PLANT ISOFLAVONES: BIOSYNHTESIS, DETECTION AND BIOLOGICAL PROPERTIES V. D. Naumenko, B. V. Sorochinsky, V. I. Kolychev

Details: Hits: 1706

ISSN 2410-776X (Online),
ISSN 2410-7751 (Print)

5 2013

"Biotechnologia Acta" v. 6, no. 5, 2013
https://doi.org/10.15407/biotech6.05.062
Р.62-78, Bibliography122, Ukrainian
Universal Decimal classification: 577.19: 581.192.7:633.3

PLANT ISOFLAVONES: BIOSYNHTESIS, DETECTION AND BIOLOGICAL PROPERTIES

V. D. Naumenko, B. V. Sorochinsky, V. I. Kolychev

PI “Institute of Food Biotechnology and Genomics” of National Academy of Sciences of Ukraine, Kyiv, Ukraine

Biological properties, chemical structures and biosynthesis pathways of plant isoflavones, especially soybean isoflavones (daidzein, genistein and glycitein) are reviewed. The structures of isoflavones, and their aglicone and glucosides (glycosides) forms as well as isoflavone biosynthesis pathways are described. General information about the advanced methods for the detection of isoflavones and their conjugates are considered. The importance of the profiling of isoflavones, flavonoids and their conjugates by means of analytical tools and methods to dissolve some questions in biology and medicine is discussed. The review provides data on the major isoflavone content in some vegetable crops and in the tissues of different soybean varieties. Health benefits and treatment or preventive properties of isoflavones for cancer, cardiovascular, endocrine diseases and metabolic disorders are highlighted. The mechanisms that may explain their positive biological effects are considered. The information on the application of advanced technologies to create new plant forms producing isoflavonoids with a predicted level of isoflavones, which is the most favorable for the treatment is given. The possibilities to use the metabolic engineering for the increasing of accumulation and synthesis of isoflavones at the non-legume crops such as tobacco, Arabidopsis and maize are considered. The examples how the plant tissues, which are not naturally produced of the isoflavones, can obtain potential for the synthesis of biologically active compounds via inducing of the activity of the introduced enzyme isoflavon synthase, are given. Specific biochemical pathways for increasing the synthesis of isoflavone genistein in Arabidopsis thaliana tissues are discussed. It is concluded that plant genetic engineering which is focused on modification of the secondary metabolites contain in plant tissues, enables to create the new crop varieties with improved agronomic properties and nutritional characteristics.

Key words: isoflavones, daidzein, genistein, glycitein, soy, biosynthesis, biological properties, metabolic engineering.

References

1. Delmonte P., Rader J. I. Analysis of isoflavones in foods and dietary supplements. AOAC Int. 2006, 89 (4), 1138–1146.

2. Barkhem T., Carlsson B., Nilsson Y. Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol. Pharmacol. 1998, 54 (1), 105–112.

3. Rostagno M. A., Villaresa A., Guillam?na E. Sample preparation for the analysis of iso?avones from soybeans and soy foods. J. Chromatogr. A. 2009, 1216 (1), 2–29.
https://doi.org/10.1016/j.chroma.2008.11.035

4. Jackson C. J. C., Dini J. P., Lavandier C. Effects of processing on the content and composition of isoflavones during manufacturing of soy beverage and tofu. Proc. Biochem. 2002, 37 (10), 1117–1123.
https://doi.org/10.1016/S0032-9592(01)00323-5

5. Simonne A. H., Smith M., Weaver D. B. Retention and Changes of Soy Isoflavones and Carotenoids in Immature Soybean Seeds (Edamame) during Processing. J. Agric. Food Chem. 2000, 48 (12), 6061–6069.
https://doi.org/10.1021/jf000247f

6. Izumi T., Piskula M. K., Osawa S. Soy isoflavone aglycones are absorbed faster and in higher amounts than their glycosides in humans. J. Nutr. 2000, 130 (7), 1695–1699.

7. Zubik L., Meydani M. Bioavailability of soybean isoflavones from aglycone and glucoside forms in American women. Am. J. Clin. Nutr. 2003, 77 (6), 1459–1465.

8. Setchell K. D. R., Brown N. M., Zimmer-Nechemias L. Evidence for lack of absorption of soy isoflavone glycosides in humans, supporting the crucial role of intestinal metabolism for bioavailability. Am. J. Clin. Nutr. 2002, 76 (2), 447–453.

9. Kudou S., Fleury Y., Welti D. Malonyl isoflavone glycosides in soybean seeds (Glycine max Merrill). Agric. Biol. Chem. 1991, 55 (9), 2227–2233.
https://doi.org/10.1271/bbb1961.55.2227

10. Stafford H. A. Possible multienzyme complexes regulating the formation of C₆-C₃phenolic compounds and lignins in higher plants. In: Metabolism and Regulation of Secondary Plant Products. Recent Adv. Phytochem. 1974, V. 8, P. 53–79.
https://doi.org/10.1016/B978-0-12-612408-8.50009-3

11. Hrazdina G., Wagner G. J., Siegelman H. W. Subcellular localization of enzymes of anthocyanin biosynthesis in protoplasts. Phytochemistry. 1978, 17 (1), 53–56.
https://doi.org/10.1016/S0031-9422(00)89679-X

12. Hrazdina G. Compartmentation in aromatic metabolism. Phenolic Metabolism in Plants. Stafford H. A. and. Ibrahim R. K., eds. New York: Plenum Press. 1992, P. 1–23.
https://doi.org/10.1007/978-1-4615-3430-3_1

13. Winkel-Shirley B. Evidence for enzyme complexes in the phenylpropanoid and flavonoid pathways. Physiol. Plant. 1999, 107 (1), 142–149.
https://doi.org/10.1034/j.1399-3054.1999.100119.x

14. Saslowsky D., Winkel-Shirley B. Localization of flavonoid enzymes in Arabidopsis roots. Plant J. 2001, 27 (1), 37–48.
https://doi.org/10.1046/j.1365-313x.2001.01073.x

15. Abdrakhimova J. R. Valiev A. I. secondary metabolites of plants: physiological and biochemical aspects (Part 3 Phenolic compounds). Uch. method. Guide. Ed. Bagaeva TV Kazan: Kazan Federal University. 2010, 41 p. (In Russian).

16. Blaut M., Schoefer L., Braune A. Transformation of flavonoids by intestinal microorganisms. Int. J. Vitamin Nutr. Res. 2003, 73 (2), 79–87.
https://doi.org/10.1024/0300-9831.73.2.79

17. Sfakiaos J., Coward L., Kirk M., Barnes S. Intestinal uptake and biliary excretion of the isoflavone genistein in rats. J. Nutr. 1997, 127 (7), 1260–1269.

18. Yasuda T., Kano Y., Saito K., Ohsawa K. Urinary and biliary metabolites of daidzin and daidzein in rats. Biol. Pharm. Bull. 1994, 17 (10), 1369–1374.
http://dx.doi.org/10.1248/bpb.17.1369

19. Fiehn O. Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks. Comp. Funct. Genomics. 2001, 2 (3), 155–168.
https://doi.org/10.1002/cfg.82

20. Hall R., Beale M., Fiehn O. Plant metabolomics: the missing link in functional genomics strategies. Plant Cell. 2002, 14 (7), 1437–1440.
https://doi.org/10.1105/tpc.140720

21. Sumner L. W., Mendes P., Dixon R. A. Plant metabolomics: large-scale phytochemistry in the functional genomics era. Phytochemistry. 2003, 62 (6), 817–836.
https://doi.org/10.1016/S0031-9422(02)00708-2

22. Fernie A. R., Trethewey R. N., Krotzky A. J., Willmitzer L. Metabolite profiling: from diagnostics to systems biology. Nat. Cell Biol. 2004, 5 (9), 763–769.
https://doi.org/10.1038/nrm1451

23. Bovy A., de Vos R., Kemper M. High-flavonol tomatoes resulting from the heterologous expression of the maize transcription factor genes LC and C1. Plant Cell. 2002, 14 (10), 2509–2526.
https://doi.org/10.1105/tpc.004218

24. Dixon R. A., Steel C. L. Flavonoids and isoflavonoids — a gold mine for metabolic engineering. Trends Plant Sci. 1999, 4 (10), 394–400.
https://doi.org/10.1016/S1360-1385(99)01471-5

25. Fisher R., Stoger E., Schillberg S. Plant-based production of biopharmaceuticals. Curr. Opin. Plant Biol. 2004, 7 (2), 152–158.
https://doi.org/10.1016/j.pbi.2004.01.007

26. Trethewey R. N. Metabolite profiling as an aid to metabolic engineering in plants. Curr. Opin. Plant Biol. 2004, 7 (2), 196–201.
https://doi.org/10.1016/j.pbi.2003.12.003

27. Verpoorte R., Memelink J. Engineering secondary metabolite production in plants. Curr. Opin. Biotechnol. 2002, 13 (2), 181–187.
https://doi.org//10.1016/S0958-1669(02)00308-7

28. Luthria D. L., Natarajan S. S. Influence of sample preparation on the assay of isoflavones. Planta Med. 2009, 75 (7), 704–710.
https://doi.org/10.1055/s-0029-1185439

29. Vas G., Veckey K. Solid-phase microextraction: a powerful sample preparation tool prior to mass spectrometric analysis. J. Mass Spectrom. 2004, 39 (3), 233–254.
https://doi.org/10.1002/jms.606

30. Naczk M., Shahidi F. Extraction and analysis of phenolics in food. J. Chromatogr. A. 2004, 1054 (1–2), 95–111.
https://doi.org/10.1016/S0021-9673(04)01409-8

31. Robards K. Strategies for the determination of bioactive phenols in plants, fruit and vegetables. J. Chromatogr. A. 2003, 1000 (1–2), 657–691.
https://doi.org/10.1016/S0021-9673(03)00058-X

32. Strobiecki M., Kachlicki P. Isolation and identification of flavonoids. The Science of Flavonoidsand, ed. Grotewold. Ohio, USA: Springer.2006, P. 47–69.

33. The Science of Flavonoids, ed. Grotewold. Ohio, USA: Springer. 2006, 274 p.

34. Wang J., Sporns P., Maldi-Tof M. S. Analysis of Isoflavones in Soy Products. J. Agric. Food Chem. 2000a, 48 (12), 5887–5892.
https://doi.org/10.1021/jf0008947

35. Wang J., Sporns P., Maldi-Tof M. S. Analisis of food flavonol glycosides. J. Agric. Food Chem. 2000b, 48 (5), 1657–1662.
https://doi.org/10.1021/jf991035p

36. Prasain J. K., Wang C-C., Barnes S. Mass spectrometric methods for the determination of flavonoids in biological samples. Free Rad. Bio Med. 2004, 37 (9), 1324–1350.
https://doi.org/10.1016/j.freeradbiomed.2004.07.026

37. Mazur W. Phytoestrogen content in foods. Baillieres Clin. Endrocrinol. Metab. 1998, 12 (4), P. 729–742.
https://doi.org/10.1016/S0950-351X(98)80013-X

38. Liggins J., Bluck L. J., Runswick S. Daidzein and genistein content of fruits and nuts. J. Nutr. Biochem. 2000, 11 (6), 326–331.
https://doi.org/10.1016/S0955-2863(00)00085-1

39. Liggins J., Bluck L. J., Runswick S. Daidzein and genistein contents of vegetables. Br. J. Nutr. 2000, 84 (5), 717–725.

40. Liggins J., Mulligan A., Runswick S., Bingham S. A. Daidzein and genistein content of cereals. Eur. J. Clin. Nutr. 2002, 56 (10), 961–966.
https://doi.org/10.1038/sj.ejcn.1601419

41. Available at http://www.nal.usda.gov/fnic/foodcomp/ Data/isoflav/isfl_tbl.pdf

42. Zhu D., Hettiarachchy N. S., Horax R., Chen P. Isoflavone contents in germinated soybean seeds. Plant Foods Hum. Nutr. 2005, 60 (3), 147–151.
https://doi.org/10.1007/s11130-005-6931-0

43. Sakthivelu G., Akitha Devi M. K., Giridhar P. Isoflavone composition, phenol content, and antioxidant activity of soybean seeds from India and Bulgaria. J. Agric. Food Chem. 2008, 56 (6), 2090–2095.
https://doi.org/10.1021/jf072939a

44. Setchel K. D. R., Cassidy A. Dietary Isoflavones: Biological Effects and Relevance to Human Health. J. Nutr. 1999, 129 (3), 758–767.

45. Wu A. H., Yu M. C.,Tseng C.-C., Pike M. C. Epidemiology of soy exposures and breast cancer risk. Brit. J. Cancer. 2008, 98 (1), 9–14.
https://doi.org/10.1038/sj.bjc.6604145

46. Lee M.M., Chang I. Y., Horng C. F. Breast cancer and dietary factors in Taiwanese women. Cancer Caus. Contr. 2005, 16 (8), 929–937.
https://doi.org/10.1007/s10552-005-4932-9

47. Phytoestrogens and Health. Gilani G. S, Anderson J. J. B., eds. USA: AOCS Press,Champaign, IL. 2002, 660 p.

48. Lee H. P., Gourley L., Duffy S. W. Dietary effects on breast cancer risk in Singapore. Lancet. 1991, 337 (8751), 1197–1200.
https://doi.org/10.1016/0140-6736(91)92867-2

49. Katz J., Blake E., Medrano T. A. Isoflavones and gamma irradiation inhibit cell growth in human salivary gland cells. Sci. Dir. Cancer Lett. 2008, 270 (1), 87–94.
https://doi.org/10.1016/j.canlet.2008.04.051

50. Alhasan S. A., Ensley J. F., Sarkar F. H. Genistein induced molecular changes in a squamous cell carcinoma of the head and neck cell line. J. Oncol. 2000, 16 (2), 333–338.
https://doi.org/10.3892/ijo.16.2.333

51. Fotsis T., Pepper M., Aktas E. Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. Cancer Res. 1997, 57 (14), 2912–2916.

52. Fotsis T., Pepper M., Adlercreutz H. Genistein, a dietary ingested isoflavonoid, inhibits cell proliferation and in vitro angiogenesis. J. Nutr. 1995, 125 (3), 790–797.

53. Wahl O., Oswald M., Tretzel L. Inhibition of tumor angiogenesis by antibodies, synthetic small molecules and natural products. Curr. Med. Chem. 2011, 18 (21), 3136–3155.
https://doi.org/10.2174/092986711796391570

54. Handayani R., Rice L., Cui Y. Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J. Nutr. 2006, 136 (1), 75–82.

55. Messina M. J., Loprinzi C. L. Soy for breast cancer survivors: a critical review of the literature. J. Nutr. 2001, 131 (11), 3095–3108.

56. Li Y., Sarkar F. H. Inhibition of nuclear factor kappaB activation in PC3 cells by genistein is mediated via Akt signaling pathway. Clin. Cancer Res. 2002, 8 (7), 2369–2377.

57. Pollard M., Luckert P. H. Influence of isoflavones in soy protein isolates on development of induced prostate-related cancers in L-W rats. Nutr. Cancer. 1997, 28 (1), 41–45.
https://doi.org/10.1080/01635589709514551

58. Baggott J. E., Ha T., Vaughn W. H. Effect of miso (Japanese soybean paste) and NaCl on DMBA-induced rat mammary tumors. Nutr. Cancer. 1990, 14 (2), 103–109.
https://doi.org/10.1080/01635589009514083

59. Constantinou A. I., Lantvit D., Hawthorne M. Chemopreventive effects of soy protein and purified soy isoflavones on DMBA-induced mammary tumors in female Sprague-Dawley rats. Nutr. Cancer. 2001, 41 (1–2), 75–81.
https://doi.org/10.1080/01635581.2001.9680615

60. Pugalendhi P., Manoharan S. Chemopreventive potential of genistein and daidzein in combination during 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinogenesis in Sprague-Dawley rats. Pak. J. Biol. Sci. 2010, 13 (6), 279–286.
https://doi.org/10.3923/pjbs.2010.279.286

61. Troll W., Wiesner R., Shellabarger C. J. Soybean diet lowers breast tumor incidence in irradiated rats. Carcinogenesis. 1980, 1 (6), 469–472.
https://doi.org/10.1093/carcin/1.6.469

62. Carroll K. K. Hypercholesterolemia and atherosclerosis: effects of dietary protein. Fed. Proc. 1982, 41 (11), 2792–2796.

63. Sirtori C. R., Lovati M. R., Manzoni C. Soy and cholesterol reduction: clinical experience. J. Nutr. 1995, 125 (3), 598–605.

64. Clarkson T. B. Soy, soy phytoestrogens and cardiovascular disease. J. Nutr. 2002, 132 (3), 566–569.

65. Hermansen K., Dinesen B., Hoie L. H. Effects of soy and other natural products on LDL:HDL ratio and other lipid parameters: a literature review. Adv. Ther. 2003, 20 (1), 50–78.
https://doi.org/10.1007/BF02850119

66. Anthony M. S., Clarkson T. B., Bullock B. C., Wagner J. D. Soy protein versus soy phytoestrogens in the prevention of diet-induced coronary artery atherosclerosis of male cynomolgus monkeys. Arterioscler. Thromb. Vasc. Biol. 1997, 17 (11), 2524–2531.
https://doi.org/10.1161/01.ATV.17.11.2524

67. Anthony M. S., Clarkson T. B., Hughes C. L. Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys. J. Nutr. 1996, 126 (1), 43–50.

68. Anderson J. W., Johnstone B. M., Cook-Newell M. E. Meta-analysis of the effects of soy protein intake on serum lipids. New Engl. J. Med. 1995, 333 (5), 276–282.
https://doi.org/10.1056/NEJM199508033330502

69. Zhan S., Ho S. C. Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile. Am. J. Clin. Nutr. 2005, 81 (2), 397–408.

70. Duane W. Effects of legume consumption on serum cholesterol, biliary lipids, and sterol metabolism in humans. J. Lipid Res. 1997, 38 (6), 1120–1128.

71. Kirk E. A., Sutherland P., Wang S. A. Dietary isoflavones reduce plasma cholesterol and atherosclerosis in C57BL/6 mice but not LDL receptor-deficient mice. J. Nutr. 1998, 128 (6), 954–969.

72. Setchell K. D. R. Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. Estrogens in the Environment. II: Influences on Development, ed. McLachlan J. A. New York: Elsevier. 1985, P. 69–85.

73. Crouse J. R., Morgan T., Terry J. G. A randomized trial comparing the effect of casein with that of soy protein containing varying amounts of isoflavones on plasma concentrations of lipids and lipoproteins. Arch. Intern. Med. 1999, 159 (17), 2070–2076.
https://doi.org/10.1001/archinte.159.17.2070

74. Anderson J. W., Bush H. M. Soy protein effects on serum lipoproteins: a quality assessment and meta-analysis of randomized, controlled studies. J. Am. Coll. Nutr. 2011, 30 (2), 79–91.
https://doi.org/10.1080/07315724.2011.10719947

75. Kapiotis S., Hermann M. Genistein, the Dietary-Derived Angiogenesis Inhibitor, Prevents LDL Oxidation and Protects Endothelial Cells From Damage by Atherogenic LDL. Arterioscler. Thromb. Vasc. Biol. 1997, 17 (11), 2868–2874.
https://doi.org/10.1161/01.ATV.17.11.2868

76. Ruiz-Larrea M. B., Mohan A. R., Paganga G. Antioxidant activity of phytoestrogenic isoflavones. Free Radic. Res. 1997, 26 (1), 63–70.
https://doi.org/10.3109/10715769709097785

77. Tikkanen M. J., Adlercreutz H. Dietary soy-derived isoflavone phytoestrogens. Could they have a role in coronary heart disease prevention? Biochem. Pharmacol. 2000, 60 (1), 1–5.
https://doi.org/10.1016/S0006-2952(99)00409-8

78. Honore E. K., Williams J. K., Anthony Soy isoflavones enhance coronary vascular reactivity in atherosclerotic female macaque. Fertil. Steril. 1997, 67 (1), 148–154.
https://doi.org/10.1016/S0015-0282(97)81872-9

79. Sargeant P., Farndale R. W., Sage S. O. The tyrosine kinase inhibitors methyl 2,5-dihydroxycinnamate and genistein reduce thrombin-evoked tyrosine phosphorylation and Ca²⁺ entry in human platelets. FEBS Lett. 1993, 315 (3), 242–246.
https://doi.org/10.1016/0014-5793(93)81172-V

80. Wilcox J. N., Blumenthal B. F. Thrombotic mechanisms in atherosclerosis: potential impact of soy proteins. J. Nutr. 1995, 125 (3), 631–638.

81. Akiyama T., Ishida J., Nakagava S. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J. Biol. Chem. 1987, 262 (12), 5592–5595.

82. Anthony M. S., Clarkson T. B. Comparison of soy phytoestrogens and conjugated equine estrogens on atherosclerosis progression in post-menopausal monkeys (abs.). Circulation. 1998, V. 97, P. 829.

83. Rimbach G., Boesch-Saadatmandi C., Frank J. Dietary iso?avones in the prevention of cardiovascular disease. — A molecular perspective. Food Chem. Toxicol. 2008, 48 (4), 1308–1319.
https://doi.org/10.1016/j.fct.2007.06.029

84. Yoshida K., Tsukamoto T., Torii H. Disposition of ipriflavone (TC-80) in rats and dogs. Radioisotopes. 1985, 34 (11), 618–623.
https://doi.org/10.3769/radioisotopes.34.11_618

85. Cheng S. L, Zhang S. F., Nelson T. L. Stimulation of human osteoblast differentiation and function by ipriflavone and its metabolites. Calcif. Tissue Int. 1994, 55 (5), 356–362.
https://doi.org/10.1007/BF00299315

86. Yao J., Zhang J., Hou J. F. Effects of ipriflavone on caged layer bone metabolism in vitro and in vivo. Poult. Sci. 2007, 86 (3), 503– 507.
https://doi.org/10.1093/ps/86.3.503

87. Brandi M. L. New treatment strategies: ipriflavone, strontium, vitamin D metabolites and analogs. Am. J. Med. 1993, 95 (5A), 69–74.
. L. New treatment strategies: ipriflavone, strontium, vitamin D metabolites and analogs. Am. J. Med. 1993, 95 (5A), 69–74.
https://doi.org/10.1016/0002-9343(93)90386-4

88. Anderson J. J., Ambrose W. W., Garner S. C. Orally dosed genistein from soy and prevention of cancellous bone loss in two ovariectomized rat models. J. Nutr. 1995, 125 (3), 799.

89. Arjmandi B. H., Alekel L., Hollis B. W. Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis. J. Nutr. 1996, 126 (1), 162–167.

90. Draper C. R., Edel M. J., Dick I. M. Phytoestrogens reduce bone loss and bone resorption in oophorectomized rats. J. Nutr. 1997, 127 (9), 1795–1799.

91. Tsutsumi N., Kawashima K., Nagata H. Effects of KCA-012 on bone metabolism in organ culture. Jpn. J. Pharmacol. 1995, 67 (2), 169–171.
https://doi.org/10.1254/jjp.67.169

92. Blair H. C., Jordan S. E., Peterson T. G., Barnes S. Variable effects of tyrosine kinase inhibitors on avian osteoclastic activity and reduction of bone loss in ovariectomized rats. J. Cell. Biochem. 1996, 61 (4), 629–637.
https://doi.org/10.1002/(SICI)1097-4644(19960616)61:4<629::AID-JCB17>3.0.CO;2-A

93. Kuiper G. G., Nilsson S., Gustaffson, J.-A. Characteristics and function of the novel estrogen receptor b. Hormones and Signaling, ed. O’Malley B. W. New York: Academic Press. 1998, V. 1, P. 89–112.
https://doi.org/10.1016/b978-012312411-1/50005-6

94. Kuiper G. G., Carlsson B., Grandien K. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 1997, 138 (3), 863–870.

95. Manolagas S. C., Jilka R. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N. Engl. J. Med. 1995, 332 (5), 305–311.
https://doi.org/10.1056/NEJM199502023320506

96. Kim H., Peterson T. G., Barnes S. Mechanisms of action of the soy isoflavone genistein: emerging role for its effects via transforming growth factor beta signaling pathways. Am. J. Clin. Nutr. 1998, 68 (6), 1418–1425.

97. Potter S. M., Baum J. A., Teng H. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am. J. Clin. Nutr. 1998, 68 (6), 1375–1379.

98. Ishimi Y. Nutrition and bone health. Isoflavones in bone health. Clin. Calcium. 2009, 19 (10), 1506–1513.

99. Pansini F., Bonaccorsi G., Albertazzi P. Soy phytoestrogens and bone. Proceedings of North American Menopause Society (abs.). 1997, P. 44.

100. Ho S. C. Body measurements, bone mass, and fractures. Does the East differ from the West? Clin. Orthop. Relat. Res. 1996, V. 323, P. 75–80.
https://doi.org/10.1097/00003086-199602000-00010

101. Potter S. M., Bakhit R. M., Essex-SorlieD. L. Depression of plasma cholesterol in men by consumption of baked products containing soy protein. Am. J. Clin. Nutr. 1993, 58 (4), 501–506.

102. Teixeira S.R., Potter S. M., Weigel R. Effects of feeding 4 levels of soy protein for 3 and 6 wk on blood lipids and apolipoproteins in moderately hypercholesterolemic men. Am. J. Clin. Nutr. 2000, 71 (5), 1077–1084.

103. Cassidy A., Faughnan M., Hughes R. Hormonal effects of phytoestrogens in postmenopausal women and middle-aged men. Am. J. Clin. Nutr. 1998, 68 (6), 1531.

104. Cassidy A, Faughnan M. Phyto-oestrogens through the life cycle. Proc. Nutr. Soc. Am. 2000, 59 (3), 489–496.
https://doi.org/10.1017/S0029665100000719

105. Gooderham M. J., Adlercreutz, H. A., Ojala S. T. A soy protein isolate rich in genistein and daidzein and its effects on plasma isoflavone concentrations, platelet aggregation, blood lipids and fatty acid composition of plasma phospholipid in normal men. J. Nutr. 1996, 126 (8), 2000–2006.

106. Morton M. S., Chan P. S. F., Cheng C. Lignans and isoflavonoids in plasma and prostatic fluid in men: samples from Portugal, Hong Kong, and the United Kingdom. Prostate. 1997, 32 (2), 122–128.
https://doi.org/10.1002/(SICI)1097-0045(19970701)32:2<122::AID-PROS7>3.0.CO;2-O

107. Evans B. A. J., Griffiths K., Morton M. S. Inhibition of 5 alpha-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids. J. Endocrinol. 1995, 147 (2), 295–302.
https://doi.org/10.1677/joe.0.1470295

108. Peterson G., Barnes S. Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation. Prostate. 1993, 22 (4), 335–345.
https://doi.org/10.1002/pros.2990220408

109. Hedlund T. E., Johannes W. U., Miller G. J. Soy isoflavonoid equol modulates the growth of benign and malignant prostatic epithelial cells in vitro. Prostate. 2003, 54 (1), 68–78.
https://doi.org/10.1002/pros.10137

110. Sharma O. P., Adlercreutz H., Strandberg J. D. Soy of dietary source plays a preventive role against the pathogenesis of prostatitis in rats. J. Steroid Biochem. Mol. Biol. 1992, 43 (6), 557–564.
https://doi.org/0.1016/0960-0760(92)90244-D

111. Makela S. I., Pylkkanen L. H., Santti R., Adlercreutz H. Dietary soybean may be antiestrogenic in male mice. J. Nutr. 1995, 125 (3), 437 –445.

112. Makela S. I., Santti R., Salo L., McLachlan J. A. Phytoestrogens are partial estrogen agonists in the adult male mouse. Environ. Health Perspect. 1995,103 (7), 123–127.

113. Morrissey C., Watson R. W. Phytoestrogens and prostate cancer. Curr. Drug. Targets. 2003, 4 (3), 231–241.

114. Miyanaga N., Akaza H., Hinotsu S. Prostate cancer chemoprevention study: an investigative randomized control study using purified isoflavones in men with rising prostate-specific antigen. Cancer Sci. 2012, 103 (1), 125–130.

115. Baraboi В. A. Soy isoflavones: biological activity and application. Bioteckhnolohiia. 2009, 2 (3), 44–54. (In Ukrainian).

116. Naumenko V. D,, Sorochynskii B. V., Kolychev V. I. Soy isoflavones: biological activity and application. Probl. kharch. 2011, 24 (1–2), 58–69. (In Ukrainian).

117. Dixon R. A., Ferreira D. Genistein. Phytochemistry. 2002, 60 (3), 205–211.
https://doi.org/0.1016/S0031-9422(02)00116-4

118. Liu R., Hu Y., Lin Zh. Production of soybean isoflavone genistein in non-legume plants via genetically modified secondary metabolism pathway. Metabol. Engineer. 2007, 9 (1), 1–7.
https://doi.org//10.1016/j.ymben.2006.08.003

119. Sreevidya V. S., Srinivasa Rao C., Sullia S. B. Metabolic engineering of rice with soybean isoflavone synthase for promoting nodulation gene expression in rhizobia. J. Exp. Bot. 2006, 59 (9), 1957–1969.
https://doi.org/10.1093/jxb/erj143

120. Liu C. J., Blount J. W., Steele C. L., Dixon R. A. Bottlenecks for metabolic engineering of isoflavone glycoconjugates in Arabidopsis. Proc. Natl. Acad. Sci. U S A. 2002, 99 (22), 14578–14583.
http://dx.doi.org/10.1073/pnas.212522099

121. Oliver Y., Woosuk J., June S. Production of the Isoflavones Genistein and Daidzein in Non-Legume Dicot and Monocot Tissues. Plant Physiol. 2000, 124 (2), 781–794.
https://doi.org/10.1104/pp.124.2.781

122. Li X., Qin J.C., Wang Q.Y. Metabolic engineering of isoflavone genistein in Brassica napus with soybean isoflavone synthase. Plant Cell Rep. 2011, 30 (8), 1435–1442.
https://doi.org/10.1007/s00299-011-1052-8