Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Sep 1, 1993; 90(17): 7915–7922.

Oxidants, antioxidants, and the degenerative diseases of aging.


Metabolism, like other aspects of life, involves tradeoffs. Oxidant by-products of normal metabolism cause extensive damage to DNA, protein, and lipid. We argue that this damage (the same as that produced by radiation) is a major contributor to aging and to degenerative diseases of aging such as cancer, cardiovascular disease, immune-system decline, brain dysfunction, and cataracts. Antioxidant defenses against this damage include ascorbate, tocopherol, and carotenoids. Dietary fruits and vegetables are the principal source of ascorbate and carotenoids and are one source of tocopherol. Low dietary intake of fruits and vegetables doubles the risk of most types of cancer as compared to high intake and also markedly increases the risk of heart disease and cataracts. Since only 9% of Americans eat the recommended five servings of fruits and vegetables per day, the opportunity for improving health by improving diet is great.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.9M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Adelman R, Saul RL, Ames BN. Oxidative damage to DNA: relation to species metabolic rate and life span. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2706–2708. [PMC free article] [PubMed]
  • Shigenaga MK, Gimeno CJ, Ames BN. Urinary 8-hydroxy-2'-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9697–9701. [PMC free article] [PubMed]
  • Loft S, Vistisen K, Ewertz M, Tjønneland A, Overvad K, Poulsen HE. Oxidative DNA damage estimated by 8-hydroxydeoxyguanosine excretion in humans: influence of smoking, gender and body mass index. Carcinogenesis. 1992 Dec;13(12):2241–2247. [PubMed]
  • Ames BN, Shigenaga MK. Oxidants are a major contributor to aging. Ann N Y Acad Sci. 1992 Nov 21;663:85–96. [PubMed]
  • Fraga CG, Shigenaga MK, Park JW, Degan P, Ames BN. Oxidative damage to DNA during aging: 8-hydroxy-2'-deoxyguanosine in rat organ DNA and urine. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4533–4537. [PMC free article] [PubMed]
  • Sai K, Takagi A, Umemura T, Hasegawa R, Kurokawa Y. Changes of 8-hydroxydeoxyguanosine levels in rat organ DNA during the aging process. J Environ Pathol Toxicol Oncol. 1992 May-Jun;11(3):139–143. [PubMed]
  • Stadtman ER. Protein oxidation and aging. Science. 1992 Aug 28;257(5074):1220–1224. [PubMed]
  • Harman D. The aging process. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7124–7128. [PMC free article] [PubMed]
  • Harman D. Free radical theory of aging. Mutat Res. 1992 Sep;275(3-6):257–266. [PubMed]
  • Wagner JR, Hu CC, Ames BN. Endogenous oxidative damage of deoxycytidine in DNA. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3380–3384. [PMC free article] [PubMed]
  • Marnett LJ, Hurd HK, Hollstein MC, Levin DE, Esterbauer H, Ames BN. Naturally occurring carbonyl compounds are mutagens in Salmonella tester strain TA104. Mutat Res. 1985 Jan-Feb;148(1-2):25–34. [PubMed]
  • Park EM, Shigenaga MK, Degan P, Korn TS, Kitzler JW, Wehr CM, Kolachana P, Ames BN. Assay of excised oxidative DNA lesions: isolation of 8-oxoguanine and its nucleoside derivatives from biological fluids with a monoclonal antibody column. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3375–3379. [PMC free article] [PubMed]
  • Grist SA, McCarron M, Kutlaca A, Turner DR, Morley AA. In vivo human somatic mutation: frequency and spectrum with age. Mutat Res. 1992 Apr;266(2):189–196. [PubMed]
  • Branda RF, Sullivan LM, O'Neill JP, Falta MT, Nicklas JA, Hirsch B, Vacek PM, Albertini RJ. Measurement of HPRT mutant frequencies in T-lymphocytes from healthy human populations. Mutat Res. 1993 Feb;285(2):267–279. [PubMed]
  • Michaels ML, Cruz C, Grollman AP, Miller JH. Evidence that MutY and MutM combine to prevent mutations by an oxidatively damaged form of guanine in DNA. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7022–7025. [PMC free article] [PubMed]
  • Richter C, Park JW, Ames BN. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6465–6467. [PMC free article] [PubMed]
  • Cortopassi GA, Shibata D, Soong NW, Arnheim N. A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7370–7374. [PMC free article] [PubMed]
  • Wallace DC. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science. 1992 May 1;256(5057):628–632. [PubMed]
  • Oliver CN, Ahn BW, Moerman EJ, Goldstein S, Stadtman ER. Age-related changes in oxidized proteins. J Biol Chem. 1987 Apr 25;262(12):5488–5491. [PubMed]
  • Oliver CN, Starke-Reed PE, Stadtman ER, Liu GJ, Carney JM, Floyd RA. Oxidative damage to brain proteins, loss of glutamine synthetase activity, and production of free radicals during ischemia/reperfusion-induced injury to gerbil brain. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5144–5147. [PMC free article] [PubMed]
  • Brunk UT, Jones CB, Sohal RS. A novel hypothesis of lipofuscinogenesis and cellular aging based on interactions between oxidative stress and autophagocytosis. Mutat Res. 1992 Sep;275(3-6):395–403. [PubMed]
  • Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev. 1979 Jul;59(3):527–605. [PubMed]
  • Kasai H, Okada Y, Nishimura S, Rao MS, Reddy JK. Formation of 8-hydroxydeoxyguanosine in liver DNA of rats following long-term exposure to a peroxisome proliferator. Cancer Res. 1989 May 15;49(10):2603–2605. [PubMed]
  • Kiyosawa H, Suko M, Okudaira H, Murata K, Miyamoto T, Chung MH, Kasai H, Nishimura S. Cigarette smoking induces formation of 8-hydroxydeoxyguanosine, one of the oxidative DNA damages in human peripheral leukocytes. Free Radic Res Commun. 1990;11(1-3):23–27. [PubMed]
  • Frei B, Forte TM, Ames BN, Cross CE. Gas phase oxidants of cigarette smoke induce lipid peroxidation and changes in lipoprotein properties in human blood plasma. Protective effects of ascorbic acid. Biochem J. 1991 Jul 1;277(Pt 1):133–138. [PMC free article] [PubMed]
  • Reznick AZ, Cross CE, Hu ML, Suzuki YJ, Khwaja S, Safadi A, Motchnik PA, Packer L, Halliwell B. Modification of plasma proteins by cigarette smoke as measured by protein carbonyl formation. Biochem J. 1992 Sep 1;286(Pt 2):607–611. [PMC free article] [PubMed]
  • Schectman G, Byrd JC, Hoffmann R. Ascorbic acid requirements for smokers: analysis of a population survey. Am J Clin Nutr. 1991 Jun;53(6):1466–1470. [PubMed]
  • Duthie GG, Arthur JR, James WP. Effects of smoking and vitamin E on blood antioxidant status. Am J Clin Nutr. 1991 Apr;53(4 Suppl):1061S–1063S. [PubMed]
  • Bui MH, Sauty A, Collet F, Leuenberger P. Dietary vitamin C intake and concentrations in the body fluids and cells of male smokers and nonsmokers. J Nutr. 1992 Feb;122(2):312–316. [PubMed]
  • Shopland DR, Eyre HJ, Pechacek TF. Smoking-attributable cancer mortality in 1991: is lung cancer now the leading cause of death among smokers in the United States? J Natl Cancer Inst. 1991 Aug 21;83(16):1142–1148. [PubMed]
  • Kneller RW, You WC, Chang YS, Liu WD, Zhang L, Zhao L, Xu GW, Fraumeni JF, Jr, Blot WJ. Cigarette smoking and other risk factors for progression of precancerous stomach lesions. J Natl Cancer Inst. 1992 Aug 19;84(16):1261–1266. [PubMed]
  • Honjo S, Kono S, Shinchi K, Imanishi K, Hirohata T. Cigarette smoking, alcohol use and adenomatous polyps of the sigmoid colon. Jpn J Cancer Res. 1992 Aug;83(8):806–811. [PubMed]
  • Peto R, Lopez AD, Boreham J, Thun M, Heath C., Jr Mortality from tobacco in developed countries: indirect estimation from national vital statistics. Lancet. 1992 May 23;339(8804):1268–1278. [PubMed]
  • Salonen JT, Nyyssönen K, Korpela H, Tuomilehto J, Seppänen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation. 1992 Sep;86(3):803–811. [PubMed]
  • Salonen JT, Salonen R, Korpela H, Suntioinen S, Tuomilehto J. Serum copper and the risk of acute myocardial infarction: a prospective population study in men in eastern Finland. Am J Epidemiol. 1991 Aug 1;134(3):268–276. [PubMed]
  • Sullivan JL. The iron paradigm of ischemic heart disease. Am Heart J. 1989 May;117(5):1177–1188. [PubMed]
  • Ames BN, Profet M, Gold LS. Dietary pesticides (99.99% all natural). Proc Natl Acad Sci U S A. 1990 Oct;87(19):7777–7781. [PMC free article] [PubMed]
  • Gold LS, Slone TH, Stern BR, Manley NB, Ames BN. Rodent carcinogens: setting priorities. Science. 1992 Oct 9;258(5080):261–265. [PubMed]
  • Stamler JS, Singel DJ, Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms. Science. 1992 Dec 18;258(5090):1898–1902. [PubMed]
  • Ischiropoulos H, Zhu L, Beckman JS. Peroxynitrite formation from macrophage-derived nitric oxide. Arch Biochem Biophys. 1992 Nov 1;298(2):446–451. [PubMed]
  • Shacter E, Beecham EJ, Covey JM, Kohn KW, Potter M. Activated neutrophils induce prolonged DNA damage in neighboring cells. Carcinogenesis. 1988 Dec;9(12):2297–2304. [PubMed]
  • Yamashina K, Miller BE, Heppner GH. Macrophage-mediated induction of drug-resistant variants in a mouse mammary tumor cell line. Cancer Res. 1986 May;46(5):2396–2401. [PubMed]
  • Morrison DG, Daniel J, Lynd FT, Moyer MP, Esparza RJ, Moyer RC, Rogers W. Retinyl palmitate and ascorbic acid inhibit pulmonary neoplasms in mice exposed to fiberglass dust. Nutr Cancer. 1981;3(2):81–85. [PubMed]
  • Sanders CL, Mahaffey JA. Action of vitamin C on pulmonary carcinogenesis from inhaled 239PuO2. Health Phys. 1983 Sep;45(3):794–798. [PubMed]
  • Marsh JP, Mossman BT. Role of asbestos and active oxygen species in activation and expression of ornithine decarboxylase in hamster tracheal epithelial cells. Cancer Res. 1991 Jan 1;51(1):167–173. [PubMed]
  • Korkina LG, Durnev AD, Suslova TB, Cheremisina ZP, Daugel-Dauge NO, Afanas'ev IB. Oxygen radical-mediated mutagenic effect of asbestos on human lymphocytes: suppression by oxygen radical scavengers. Mutat Res. 1992 Feb;265(2):245–253. [PubMed]
  • Sobala GM, Pignatelli B, Schorah CJ, Bartsch H, Sanderson M, Dixon MF, Shires S, King RF, Axon AT. Levels of nitrite, nitrate, N-nitroso compounds, ascorbic acid and total bile acids in gastric juice of patients with and without precancerous conditions of the stomach. Carcinogenesis. 1991 Feb;12(2):193–198. [PubMed]
  • Kneller RW, Guo WD, Hsing AW, Chen JS, Blot WJ, Li JY, Forman D, Fraumeni JF., Jr Risk factors for stomach cancer in sixty-five Chinese counties. Cancer Epidemiol Biomarkers Prev. 1992 Jan-Feb;1(2):113–118. [PubMed]
  • Arroyo PL, Hatch-Pigott V, Mower HF, Cooney RV. Mutagenicity of nitric oxide and its inhibition by antioxidants. Mutat Res. 1992 Mar;281(3):193–202. [PubMed]
  • Tabor E, Kobayashi K. Hepatitis C virus, a causative infectious agent of non-A, non-B hepatitis: prevalence and structure--summary of a conference on hepatitis C virus as a cause of hepatocellular carcinoma. J Natl Cancer Inst. 1992 Jan 15;84(2):86–90. [PubMed]
  • Yu MW, You SL, Chang AS, Lu SN, Liaw YF, Chen CJ. Association between hepatitis C virus antibodies and hepatocellular carcinoma in Taiwan. Cancer Res. 1991 Oct 15;51(20):5621–5625. [PubMed]
  • SHANMUGARATNAM K. Primary carcinomas of the liver and biliary tract. Br J Cancer. 1956 Jun;10(2):232–246. [PMC free article] [PubMed]
  • Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, Sibley RK. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991 Oct 17;325(16):1127–1131. [PubMed]
  • Dooley CP, Cohen H, Fitzgibbons PL, Bauer M, Appleman MD, Perez-Perez GI, Blaser MJ. Prevalence of Helicobacter pylori infection and histologic gastritis in asymptomatic persons. N Engl J Med. 1989 Dec 7;321(23):1562–1566. [PubMed]
  • Cover TL, Blaser MJ. Helicobacter pylori and gastroduodenal disease. Annu Rev Med. 1992;43:135–145. [PubMed]
  • Howson CP, Hiyama T, Wynder EL. The decline in gastric cancer: epidemiology of an unplanned triumph. Epidemiol Rev. 1986;8:1–27. [PubMed]
  • Kirkwood TB. Comparative life spans of species: why do species have the life spans they do? Am J Clin Nutr. 1992 Jun;55(6 Suppl):1191S–1195S. [PubMed]
  • Kirkwood TB. Towards a unified theory of cellular ageing. Monogr Dev Biol. 1984;17:9–20. [PubMed]
  • Williams GC, Nesse RM. The dawn of Darwinian medicine. Q Rev Biol. 1991 Mar;66(1):1–22. [PubMed]
  • Weitzman SA, Gordon LI. Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis. Blood. 1990 Aug 15;76(4):655–663. [PubMed]
  • Cohen SM, Purtilo DT, Ellwein LB. Ideas in pathology. Pivotal role of increased cell proliferation in human carcinogenesis. Mod Pathol. 1991 May;4(3):371–382. [PubMed]
  • Roe FJ. Non-genotoxic carcinogenesis: implications for testing and extrapolation to man. Mutagenesis. 1989 Nov;4(6):407–411. [PubMed]
  • Roe FJ, Lee PN, Conybeare G, Tobin G, Kelly D, Prentice D, Matter B. Risks of premature death and cancer predicted by body weight in early adult life. Hum Exp Toxicol. 1991 Jul;10(4):285–288. [PubMed]
  • Pariza MW, Boutwell RK. Historical perspective: calories and energy expenditure in carcinogenesis. Am J Clin Nutr. 1987 Jan;45(1 Suppl):151–156. [PubMed]
  • Lutz WK, Schlatter J. Chemical carcinogens and overnutrition in diet-related cancer. Carcinogenesis. 1992 Dec;13(12):2211–2216. [PubMed]
  • Holehan AM, Merry BJ. Modification of the oestrous cycle hormonal profile by dietary restriction. Mech Ageing Dev. 1985 Oct 14;32(1):63–76. [PubMed]
  • Holliday R. Food, reproduction and longevity: is the extended lifespan of calorie-restricted animals an evolutionary adaptation? Bioessays. 1989 Apr;10(4):125–127. [PubMed]
  • Youngman LD, Park JY, Ames BN. Protein oxidation associated with aging is reduced by dietary restriction of protein or calories. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9112–9116. [PMC free article] [PubMed]
  • Weraarchakul N, Strong R, Wood WG, Richardson A. The effect of aging and dietary restriction on DNA repair. Exp Cell Res. 1989 Mar;181(1):197–204. [PubMed]
  • Koizumi A, Weindruch R, Walford RL. Influences of dietary restriction and age on liver enzyme activities and lipid peroxidation in mice. J Nutr. 1987 Feb;117(2):361–367. [PubMed]
  • Kubo C, Johnson BC, Day NK, Good RA. Calorie source, calorie restriction, immunity and aging of (NZB/NZW)F1 mice. J Nutr. 1984 Oct;114(10):1884–1899. [PubMed]
  • Lok E, Scott FW, Mongeau R, Nera EA, Malcolm S, Clayson DB. Calorie restriction and cellular proliferation in various tissues of the female Swiss Webster mouse. Cancer Lett. 1990 May 15;51(1):67–73. [PubMed]
  • Heller TD, Holt PR, Richardson A. Food restriction retards age-related histological changes in rat small intestine. Gastroenterology. 1990 Feb;98(2):387–391. [PubMed]
  • Nakamura KD, Duffy PH, Lu MH, Turturro A, Hart RW. The effect of dietary restriction on myc protooncogene expression in mice: a preliminary study. Mech Ageing Dev. 1989 May;48(2):199–205. [PubMed]
  • Sylvester PW, Aylsworth CF, Van Vugt DA, Meites J. Influence of underfeeding during the "critical period" or thereafter on carcinogen-induced mammary tumors in rats. Cancer Res. 1982 Dec;42(12):4943–4947. [PubMed]
  • Biemond P, van Eijk HG, Swaak AJ, Koster JF. Iron mobilization from ferritin by superoxide derived from stimulated polymorphonuclear leukocytes. Possible mechanism in inflammation diseases. J Clin Invest. 1984 Jun;73(6):1576–1579. [PMC free article] [PubMed]
  • Wolff S, Afzal V, Wiencke JK, Olivieri G, Michaeli A. Human lymphocytes exposed to low doses of ionizing radiations become refractory to high doses of radiation as well as to chemical mutagens that induce double-strand breaks in DNA. Int J Radiat Biol Relat Stud Phys Chem Med. 1988 Jan;53(1):39–47. [PubMed]
  • Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer. 1992;18(1):1–29. [PubMed]
  • Howe GR, Hirohata T, Hislop TG, Iscovich JM, Yuan JM, Katsouyanni K, Lubin F, Marubini E, Modan B, Rohan T, et al. Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies. J Natl Cancer Inst. 1990 Apr 4;82(7):561–569. [PubMed]
  • Gaziano JM, Manson JE, Buring JE, Hennekens CH. Dietary antioxidants and cardiovascular disease. Ann N Y Acad Sci. 1992 Sep 30;669:249–259. [PubMed]
  • Patterson BH, Block G, Rosenberger WF, Pee D, Kahle LL. Fruit and vegetables in the American diet: data from the NHANES II survey. Am J Public Health. 1990 Dec;80(12):1443–1449. [PMC free article] [PubMed]
  • Patterson BH, Block G. Food choices and the cancer guidelines. Am J Public Health. 1988 Mar;78(3):282–286. [PMC free article] [PubMed]
  • Block G. The data support a role for antioxidants in reducing cancer risk. Nutr Rev. 1992 Jul;50(7):207–213. [PubMed]
  • Gridley G, McLaughlin JK, Block G, Blot WJ, Gluch M, Fraumeni JF., Jr Vitamin supplement use and reduced risk of oral and pharyngeal cancer. Am J Epidemiol. 1992 May 15;135(10):1083–1092. [PubMed]
  • Krinsky NI. Antioxidant functions of carotenoids. Free Radic Biol Med. 1989;7(6):617–635. [PubMed]
  • Rousseau EJ, Davison AJ, Dunn B. Protection by beta-carotene and related compounds against oxygen-mediated cytotoxicity and genotoxicity: implications for carcinogenesis and anticarcinogenesis. Free Radic Biol Med. 1992 Oct;13(4):407–433. [PubMed]
  • Palozza P, Krinsky NI. beta-Carotene and alpha-tocopherol are synergistic antioxidants. Arch Biochem Biophys. 1992 Aug 15;297(1):184–187. [PubMed]
  • Sies H, Stahl W, Sundquist AR. Antioxidant functions of vitamins. Vitamins E and C, beta-carotene, and other carotenoids. Ann N Y Acad Sci. 1992 Sep 30;669:7–20. [PubMed]
  • Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. 1981 Nov;78(11):6858–6862. [PMC free article] [PubMed]
  • Frei B, Kim MC, Ames BN. Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4879–4883. [PMC free article] [PubMed]
  • Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987 Feb 27;235(4792):1043–1046. [PubMed]
  • Kohen R, Yamamoto Y, Cundy KC, Ames BN. Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain. Proc Natl Acad Sci U S A. 1988 May;85(9):3175–3179. [PMC free article] [PubMed]
  • Stocker R, Bowry VW, Frei B. Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1646–1650. [PMC free article] [PubMed]
  • Mohr D, Bowry VW, Stocker R. Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation. Biochim Biophys Acta. 1992 Jun 26;1126(3):247–254. [PubMed]
  • Suarna C, Hood RL, Dean RT, Stocker R. Comparative antioxidant activity of tocotrienols and other natural lipid-soluble antioxidants in a homogeneous system, and in rat and human lipoproteins. Biochim Biophys Acta. 1993 Feb 24;1166(2-3):163–170. [PubMed]
  • Ames BN, Gold LS. Chemical carcinogenesis: too many rodent carcinogens. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7772–7776. [PMC free article] [PubMed]
  • Henderson BE, Ross RK, Pike MC, Casagrande JT. Endogenous hormones as a major factor in human cancer. Cancer Res. 1982 Aug;42(8):3232–3239. [PubMed]
  • Moalli PA, MacDonald JL, Goodglick LA, Kane AB. Acute injury and regeneration of the mesothelium in response to asbestos fibers. Am J Pathol. 1987 Sep;128(3):426–445. [PMC free article] [PubMed]
  • Columbano A, Ledda-Columbano GM, Ennas MG, Curto M, Chelo A, Pani P. Cell proliferation and promotion of rat liver carcinogenesis: different effect of hepatic regeneration and mitogen induced hyperplasia on the development of enzyme-altered foci. Carcinogenesis. 1990 May;11(5):771–776. [PubMed]
  • Cerutti PA. Oxidant stress and carcinogenesis. Eur J Clin Invest. 1991 Feb;21(1):1–5. [PubMed]
  • Amstad PA, Krupitza G, Cerutti PA. Mechanism of c-fos induction by active oxygen. Cancer Res. 1992 Jul 15;52(14):3952–3960. [PubMed]
  • Boscoboinik D, Szewczyk A, Azzi A. Alpha-tocopherol (vitamin E) regulates vascular smooth muscle cell proliferation and protein kinase C activity. Arch Biochem Biophys. 1991 Apr;286(1):264–269. [PubMed]
  • Boscoboinik D, Szewczyk A, Hensey C, Azzi A. Inhibition of cell proliferation by alpha-tocopherol. Role of protein kinase C. J Biol Chem. 1991 Apr 5;266(10):6188–6194. [PubMed]
  • Bertram JS, Pung A, Churley M, Kappock TJ, 4th, Wilkins LR, Cooney RV. Diverse carotenoids protect against chemically induced neoplastic transformation. Carcinogenesis. 1991 Apr;12(4):671–678. [PubMed]
  • Wolf G. Retinoids and carotenoids as inhibitors of carcinogenesis and inducers of cell-cell communication. Nutr Rev. 1992 Sep;50(9):270–274. [PubMed]
  • Block G. Vitamin C and cancer prevention: the epidemiologic evidence. Am J Clin Nutr. 1991 Jan;53(1 Suppl):270S–282S. [PubMed]
  • Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992 May;3(3):194–202. [PubMed]
  • Byers T, Perry G. Dietary carotenes, vitamin C, and vitamin E as protective antioxidants in human cancers. Annu Rev Nutr. 1992;12:139–159. [PubMed]
  • Le Marchand L, Hankin JH, Kolonel LN, Beecher GR, Wilkens LR, Zhao LP. Intake of specific carotenoids and lung cancer risk. Cancer Epidemiol Biomarkers Prev. 1993 May-Jun;2(3):183–187. [PubMed]
  • Daoud AH, Griffin AC. Effect of retinoic acid, butylated hydroxytoluene, selenium and sorbic acid on azo-dye hepatocarcinogenesis. Cancer Lett. 1980 Jun;9(4):299–304. [PubMed]
  • Kushida H, Wakabayashi K, Suzuki M, Takahashi S, Imaida K, Sugimura T, Nagao M. Suppression of spontaneous hepatocellular carcinoma development in C3H/HeNCrj mice by the lipophilic ascorbic acid, 2-O-octadecylascorbic acid (CV-3611). Carcinogenesis. 1992 Jun;13(6):913–915. [PubMed]
  • Bagnasco M, Bennicelli C, Camoirano A, Balansky RM, De Flora S. Metabolic alterations produced by cigarette smoke in rat lung and liver, and their modulation by oral N-acetylcysteine. Mutagenesis. 1992 Jul;7(4):295–301. [PubMed]
  • Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, Cebula TA, Koch WH, Andrews AW, Allen JS, et al. DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science. 1991 Nov 15;254(5034):1001–1003. [PubMed]
  • Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed]
  • Knight TM, Forman D, Ohshima H, Bartsch H. Endogenous nitrosation of L-proline by dietary-derived nitrate. Nutr Cancer. 1991;15(3-4):195–203. [PubMed]
  • Gey KF, Puska P, Jordan P, Moser UK. Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr. 1991 Jan;53(1 Suppl):326S–334S. [PubMed]
  • Gey KF, Moser UK, Jordan P, Stähelin HB, Eichholzer M, Lüdin E. Increased risk of cardiovascular disease at suboptimal plasma concentrations of essential antioxidants: an epidemiological update with special attention to carotene and vitamin C. Am J Clin Nutr. 1993 May;57(5 Suppl):787S–797S. [PubMed]
  • Riemersma RA, Wood DA, Macintyre CC, Elton RA, Gey KF, Oliver MF. Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene. Lancet. 1991 Jan 5;337(8732):1–5. [PubMed]
  • Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993 May 20;328(20):1444–1449. [PubMed]
  • Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993 May 20;328(20):1450–1456. [PubMed]
  • Steinberg D. Antioxidant vitamins and coronary heart disease. N Engl J Med. 1993 May 20;328(20):1487–1489. [PubMed]
  • Esterbauer H, Gebicki J, Puhl H, Jürgens G. The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med. 1992 Oct;13(4):341–390. [PubMed]
  • Parthasarathy S, Steinberg D, Witztum JL. The role of oxidized low-density lipoproteins in the pathogenesis of atherosclerosis. Annu Rev Med. 1992;43:219–225. [PubMed]
  • Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989 Apr 6;320(14):915–924. [PubMed]
  • Salonen JT, Ylä-Herttuala S, Yamamoto R, Butler S, Korpela H, Salonen R, Nyyssönen K, Palinski W, Witztum JL. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet. 1992 Apr 11;339(8798):883–887. [PubMed]
  • Regnström J, Nilsson J, Tornvall P, Landou C, Hamsten A. Susceptibility to low-density lipoprotein oxidation and coronary atherosclerosis in man. Lancet. 1992 May 16;339(8803):1183–1186. [PubMed]
  • Haberland ME, Fless GM, Scanu AM, Fogelman AM. Malondialdehyde modification of lipoprotein(a) produces avid uptake by human monocyte-macrophages. J Biol Chem. 1992 Feb 25;267(6):4143–4151. [PubMed]
  • Jialal I, Grundy SM. Effect of dietary supplementation with alpha-tocopherol on the oxidative modification of low density lipoprotein. J Lipid Res. 1992 Jun;33(6):899–906. [PubMed]
  • Verlangieri AJ, Bush MJ. Effects of d-alpha-tocopherol supplementation on experimentally induced primate atherosclerosis. J Am Coll Nutr. 1992 Apr;11(2):131–138. [PubMed]
  • Frei B. Ascorbic acid protects lipids in human plasma and low-density lipoprotein against oxidative damage. Am J Clin Nutr. 1991 Dec;54(6 Suppl):1113S–1118S. [PubMed]
  • Esterbauer H, Striegl G, Puhl H, Oberreither S, Rotheneder M, el-Saadani M, Jürgens G. The role of vitamin E and carotenoids in preventing oxidation of low density lipoproteins. Ann N Y Acad Sci. 1989;570:254–267. [PubMed]
  • Esterbauer H, Puhl H, Dieber-Rotheneder M, Waeg G, Rabl H. Effect of antioxidants on oxidative modification of LDL. Ann Med. 1991;23(5):573–581. [PubMed]
  • Sato K, Niki E, Shimasaki H. Free radical-mediated chain oxidation of low density lipoprotein and its synergistic inhibition by vitamin E and vitamin C. Arch Biochem Biophys. 1990 Jun;279(2):402–405. [PubMed]
  • Makinodan T, Kay MM. Age influence on the immune system. Adv Immunol. 1980;29:287–330. [PubMed]
  • Sheffy BE, Schultz RD. Influence of vitamin E and selenium on immune response mechanisms. Fed Proc. 1979 Jun;38(7):2139–2143. [PubMed]
  • Meeker HC, Eskew ML, Scheuchenzuber W, Scholz RW, Zarkower A. Antioxidant effects on cell-mediated immunity. J Leukoc Biol. 1985 Oct;38(4):451–458. [PubMed]
  • Bendich A. Carotenoids and the immune response. J Nutr. 1989 Jan;119(1):112–115. [PubMed]
  • Meydani SN, Barklund MP, Liu S, Meydani M, Miller RA, Cannon JG, Morrow FD, Rocklin R, Blumberg JB. Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am J Clin Nutr. 1990 Sep;52(3):557–563. [PubMed]
  • Penn ND, Purkins L, Kelleher J, Heatley RV, Mascie-Taylor BH, Belfield PW. The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: a randomized controlled trial. Age Ageing. 1991 May;20(3):169–174. [PubMed]
  • Metzger Z, Hoffeld JT, Oppenheim JJ. Macrophage-mediated suppression. I. Evidence for participation of both hdyrogen peroxide and prostaglandins in suppression of murine lymphocyte proliferation. J Immunol. 1980 Feb;124(2):983–988. [PubMed]
  • Gregory SH, Wing EJ, Hoffman RA, Simmons RL. Reactive nitrogen intermediates suppress the primary immunologic response to Listeria. J Immunol. 1993 Apr 1;150(7):2901–2909. [PubMed]
  • Gougerot-Pocidalo MA, Fay M, Roche Y, Lacombe P, Marquetty C. Immune oxidative injury induced in mice exposed to normobaric O2: effects of thiol compounds on the splenic cell sulfhydryl content and Con A proliferative response. J Immunol. 1985 Sep;135(3):2045–2051. [PubMed]
  • al-Ramadi BK, Meissler JJ, Jr, Huang D, Eisenstein TK. Immunosuppression induced by nitric oxide and its inhibition by interleukin-4. Eur J Immunol. 1992 Sep;22(9):2249–2254. [PubMed]
  • Weindruch RH, Kristie JA, Cheney KE, Walford RL. Influence of controlled dietary restriction on immunologic function and aging. Fed Proc. 1979 May;38(6):2007–2016. [PubMed]
  • Taylor A. Role of nutrients in delaying cataracts. Ann N Y Acad Sci. 1992 Sep 30;669:111–124. [PubMed]
  • Leske MC, Chylack LT, Jr, Wu SY. The Lens Opacities Case-Control Study. Risk factors for cataract. Arch Ophthalmol. 1991 Feb;109(2):244–251. [PubMed]
  • Jacques PF, Chylack LT., Jr Epidemiologic evidence of a role for the antioxidant vitamins and carotenoids in cataract prevention. Am J Clin Nutr. 1991 Jan;53(1 Suppl):352S–355S. [PubMed]
  • Robertson JM, Donner AP, Trevithick JR. Vitamin E intake and risk of cataracts in humans. Ann N Y Acad Sci. 1989;570:372–382. [PubMed]
  • Hankinson SE, Stampfer MJ, Seddon JM, Colditz GA, Rosner B, Speizer FE, Willett WC. Nutrient intake and cataract extraction in women: a prospective study. BMJ. 1992 Aug 8;305(6849):335–339. [PMC free article] [PubMed]
  • Knekt P, Heliövaara M, Rissanen A, Aromaa A, Aaran RK. Serum antioxidant vitamins and risk of cataract. BMJ. 1992 Dec 5;305(6866):1392–1394. [PMC free article] [PubMed]
  • Hankinson SE, Willett WC, Colditz GA, Seddon JM, Rosner B, Speizer FE, Stampfer MJ. A prospective study of cigarette smoking and risk of cataract surgery in women. JAMA. 1992 Aug 26;268(8):994–998. [PubMed]
  • Christen WG, Manson JE, Seddon JM, Glynn RJ, Buring JE, Rosner B, Hennekens CH. A prospective study of cigarette smoking and risk of cataract in men. JAMA. 1992 Aug 26;268(8):989–993. [PubMed]
  • Garner MH, Spector A. Selective oxidation of cysteine and methionine in normal and senile cataractous lenses. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1274–1277. [PMC free article] [PubMed]
  • Mårtensson J, Steinherz R, Jain A, Meister A. Glutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8727–8731. [PMC free article] [PubMed]
  • Favit A, Nicoletti F, Scapagnini U, Canonico PL. Ubiquinone protects cultured neurons against spontaneous and excitotoxin-induced degeneration. J Cereb Blood Flow Metab. 1992 Jul;12(4):638–645. [PubMed]
  • Nisticò G, Ciriolo MR, Fiskin K, Iannone M, De Martino A, Rotilio G. NGF restores decrease in catalase activity and increases superoxide dismutase and glutathione peroxidase activity in the brain of aged rats. Free Radic Biol Med. 1992;12(3):177–181. [PubMed]
  • Adams JD, Jr, Odunze IN. Oxygen free radicals and Parkinson's disease. Free Radic Biol Med. 1991;10(2):161–169. [PubMed]
  • Behl C, Davis J, Cole GM, Schubert D. Vitamin E protects nerve cells from amyloid beta protein toxicity. Biochem Biophys Res Commun. 1992 Jul 31;186(2):944–950. [PubMed]
  • Halliwell B. Oxygen radicals as key mediators in neurological disease: fact or fiction? Ann Neurol. 1992;32 (Suppl):S10–S15. [PubMed]
  • Floyd RA, Carney JM. Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress. Ann Neurol. 1992;32 (Suppl):S22–S27. [PubMed]
  • Bindoli A, Rigobello MP, Deeble DJ. Biochemical and toxicological properties of the oxidation products of catecholamines. Free Radic Biol Med. 1992 Oct;13(4):391–405. [PubMed]
  • Zaman Z, Roche S, Fielden P, Frost PG, Niriella DC, Cayley AC. Plasma concentrations of vitamins A and E and carotenoids in Alzheimer's disease. Age Ageing. 1992 Mar;21(2):91–94. [PubMed]
  • Jesberger JA, Richardson JS. Oxygen free radicals and brain dysfunction. Int J Neurosci. 1991 Mar;57(1-2):1–17. [PubMed]
  • Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Mar 4;362(6415):59–62. [PubMed]
  • Hall ED, Braughler JM. Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation. Free Radic Biol Med. 1989;6(3):303–313. [PubMed]
  • Kinouchi H, Epstein CJ, Mizui T, Carlson E, Chen SF, Chan PH. Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11158–11162. [PMC free article] [PubMed]
  • Dawson VL, Dawson TM, Uhl GR, Snyder SH. Human immunodeficiency virus type 1 coat protein neurotoxicity mediated by nitric oxide in primary cortical cultures. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3256–3259. [PMC free article] [PubMed]
  • Cazevieille C, Muller A, Meynier F, Bonne C. Superoxide and nitric oxide cooperation in hypoxia/reoxygenation-induced neuron injury. Free Radic Biol Med. 1993 Apr;14(4):389–395. [PubMed]
  • Koppenol WH, Moreno JJ, Pryor WA, Ischiropoulos H, Beckman JS. Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem Res Toxicol. 1992 Nov-Dec;5(6):834–842. [PubMed]
  • Beckman JS. The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Dev Physiol. 1991 Jan;15(1):53–59. [PubMed]
  • Fraga CG, Motchnik PA, Shigenaga MK, Helbock HJ, Jacob RA, Ames BN. Ascorbic acid protects against endogenous oxidative DNA damage in human sperm. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11003–11006. [PMC free article] [PubMed]
  • Dawson EB, Harris WA, Teter MC, Powell LC. Effect of ascorbic acid supplementation on the sperm quality of smokers. Fertil Steril. 1992 Nov;58(5):1034–1039. [PubMed]
  • Magnani C, Pastore G, Luzzatto L, Terracini B. Parental occupation and other environmental factors in the etiology of leukemias and non-Hodgkin's lymphomas in childhood: a case-control study. Tumori. 1990 Oct 31;76(5):413–419. [PubMed]
  • Mau G, Netter P. Die Auswirkungen des väterlichen Zigarettenkonsums auf die perinatale Sterblichkeit und die Missbildungshäufigkeit. Dtsch Med Wochenschr. 1974 May 24;99(21):1113–1118. [PubMed]
  • Savitz DA, Schwingl PJ, Keels MA. Influence of paternal age, smoking, and alcohol consumption on congenital anomalies. Teratology. 1991 Oct;44(4):429–440. [PubMed]
  • Estel C, Böttcher A, Semman K. Uber den Einfluss mütterlicher und väterlicher Rauchgewohnheiten auf das Geburtsgewicht und die Missbildungsrate des Neugeborenen. Zentralbl Gynakol. 1982;104(9):563–567. [PubMed]
  • Koo LC, Ho JH, Rylander R. Life-history correlates of environmental tobacco smoke: a study on nonsmoking Hong Kong Chinese wives with smoking versus nonsmoking husbands. Soc Sci Med. 1988;26(7):751–760. [PubMed]
  • Hearey CD, Harris JA, Usatin MS, Epstein DM, Ury HK, Neutra RR. Investigation of a cluster of anencephaly and spina bifida. Am J Epidemiol. 1984 Oct;120(4):559–564. [PubMed]
  • Preston-Martin S, Yu MC, Benton B, Henderson BE. N-Nitroso compounds and childhood brain tumors: a case-control study. Cancer Res. 1982 Dec;42(12):5240–5245. [PubMed]
  • John EM, Savitz DA, Sandler DP. Prenatal exposure to parents' smoking and childhood cancer. Am J Epidemiol. 1991 Jan 15;133(2):123–132. [PubMed]
  • Sandler DP, Everson RB, Wilcox AJ, Browder JP. Cancer risk in adulthood from early life exposure to parents' smoking. Am J Public Health. 1985 May;75(5):487–492. [PMC free article] [PubMed]
  • Grufferman S, Delzell ES, Maile MC, Michalopoulos G. Parents' cigarette smoking and childhood cancer. Med Hypotheses. 1983 Sep;12(1):17–20. [PubMed]
  • Crow JF. How much do we know about spontaneous human mutation rates? Environ Mol Mutagen. 1993;21(2):122–129. [PubMed]
  • MacGregor JT, Schlegel R, Wehr CM, Alperin P, Ames BN. Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9962–9965. [PMC free article] [PubMed]
  • Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992 Aug 19;268(7):877–881. [PubMed]
  • Orrenius S, Burkitt MJ, Kass GE, Dypbukt JM, Nicotera P. Calcium ions and oxidative cell injury. Ann Neurol. 1992;32 (Suppl):S33–S42. [PubMed]
  • Chen J, Geissler C, Parpia B, Li J, Campbell TC. Antioxidant status and cancer mortality in China. Int J Epidemiol. 1992 Aug;21(4):625–635. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...