume 13, pp. 1007-1024 (1999)

There has been some concern as to whether, in some circumstances, vitamin C might act as a pro-oxidant in the body. Drs. Carr and Frei have reviewed the relevant literature to determine whether vitamin C acts as a pro-oxidant—damaging DNA, proteins, and lipids in the body. Most studies in humans have documented a reduction in oxidative DNA damage by vitamin C, while some have shown no effect. A few have shown an increase in DNA damage, but Drs. Carr and Frei point out that methodological problems may account for these results. Animal studies demonstrate that vitamin C protects against protein damage, but few studies have been carried out in humans. The results of most of the in vitro and in vivo studies in animals and humans support an antioxidant role for vitamin C. Even in the presence of iron, vitamin C still protects lipids and DNA from oxidative damage. Therefore, Drs. Carr and Frei conclude that vitamin C does not act as a pro-oxidant under physiological conditions.

Carr, Anitra and Frei, Balz. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. The American Journal of Clinical Nutrition, volume 69, pp. 1086-1107 (1999)

The Food and Nutrition Board is currently evaluating the RDAs for antioxidant vitamins. Drs. Carr and Frei have reviewed the evidence for a protective role of vitamin C against cancer, cataracts, and heart disease in the context of the RDA for vitamin C. The accumulated biochemical, clinical, and epidemiological investigations support a revision of the RDA for vitamin C to 120 mg/ day, twice the present RDA. This amount of vitamin C provides substantial protection against age-related diseases.


Dashwood, Roderick. Cancer chemoprevention from the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Mutation Research, volume 405, pp. 109-110 (1998)

In this paper, Dr. Dashwood addresses the complexity of cancer protection by dietary compounds. For instance, some phytochemicals (plant-derived compounds) may suppress tumor formation when taken before or during the exposure to a dietary carcinogen, but may enhance tumor formation when given after cancer initiation or cause other undesirable effects. Chorophyllin, a derivative of chlorophyll, binds to aflatoxins (mold toxins) and heterocyclic amines (formed in meat, fish, and poultry as the result of high temperature cooking) in the gut, thereby aiding in their removal from the body. However, we do not yet know if chlorophyllin also binds to other nutritive compounds with chemical structures similar to the carcinogens and assists in their excretion, too. Dr. Dashwood emphasizes that an understanding of molecular mechanisms is critical to the development of successful cancer chemoprotection strategies.

Dashwood, Roderick. The "sufficiency principle" from the perspective of cancer prevention. Japanese Journal of Clinical Oncology, vol. 28, number 6, pp. 410-412 (1998)

Dashwood, Roderick; Xu, Meirong; Hernaez, Judith; Hasaniya, Nahidh; Youn, Kristi; and Razzuk, Aziz. Cancer chemopreventive mechanisms of tea against heterocyclic amine mutagens from cooked meat. Proceedings of the Society for Experimental Biology and Medicine, volume 220, number 4, pp. 239-243 (1999)

Heterocyclic amines (HCA) are potent mutagens formed in meat cooked at very high temperatures, such as those attained in grilling. HCA have been shown to cause colon cancer in rats, which suggests that they may contribute to colon cancer in humans. Dr. Dashwood and his colleagues carried out several experiments to determine the possible protective effects of green tea and black tea against precancerous lesions (aberrant crypt foci, or ACF) in rats given HCA. In the first experiment, they found that the daily consumption of either green tea or black tea brewed for 5 minutes inhibited the formation of ACF. In the second experiment, rats were given green tea or black tea before and during the exposure to the carcinogen, after the exposure to the carcinogen, or during the entire experimental period. The number of rats with ACF was reduced by the continuous exposure to both teas, and green tea was particularly effective when administered before and during the treatment with the carcinogen. Mechanistic studies revealed that both teas enhanced the metabolism and detoxification of HCA and also quenched free radicals derived from HCA. Catechins in green tea were especially effective in quenching radicals. Using a bacterial mutagenicity assay, Dr. Dashwood and colleagues were able to show that certain catechins, concentrated in green tea, functioned as antimutagens in a dose-dependent manner.

Dashwood, Roderick; Suzui, Masumi; Nakagama, Hitoshi; Sugimura, Takashi; and Nagao, Minako. High frequency of beta-catenin (Ctnnb1) mutations in the colon tumors induced by two heterocyclic amines in the F344 rat. Cancer Research, volume 58, pp. 1127-1129 (1998)

Orner, Gayle; Hendricks, Jerry; Arbogast, Dan; and Williams, David. Modulation of aflatoxin-B1 hepato-carcinogenesis in trout by dehydroepiandrosterone: Initiation/post-initiation and latency effects. Carcinogenesis, volume 19, number 1, pp. 161-167 (1998)

Dehydroepiandrosterone (DHEA) is an adrenal hormone that is commonly sold as a nutritional supplement. Based on animal studies and short-term human studies, DHEA has been promoted to help reverse or slow aging and as a treatment for various diseases. Research in Dr. Williams' lab has shown that DHEA acts as a carcinogen and promotes liver tumors in trout following exposure to aflatoxin (a carcinogenic substance produced by molds on grain) through mechanisms that are relevant to humans. In the experiments described in this paper, the authors confirmed that giving DHEA to trout after they have been exposed to aflatoxin increases the number of trout with liver tumors as well as the number of tumors in individual trout. It also hastened the appearance of the first tumor. The authors further report that when given before or during, rather than after the exposure to the carcinogen, DHEA also enhanced tumor formation.

Oganesian, Aram; Hendricks, Jerry; Pereira, Cliff; Orner, Gayle; Bailey, George; and Williams, David. Potency of dietary indole-3-carbinol as a promoter of aflatoxin B1-initiated hepatocarcinogenesis: Results from a 9000 animal tumor study. Carcinogenesis, volume 20, number 3, pp. 453-458 (1999)

Many substances in cruciferous vegetables (e.g. broccoli, cauliflower, Brussels sprouts) have been shown to provide protection against cancer. However, the timing of the exposure to a carcinogen relative to the timing of the intake of the putative protective substance may be important. Dr. Oganesian and his colleagues found that indole-3-carbinol (I3C), one such presumably protective substance contained in cruciferous vegetables, actually enhanced liver cancer in trout when given after exposure to the carcinogen aflatoxin. The authors speculate that this result may be due to the estrogen stimulating effect of I3C in trout, since estrogens promote liver cancer in these fish.

Roomi, M. Waheed; House, Dionna; and Tsao, Constance. Cytotoxicity of lipoic acid and dihydrolipoic acid against malignant murine leukaemia cells: A comparison with ascorbic acid and dehydroascorbic acid. Medical Science Research, volume 26, pp. 461-463 (1998)

Using mouse leukemia cells, Dr. Roomi and his colleagues tested the inhibitory effect of two antioxidants, lipoic acid and vitamin C, as well as their reduced or oxidative products, dihydrolipoic acid (DHLA) and dehydroascorbic acid, respectively. At low concentrations, DHLA was significantly more cytotoxic to the malignant cells than were the other substances, which exhibited inhibitory effects only at higher concentrations. Lipoic acid is synthesized in cells and also found in organ meats and green leafy vegetables and functions in cells as a strong antioxidants, thereby protecting against damage from free radicals. The authors speculate that the chemical structure of DHLA may be responsible for its potent cytotoxicity against cancer cells.

Roomi, M. Waheed; House, Dionna; Eckert-Maksic, M.; Maksic, Z.; and Tsao, Constance. Growth suppression of malignant leukemia cell line by in vitro ascorbic acid (vitamin C) and its derivatives. Cancer Letters, volume 122, pp. 93-99 (1998)

Dr. Roomi and his colleagues evaluated the anticancer effect of vitamin C and several of its chemical derivatives and isomers against mouse leukemia cells in culture. While vitamin C, its isomers, and some of the derivatives strongly inhibited growth of the malignant cells, other vitamin C derivatives were not cytotoxic. The results led the authors to conclude that the anticancer effect resides in the dihydroxy gamma-crotonolactone moiety of the vitamin C molecule.

Roomi, M. Waheed; House, Dionna; and Tsao, Constance. Cytotoxic effect of substitution at 2-, 6-, and 2,6-positions in ascorbic acid on malignant cell line. Cancer Biochemistry Biophysics, volume 16, pp. 295-300 (1998)

Dunham, Wolcott; Tsao, Constance; Herman, Zelek; and Pauling, Linus. A model of early cancer: the effect of ascorbate and its oxidation or degeneration products on tumor incidence and growth in syngeneic guinea pigs given minimal numbers of tumor cells. Journal of Advancement in Medicine, volume 11, pp. 173-185 (1998)

Dr. Dunham and his colleagues evaluated the anticancer effect of vitamin C and its oxidation products or derivatives in guinea pigs injected with liver cancer cells. Tumors developed much later in animals given vitamin C in their drinking water, but, once formed, grew at about the same rate as tumors in animals that did not get vitamin C. In these experiments, oxidation products and derivatives of vitamin C had no effect on either the time at which tumors first appeared or on the growth rate of tumors.

Heart Disease

Frei, Balz. Vitamin C and cardiovascular disease: Mechanisms of action. In: Vitamin C: The State of the Art in Disease Prevention Sixty Years after the Nobel Prize (Paoletti, Roldolfo; Sies, Helmut; Bug, Joachim; Grossi, Enzo; and Poli, Andrea, eds.). Milano, Italy: Springer-Verlag, pp. 59-71 (1998)

In this contribution, Dr. Frei assesses the role of vitamin C in preventing heart disease by a number of mechanisms: 1) scavenging free radicals, 2) regenerating vitamin E, 3) inhibiting the oxidation of LDL cholesterol enhanced by metal ions, and 4) destroying the products of lipid peroxidation. The oxidation of LDL cholesterol has been implicated in the development of atherosclerosis because macrophages—a type of immune system cell—absorb oxidized LDL in the arterial wall and can form foam cells—an important step in lesion formation. Epidemiological and some clinical studies have shown a protective role for vitamin C (and vitamin E) against heart disease, and some studies also show that vitamin C inhibits platelet aggregation, which may help inhibit the progression of atherosclerosis and prevent stroke.

photo of a LPI faculty and staff
Recent photo of LPI faculty and staff

Polidori, M. Cristina; Frei, Balz; Cherubini, Antonio; Nelles, Gereon; Rordorf, Guy; Keaney Jr., John; Schwamm, Lee; Mecocci, Patrizia; Koroshetz, Walter; and Beal, M. Flint. Increased plasma levels of lipid hydroperoxides in patients with ischemic stroke. Free Radical Biology & Medicine, volume 25, number 4/5, pp. 561-567 (1998)

This paper provides evidence that ischemic stroke is associated with increased levels of lipid hydroperoxides (biomarkers for oxidative stress) in the blood and that the patient's prognosis worsens with increasing levels of this biomarker.

Gokce, Noyan; Keaney Jr., John; Frei, Balz; Holbrook, Monika; Olesiak, Mariusz; Zachariah, Benoy; Leeuwenburgh, Christiaan; Heinecke, Jay; and Vita, Joseph. Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation, volume 99, pp. 3234-3240 (1999)

In 1998, the Nobel Prize in Physiology or Medicine was awarded to three scientists who discovered the role of nitric oxide as a signaling molecule in the cardiovascular system. The function of nitric oxide in relaxing the arteries and improving blood flow can be impeded by oxidative stress caused by oxidized LDL cholesterol and free radicals like superoxide, whose existence was postulated by Linus Pauling in the early 1930s based on quantum mechanical arguments. In this clinical study, forty-six patients with coronary artery disease were divided into two groups. Arterial blood flow was measured in the arteries of all patients. One group of patients was then given 2 grams of vitamin C, which would be expected to ameliorate oxidative stress, the other group got a placebo, and the arterial blood flow was measured again in two hours. One group then continued taking 500 mg/day of vitamin C for one month. Patients who received vitamin C experienced significant and substantial improvement in vasodilation after both the acute dose and long-term administration.

Forte, Trudy; Oda, Michael; Knoff, Laura; Frei, Balz; Suh, Jung; Harmony, Judith; Stuart, William; Rubin, Edward; and Ng, Dominic. Targeted disruption of the murine lecithin:cholesterol acyltransferase gene is associated with reductions in plasma paraoxonase and platelet-activating factor acetylhydrolase activities but not in apolipoprotein J concentration. Journal of Lipid Research, volume 40, pp. 1276-1283 (1999)

Retsky, Karen; Chen, Kent; Zeind, John; and Frei, Balz. Inhibition of copper-induced LDL oxidation by vitamin C is associated with decreased copper-binding to LDL and 2-oxohistidine formation. Free Radical Biology & Medicine, volume 26, number 1/2, pp. 90-98 (1999)

Kinlay, Scott; Fang, James; Hikita, Hiroyuki; Ho, Ivan; Delagrange, Danielle; Frei, Balz; Suh, Jung; Gerhard, Marie; Creager, Mark; Selwyn, Andrew; and Ganz, Peter. Plasma ?-tocopherol and coronary endothelium-dependent vasodilator function. Circulation, volume 100, pp. 219-221 (1999)

This study of 21 patients found that higher plasma vitamin E levels were associated with improved vasodilation (arterial blood flow), which is impaired in patients with atherosclerosis.


Lykkesfeldt, Jens; Hagen, Tory; Vinarsky, Vladimir; and Ames, Bruce. Age-related decline in ascorbic acid concentration, recycling, and biosynthesis in rat hepatocytes—reversal with (R)-alpha-lipoic acid supplementation. FASEB Journal, volume 12, pp. 1183-1189 (1998)

In this study, the authors examined the levels of vitamin C in liver cells from young and old rats. The levels and biosynthesis of vitamin C in the cells from the old rats were only about half of the levels in cells from young rats, and the recycling of vitamin C in response to oxidative stress was significantly impaired in the old rats. However, when the old rats were supplemented with lipoic acid, these parameters returned nearly to the values in young rats.

Hagen, Tory; Ingersoll, Russell; Wehr, Carol; Lykkesfeld, Jens; Vinarsky, Vladimir; Bartholomew, James; Song, Mi-Hye; and Ames, Bruce. Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity. Proceedings of the National Academy of Sciences, volume 95, pp. 9562-9566, (1998)

Rats experience a decline in ambulatory activity as they age, similar to humans. Dr. Hagen and his collaborators have found that the mitochondria (organelles within cells that produce energy) in liver cells from old rats do not perform as well as those in young rats, but that this age-related decline can be reversed by feeding the old rats acetyl-L-carnitine (ALCAR), which is a highly bioavailable form of the amino acid carnitine. Carnitine transports fatty acids into the mitochondria where they fuel the production of adenosine triphosphate, which is a usable chemical form of energy that powers most functions in the body. Old rats given ALCAR become almost as active as young rats, but the mitochondria in their liver cells also generate increased amounts of free radicals coupled with a decrease in antioxidants. More recent results, however, indicate that the increased level of free radicals may be specific to the liver and may be counteracted by lipoic acid supplemtation.

Other LPI Papers

Netke, Shrirang and Tsao, Constance. Liver ascorbate and glutathione disulfide levels in guinea pigs are affected by dietary ascorbate intake and the type of diet. International Journal for Vitamin and Nutrition Research, volume 65, pp. 187-192 (1995)

photo of Dr. Ivanov and Svetlana Ivanova in the lab
Dr. Vadim Ivanov and
Svetlana Ivanova in the lab

Tsao, Constance. Systemic conditioning effect of ascorbic acid. Recent Research Developments in Nutrition, volume 1, pp. 15-25 (1996)

In this article, Dr. Tsao addresses the body's adaptation to large doses of vitamin C. She notes that results for different laboratories have been inconsistent, but that the possibility exists that some individuals may become conditioned to large doses of vitamin C under certain circumstances. The adaptation to a smaller intake of vitamin C is usually very rapid.

Roomi, M. Waheed and Tsao, Constance. Thin-layer chromatographic separation of isomers of ascorbic acid and dehydroascorbic acid as sodium borate complexes on silica gel and cellulose plates. Journal of Agricultural and Food Chemistry, volume 46, number 4, pp. 1406-1409 (1998)

Roomi, M. Waheed; Netke, Shrirang; and Tsao, Constance. Modulation of drug metabolizing enzymes in guinea pig liver by high intakes of ascorbic acid. The International Journal for Vitamin and Nutrition Research, volume 68, pp. 42-47 (1998)

Phase I and Phase II enzymes are drug-metabolizing enzymes synthesized in the liver. The authors show that a large intake of vitamin C in guinea pigs (animals that, like humans, do not synthesize vitamin C) has little effect on Phase I enzymes, which metabolize xenobiotics (e. g. drugs), but increase most Phase II enzymes, which detoxify xenobiotics.

Lawson, Stephen. Linus Pauling and Albert Szent-Gyorgyi. Journal of Orthomolecular Medicine, volume 13, number 3, pp. 183-184 (1998)

In this letter, the author discusses parallels between the thinking of Albert Szent-Gyorgyi and Linus Pauling in the 1930s on optimal health and vitamins. Szent-Gyorgyi discovered the structure of vitamin C and won the Nobel Prize in Medicine or Physiology in 1937.

Lawson, Stephen. Evidence exists for some advertising claims made on the Internet. British Medical Journal, volume 318, p. 1484 (1999)

Last updated November, 1999

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