Soy isoflavone supplementation elevates erythrocyte superoxide dismutase, but not plasma ceruloplasmin in postmenopausal breast cancer survivors
Soy isoflavone antioxidant effects may help prevent breast cancer re-occurrence, but isoflavone estrogen-like actions may increase breast cancer risk. These isoflavone actions can be reflected by effects on two copper enzymes activities, superoxide dismutase 1 (SOD 1), which has antioxidant function relevant to breast cancer prevention, and ceruloplasmin, which has its synthesis up-regulated by estrogen, and for which high values are associated with high breast cancer risk. A soy isoflavone-rich concentrate supplement was examined for effects on these two copper enzyme activities in post-menopausal breast cancer survivors (n = 7) in a crossover design with a placebo (24 days on supplement or placebo; 14 day wash out). The soy concentrate, but not the placebo, increased erythrocyte SOD 1 activities, but not ceruloplasmin activities or protein. The effect on superoxide dismutase activities was not likely due to increased copper intake since analysis of the soy extract showed little copper. The effect on superoxide dismutase was not accompanied by a change in urinary contents of 8-deoxyhydroxyguanosine, a DNA oxidant product, though perhaps this would change with a longer intervention. In summary, in regard to two copper enzyme activities, an isoflavone-rich soy concentrate showed an antioxidant effect considered relevant to breast cancer, but not an effect associated with estrogenic activity and increased breast cancer risk.
Keywordsantioxidant breast cancer survivors ceruloplasmin copper estrogen-like effects isoflavones soy superoxide dismutase
Ganry, O 2002Phytoestrogen and breast cancer preventionEur J Cancer Prev11519522PubMedGoogle Scholar Atkinson, C, Bingham, SA 2002Mammographic breast density as a biomarker of effects of isoflavones on the female breastBreast Cancer Res414PubMedGoogle Scholar Barnes, S 1996Soy isoflavonoids and cancer preventionUnderlying biochemical and pharmacological issues. Adv Exp Med Biol40187100Google Scholar Barnes, S 1997The chemopreventive properties of soy isoflavonoids in animal models of breast cancerBreast Cancer Treat Chemoprevent46169179Google Scholar Lamartiniere, CA 1998Genistein studies in rats: potential for breast cancer prevention and reproductive and developmental toxicityAm J Clin Nutr681400S1405SPubMedGoogle Scholar Ohta, T, Nakatsugi, S, Watanabe, K, Kawamori, T, Ishikawa, F, Morotomi, M, Sugie, S, Toda, T, Sugimura, T, Wakabayashi, K 2000Inhibitory effects of Bifidobacterium-fermented soy milk on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced rat mammary carcinogenesis, with a partial contribution of its component isoflavonesCarcinogenesis21937941PubMedGoogle Scholar Ju, YH, Allred, CD, Allred, KF, Karko, KL, Doerge, DR, Helferich, WG 2001Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude miceJ Nutr13129572962PubMedGoogle Scholar Nakagawa, H 2000Effects of genistein and synergistic action in combination with eicosapentaenoic acid on the growth of breast cancer cell linesJ Cancer Res Clin Oncol126448454PubMedGoogle Scholar Shao, ZM, Wu, J, Shen, ZZ, Barsky, SH 1998Genistein exerts multiple suppressive effects on human breast carcinoma cellsCancer Res5848514857PubMedGoogle Scholar Lamartiniere, CA 2000Protection against breast cancer with genistein: a component of soy.Am J Clin Nutr711705S1709SPubMedGoogle Scholar Wu, AH, Ziegler, RG, Horn-Ross, PL, Nomura, AM, West, DW, Kolonel, LN, Rosenthal, JF, Hoover, RN, Pike, MC 1996Tofu and risk of breast cancer in Asian-AmericansCancer Epidemiol5901906Google Scholar Zheng, W, Dai, Q, Custer, LJ, Shu, XO, Wen, WQ, Jin, F, Franke, AA 1999Urinary excretion of isoflavonoids and the risk of breast cancerCancer Epidemiol Biomarkers Prev83540PubMedGoogle Scholar McMichael-Phillips, DF, Harding, C, Morton, M, Roberts, SA, Howell, A, Potten, CS, Bundred, NJ 1998Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast.Am J Clin Nutr68S1431S1435SGoogle Scholar Hargreaves, DF, Potten, CS, Harding, C, Shaw, LE, Morton, MS, Roberts, SA, Howell, A, Bundred, NJ 1999Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breastJ Clin Endocrinol Metab8440174024PubMedGoogle Scholar Taffe, BG, Kensler, TW 1989Role of oxidative stress in tumor promotionMiquel, JQuintanilha, ATWeber, H eds. Handbook of Free Radicals and Antioxidants in BiomedicineCRC PressBoca Raton3549Google Scholar Malins, DC, Holmes, EH, Polissar, NL, Gunselman, S 1993The etiology of breast cancer Characteristic alteration in hydroxyl radical-induced DNA base lesions during oncogenesis with potential for evaluating incidence riskCancer7130363043PubMedGoogle Scholar DiSilvestro, RA 2001Antioxidant actions of soyaFood Indust J4210220Google Scholar Kehrer, J 1993Free radicals as mediators of tissue injury and diseaseCrit Rev Toxicol232148PubMedGoogle Scholar Slaga, TJ 1995Inhibition of the induction of cancer by antioxidantsAdv Exp Med Biol369167174PubMedGoogle Scholar Werts, ED, Gould, MN 1986Relationships between cellular superoxide dismutase susceptibility to chemically induced cancer in the rat mammary glandCarcinogenesis711971201PubMedGoogle Scholar O’Shea, M, Devery, R, Lawless, F, Murphy, J, Stanton, C 2000Milk fat conjugated linoleic acid (CLA) inhibits growth of human mammary MCF-7 cancer cellsAnticancer Res2035913601PubMedGoogle Scholar Kumar, K, Thangaraju, M, Sachdanandam, P 1991Changes observed in antioxidant system in the blood of postmenopausal women with breast cancerBiochem Int25371380PubMedGoogle Scholar Punnonen, K, Ahotupa, M, Asaishi, K, Hyoti, M, Kudo, R, Punnonen, R 1994Antioxidant enzyme activities and oxidative stress in human breast cancerJ Cancer Res Clin Oncol120374377PubMedGoogle Scholar Abiaka, C, Al-Awadi, F, Al-Sayer, H, Gulshan, S, Behbehani, A, Farghally, M 2002Activities of erythrocyte antioxidant enzymes in cancer patientsJ Clin Lab Anal16167171PubMedGoogle Scholar Song, Y, Igawa, S, Horii, A 1996Antioxidant enzymes response to endurance exercise training and dietary proteins in rat skeletal muscle and liverAppl Human Sci15219225PubMedGoogle Scholar Appelt, LC, Reicks, MM 1999Soy induces phase II enzymes but does not inhibit dimethylbenz[a]anthracene-induced carcinogenesis in female ratsJ Nutr12918201826PubMedGoogle Scholar Schuschke, DA, Percival, SS, Saari, JT, Miller, FN 1999Relationship between dietary copper concentration and acetylcholine-induced vasodilation in the microcirculation of ratsBiofactors10321327PubMedGoogle Scholar Murrell, TG 1995The potential for oxytocin (OT) to prevent breast cancer: a hypothesisBreast Cancer Res Treat35225229PubMedGoogle Scholar Choi, C, Cho, H, Park, J, Cho, C, Song, Y 2003Suppressive effects of genistein on oxidative stress and NFkappaB activation in RAW 264.7 macrophagesBiosci Biotechnol Biochem6719161922PubMedGoogle Scholar Lowy, SL, Fisler, JS, Drenick, EJ, Hunt, IF, Swendseid, ME 1986Zinc and copper nutriture in obese men receiving very low calorie diets of soy or collagen proteinAm J Clin Nutr43272287PubMedGoogle Scholar Wagner, TL, DiSilvestro, RA, Medeiros, DM 1995Marginal Copper Intake and Inflammation Effects on Copper Enzyme Activities in RatsJ Trace Elem Exp Med84146Google Scholar Bui, LM, Keen, CL, Dubick, MA 1994Influence of 12-week nicotine treatment and dietary copper on blood pressure and indices of the antioxidant system in male spontaneous hypertensive ratsBiol Trace Elem Res466778CrossRefPubMedGoogle Scholar Bebe, FN, Panemangalore, M 2003Exposure to low doses of endosulfan and chlorpyrifos modifies endogenous antioxidants in tissues of ratsJ Environ Sci Health B38349363PubMedGoogle Scholar Ozturk, O, Gumuslu, S 2004Changes in glucose-6-phosphate dehydrogenase, copper, zinc-superoxide dismutase and catalase activities, glutathione and its metabolizing enzymes, and lipid peroxidation in rat erythrocytes with ageExp Gerontol39211216PubMedGoogle Scholar Carone, D, Loverro, G, Greco, P, Capuano, F, Selvaggi, L 1993Lipid peroxidation products and antioxidant enzymes in red blood cells during normal and diabetic pregnancyEur J Obstet Gynecol Reprod Biol51103109PubMedGoogle Scholar Petkau, A, Monasterski, LG, Kelly, K, Friesen, HG 1977Modification of superoxide dismutase in rat mammary carcinomaRes Commun Chem Pathol Pharmacol17125132PubMedGoogle Scholar Webster, NR, Toothill, C, Cowen, PN 1987Tissue responses to hyperoxia Biochemistry and pathologyBr J Anaesth59760771PubMedGoogle Scholar L’Abbe, MR, Fischer, PW, Chavez, ER 1989Changes in selenium and antioxidant status during DMBA-induced mammary carcinogenesis in ratsJ Nutr119766771PubMedGoogle Scholar Cousins, RJ 1985Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasminPhysiol Rev65238309PubMedGoogle Scholar Overvad, K, Wang, DY, Olsen, J, Allen, DS, Thorling, EB, Bulbrook, RD, Hayward, JL 1993Copper in human mammary carcinogenesis: a case-cohort studyAm J Epidemiol137409414PubMedGoogle Scholar Milne, DB, Johnson, PE 1993Assessment of copper status: effect of age and gender on reference ranges in healthy adultsClin Chem39883887PubMedGoogle Scholar DiSilvestro, RA, Barber, EF, David, EA, Cousins, RJ 1988An enzyme linked immunoadsorbent assay for rat ceruloplasminBiol Trace Elem Res1719PubMedGoogle Scholar Linder, MC, Moor, JR, Wright, K 1981Ceruloplasmin assays in diagnosis and treatment of human lung, breast, and gastrointestinal cancersJ Natl Cancer Inst67263275PubMedGoogle Scholar DiSilvestro, RA, David, EA 1986Ceruloplasmin enzyme immunoassay: application to serum from cancer patientsClin Chim Acta158287292PubMedGoogle Scholar Bouvenot, G, Bruguerolle, B, Arnaud, C, Bartolin, R 1989Absence of changes in elderly patients of circadian variation of various so-called inflammation proteinsAnn Biol Clin477678Google Scholar Covas, MI, Coca, L, Ricos, C, Marrugat, J 1997Biological variation of superoxide dismutase in erythrocytes and glutathione peroxidase in whole bloodClin Chem4319911993PubMedGoogle Scholar Harris, ED, DiSilvestro, RA 1981Correlation of lysyl oxidase with the p-phenylenediamine oxidase activity (ceruloplasmin) in serumProc Soc Exp Biol Med166528531PubMedGoogle Scholar Turnlund, JR, Scott, KC, Peiffer, GL, Jang, AM, Keyes, WR, Keen, CL, Sakanashi, TM 1997Copper status of young men consuming a low-copper dietAm J Clin Nutr657278PubMedGoogle Scholar Kanabrocki, EL, Murray, D, Hermida, RC, Scott, GS, Bremner, WF, Ryan, MD, Ayala, DE, Third, JLHC, Shirazi, P, Nemchausky, BA, Hooper, DC 2002Circadian variation in oxidative stress markers in healthy and type II diabetic menChronobiol Int19423439PubMedGoogle Scholar DiSilvestro, R, Marten, J 1990Effects of inflammation and copper intake on rat liver and erythrocyte Cu-Zn superoxide dismutase activity levelsJ Nutr12012231227PubMedGoogle Scholar Rice, E 1962Standardization of ceruloplasmin activity in terms of International Enzyme UnitsAnal Biochem3452456PubMedGoogle Scholar Musarrat, J, Arezina-Wilson, J, Wani, AA 1996Prognostic and aetiological relevance of 8-hydroxyguanosine in human breast carcinogenesis.Eur J Cancer32A12091214PubMedGoogle Scholar Djuric, Z, Heilbrun, LK, Simon, MS, Smith, D, Luongo, DA, LoRusso, PM, Martino, S 1996Levels of 5-hydroxymethyl-2^\prime-deoxyuridine in DNA from blood as a marker of breast cancerCancer77691696PubMedGoogle Scholar Middleton, RB, Linder, MC 1993Synthesis and turnover of ceruloplasmin in rats treated with 17 beta-estradiolArch Biochem Biophys302362368PubMedGoogle Scholar Krajcik, RA, Borofsky, ND, Massardo, S, Orentreich, N 2002Insulin-like growth factor I (IGF-I), IGF-binding proteins, and breast cancerEpidemiol Biomarkers Prev1115661573Google Scholar Bratosin, D, Mazurier, J, Tissier, JP, Estaquier, J, Huart, JJ, Ameisen, JC, Aminoff, D, Montreuil, J 1998Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophagesA review. Biochimie80173195Google Scholar Wardlaw, GM, Hampl, JS, DiSilvestro, RA 2003Perspectives in Nutrition6McGraw HillMadisonGoogle Scholar Taylor, CG, McCutchon, TL, Boermans, HJ, DiSilvestro, RA, Bray, TM 1997Comparison of zinc and vitamin E for protection against hyperoxia-induced lung damageFree Radic Biol Med22543550PubMedGoogle Scholar DiSilvestro, RA, David, EA, Collignon, C 1991Interleukin-1 slowly increases lung fibroblast Cu–Zn superoxide dismutase activity levelsProc Soc Exp Biol Med197197200PubMedGoogle Scholar Latonnelle, K, Fostier, A, Menn, F, Bennetau-Pelissero, C 2002Binding affinities of hepatic nuclear estrogen receptors for phytoestrogens in rainbow trout (Oncorhynchus mykiss) and Siberian sturgeon (Acipenser baeri)Gen Comp Endocrinol1296979PubMedGoogle Scholar