Abstract
Elevated plasma homocysteine (2-amino-4-sulfanylbutanoic acid) level is a risk factor for stroke. Moreover, it has been suggested that high levels of homocysteine in the acute phase of an ischemic stroke can predict mortality, especially in stroke patients with the large-vessel atherosclerosis subtype. In clinical studies, supplementation with genistein (5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1-benzopyran-4-one) decreased plasma homocysteine levels considerably. Therefore, genistein could be considered as a potential drug for prevention and/or treatment of stroke. However, the mechanism of the effect of genistein on homocysteine level remains to be elucidated. In this report, direct functional interactions between homocysteine and genistein are demonstrated in in vitro experimental systems for determination of methylenetetrahydrofolate reductase (MetF) and glutathione peroxidase (GPx) activities, reconstructed with purified compounds, and in a simple in vivo system, based on measurement of growth rate of Vibrio harveyi and Bacillus subtilis cultures. Results of molecular modelling indicated that homocysteine can directly interact with genistein. Therefore, genistein-mediated decrease in plasma levels of homocysteine, and alleviation of biochemical and physiological effects of one of these compounds by another, might be ascribed to formation of homocysteine-genistein complexes in which biological activities of these molecules are abolished or alleviated.
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Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M, Fukami Y. (1987) Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 25;262(12):5592-5
Bailey L, Gregory J III (1999) Polymorphism of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risk and impact on folate requirement. J Nutr 129:919–922
Banecka-Majkutewicz Z, Sawuła W, Kadziński L, Węgrzyn A, Banecki B (2012) Homocysteine, heat shock proteins, genistein and vitamins in ischemic stroke--pathogenic and therapeutic implications. Acta Biochim Pol 59(4):495–499
Belas R, Mileham A, Cohn D, Hilmen M, Simon M, Silverman M (1982) Bacterial luminescence: isolation and expression of the luciferase genes from Vibrio harveyi. Science 218:791–793
Chen C, Bakhiet R, Hart V, Holtzman G (2005) Isoflavones improve plasma homocysteine status and antioxidant defense system in healthy young men at rest but do not ameliorate oxidative stress induced by 80% VO2pk exercise. Ann Nutr Metab 49(1):33–41
Chen S, Wu P, Zhou L, Shen Y, Li Y, Song H (2015) Relationship between increase of serum homocysteine caused by smoking and oxidative damage in elderly patients with cardiovascular disease. Int J Clin Exp Med 8(3):4446–4454
D'Anna R, Baviera G, Corrado F, Cancellieri F, Crisafulli A, Squadrito F (2005) The effect of the phytoestrogen genistein and hormone replacement therapy on homocysteine and C-reactive protein level in postmenopausal women. Acta Obstet Gynecol Scand 84(5):474–477
Durmaz A, Dikmen N (2007) Homocysteine effects on cellular glutathione peroxidase (GPx-1) activity under in vitro conditions. J Enzyme Inhib Med Chem 22(6):733–738
Fuchs D, Erhard P, Rimbach G, Daniel H, Wenzel U (2005) Genistein blocks homocysteine-induced alterations in the proteome of human endothelial cells. Proteomics 5(11):2808–2818
Fuchs D, Dirscherl B, Schroot JH, Daniel H, Wenzel U (2006) Soy extract has different effects compared with the isolated isoflavones on the proteome of homocysteine-stressed endothelial cells. Mol Nutr Food Res 50(1):58–69
Grabowski M, Banecki B, Kadziński L, Jakóbkiewicz-Banecka J, Kaźmierkiewicz R, Gabig-Cimińska M, Węgrzyn G, Węgrzyn A, Banecka-Majkutewicz Z (2015) Genistein inhibits activities of methylenetetrahydrofolate reductase and lactate dehydrogenase, enzymes which use NADH as a substrate. Biochem Biophys Res Commun 465:363–367
Guenther B, Sheppard C, Tran P, Rozen R, Matthews R, Ludwig M (1999) The structure and properties of methylenetetrahydrofolate reductase from Escherichia Coli suggest how folate ameliorates human hyperhomocysteinemia. Nat Struct Biol 6:359–365
Han L, Wu Q, Wang C, Hao Y, Zhao J, Zhang L, Fan R, Liu Y, Li R, Chen Z, Zhang T, Chen S, Ma J, Liu S, Peng X, Duan S (1999) Homocysteine, ischemic stroke, and coronary heart disease in hypertensive patients: a population-based, prospective cohort study. Stroke 46(7):1777–1786
Han S, Wu H, Li W, Gao P (2015) Protective effects of genistein in homocysteine-induced endothelial cell inflammatory injury. Mol Cell Biochem 403(1–2):43–49
Jakóbkiewicz-Banecka J, Kloska A, Stepnowska M, Banecki B, Wegrzyn A, Wegrzyn G. (2005) A bacterial model for studying effects of human mutations in vivo: Escherichia coli strains mimicking a common polymorphism in the human MTHFR gene. Mutat Res 15;578(1–2):175–86
Klein G, Żmijewski M, Krzewska J, Czeczatka M, Lipińska B (1998) Cloning and characterization of the dnaK heat shock operon of the marine bacterium Vibrio harveyi. Mol Gen Genet 259:179–189
Lawrence RA, Burk RF (1976) Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 71:952–958
Marini H, Bitto A, Altavilla D, Burnett B, Polito F, Di Stefano V, Minutoli L, Atteritano M, Levy R, Frisina N, Mazzaferro S, Frisina A, D'Anna R, Cancellieri F, Cannata M, Corrado F, Lubrano C, Marini R, Adamo EB, Squadrito F (2010) Efficacy of genistein aglycone on some cardiovascular risk factors and homocysteine levels: a follow-up study. Nutr Metab Cardiovasc Dis 20(5):332–340
Markovits J, Linassier C, Fossé P, Couprie J, Pierre J, Jacquemin-Sablon A, Saucier JM, Le Pecq JB, Larsen AK. (1989) Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res 15;49(18):5111-7
Martin P, Horwitz K, Ryan D, McGuire W (1978) Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology 103(5):1860–1867
Moskot M, Montefusco S, Jakóbkiewicz-Banecka J, Mozolewski P, Węgrzyn A, Di Bernardo D, Węgrzyn G, Medina DL, Ballabio A, Gabig-Cimińska M (2014) The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation. J Biol Chem 289(24):17054–17069
Moskot M, Jakóbkiewicz-Banecka J, Kloska A, Smolińska E, Mozolewski P, Malinowska M, Rychłowski M, Banecki B, Węgrzyn G, Gabig-Cimińska M (2015) Modulation of expression of genes involved in glycosaminoglycan metabolism and lysosome biogenesis by flavonoids. Sci Rep 5:9378
Petras M, Tatarkova Z, Kovalska M, Mokra D, Dobrota D, Lehotsky J, Drgova A (2014) Hyperhomocysteinemia as a risk factor for the neuronal system disorders. J Physiol Pharmacol 65(1):15–23
Salti GI, Grewal S, Mehta RR, Das Gupta TK, Boddie AW Jr, Constantinou AI (2000) Genistein induces apoptosis and topoisomerase II-mediated DNA breakage in colon cancer cells. Eur J Cancer 36(6):796–802
Sheppard C, Trimmer E, Matthews R (1999) Purification and properties of NADH-dependent 5,10-methylenetetrahydrofolate reductase (MetF) from Escherichia Coli. J Bacteriol 181(3):718–725
Shi Z, Guan Y, Huo YR, Liu S, Zhang M, Lu H, Yue W, Wang J, Ji Y (2015) Elevated Total homocysteine levels in acute ischemic stroke are associated with long-term mortality. Stroke 46:2419–2425
Smith RK, Quigley F, Tosenovsky P, Velu R, Bradshaw B, Buettner P, Golledge J (2016) Serum homocysteine is associated with the severity of primary chronic venous disease. Phlebology 31(6):409–415
Ulanowska K, Tkaczyk A, Konopa G, Wegrzyn G (2006) Differential antibacterial activity of genistein arising from global inhibition of DNA, RNA and protein synthesis in some bacterial strains. Arch Microbiol 184(5):271–278
Ulanowska K, Majchrzyk A, Moskot M, Jakóbkiewicz-Banecka J, Węgrzyn G (2007) Assessment of antibacterial effects of flavonoids by estimation of generation times in liquid bacterial cultures. Biologia 62:132–135
Wang T, Sathyamoorthy N, Phang J (1996) Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 17(2):271–275
Wang C, Han L, Wu Q, Zhuo R, Liu K, Zhao J, Zhang L, Hao Y, Fan R, Liu Y, Li R, Chen Z, Zhang T, Chen S, Ma J, Liu S, Peng X, Duan S (2015) Association between homocysteine and incidence of ischemic stroke in subjects with essential hypertension: a matched case-control study. Clin Exp Hypertens 37(7):557-62
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This work was supported by National Science Centre (Poland) project grant no. 2011/02/A/NZ1/00009 to G.W.
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Banecka-Majkutewicz, Z., Kadziński, L., Grabowski, M. et al. Evidence for interactions between homocysteine and genistein: insights into stroke risk and potential treatment. Metab Brain Dis 32, 1855–1860 (2017). https://doi.org/10.1007/s11011-017-0078-1
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DOI: https://doi.org/10.1007/s11011-017-0078-1