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1 lZ0 Pawitan ùIed J Indones

Phytoestrogens' beneficial effects on cardiovascular system

Jeanne Adiwinata Pawitan

Abstrak

strogen, terutama isoJTavon, mulai dari bahan makanan yang t g sis t e m kardiov a s kular, efek fi t o e s tr o g en y an I me n &un un kan n tekanan darah. (MedJ Indones 2002; 11: 120-3)

Abstract

I and basic science, suSSest the plausibility of a causal, inverse

blood pressure. (Med J Indones 2002; 1I: 120-3)

Keywords: atherosclerosis, hypercholesterolemia, arterial compliance, blood pressure

lactones are Several lines of evidence, including epidemiological, found in human diets, while resorcyclic Therefore clinical tnal and basic science, suggest the plausibility mycotoxins that develop in stored crops. and of a causal, inverse relationship belween phytoesfogens they are not true phytoestrogens, of and cardiovascular disease. The well establish low can be simply divided into 3 classes.) The majority diets are the rates of cardiovascular diseases and the high intakes phytoestrogens found in typical human of dielary phytoestrogens in Asian populations and , while the major phyoestrogen relative to those in other industrialized countries are consumed by most Asian populations is isoflavones.' consistent with the potential protective effect of l-3 phytoestrogens. This review provides an overview of the potential sources and bio-availabiliry of phltoestro gens particularly to Phyloestrogens are nalurally occurring plant compounds isoflavones, and discusses their potential use that have 2-p henylnaphthalene-type chem-tcal structures prevent cardiovascular diseases. similar to those of eslrogens.' Th"y are found in many grains, green human foodstuffs including beans, POTENTL{L SOURCES OF ISOFLAVONES vegetables, fruils, and nuts.a The major sources of isoflavones in Asian diet are soy Phytoestrogens are broadly grouped into 4 and its products. The primary isoflavones in soybeans main classes, isoflavones, lignans, , and are , , a"rd their respective B-gtycosides resorcyclic lactones. The three first mentioned are ( and ). ln addition, rnuch lower arnounts of and is glycoside (glycitin) are present in soybeans.b Humans consume soybeans and thefu products Medicine, [Jniversity of Department of Histotogy, Faculty of in many forms, including whole soybeans, lempeh, tofu, Indones ia, J akarra, Indonesia l

,l l I Phytoestrogens Vol 1 1 , No 2, April - June 2002 l2l

and soy milk. The concentrations of isoflavons in its Once ingested, several factors influence the bio- degradation major sources are shov/ed in Table l. availability of isoflavones, i.e. intestinal by colonic microflora and the presence of hber in the Table l. The potential sources ofisoflavons diet, which conelate positively v/ith absorption.r

Source Concenhation (pglg)

Soybean t,176 - 4,215+ TIIE POTENSIAL USE OF PITYTOESTROGENS Roasted soybean 2,661 TO PREVENT CARDIOVASCIILAR DISEASES Soy flour 2,0t4 Soy granule 2,404 Epidemiological studies Textured vegetable proteins 2,261-2,295+ 62t Protein isolate -987t Epidemiological studies revealed low rates of Totu 260 532" - diseases among Asian populations Tempeh 865 cardiovascular phytoestrogens, relative to Miso 389 -647+ whose diets were rich in those in Western countries. This evidence suggests a Modihed from Tham et al, 1998r plausible causal inverse relationship between * More than one lot were assaYed phytoestrogens and cardiovascular disease. However, this association is confounded by other concomitant dietary differences, making it difficult to attribute the BIOAVAILABILITY OF low rates of cardiovascular diseases to PHYTOESTROGENS intake.tFurthermore, the major source of phytoestrogens in As'ian diets are soy and its products, that contain that found Phytoestrogens in plants are different from cholesterol lowering agents, such as a-linolenic acid in humans and animals. To be absorbed they shoul( and saponins. Therefore, the low rates of cardiovascular plants, be fermented/metabolized by gut microflora. In diseases among Asian populations might be attributed some isoflavons are bound to sugar residue to form to those agents, though the hypocholesterolemic glycosides, which are inactive. When the sugar effects of safonins in huirans *" tiiit speculative.6 residue is removed, the glycoside form becomes active compounds.l'6 In plants, both the glycoside and To assess the potential use of phytoestrogens to aglycon forms are present.l In humans, .isoflavone prevent cardiovascular diseases, several studies were aglycones are absorb faster and in greater, amounts conducted. Among those studies, a cross sectional than their glycosides.T The conversion process from study showed that dietary isoflavone intake was plant isoflavones to human isoflavons detected in associated with reduced cardiovascular disease risk in blood and urine is showed in Figure 1. postmenopausal women. In this study's adjusted

p-glycoside form Genistein Daidzin (in soybean)

Aglycon form

Gut microflora (fermentation)

Figire !. The conversion of plant isoflavones to human isoflavones

F f4 ,ii. 122 Pawitan Med J Indones analyses, genistein, daidzein, and total isoflavone 100 pglml, had no significant effect on thrombin- intake were each positively associated with HDL induced platelet activation. On the other hand those cholesterol and inversely associated with post workers demonstrated that daidzein, which has no challenge insulin.8 inhibitory activity for tyrosine kinase, and aiso genistein were able to suppress platelet responses elicited by both collagen and thromboxane 42. Intervèntion study that genistein and daidzein An intervention study suggested a cardioprotective However, the thought could suppress platelet activation was opposed by a role for supplemental phytoestrogen (isoflavone). In clinical trial involving 60 g/day of a soy protein this study, supplementation of 34 mg phytoestrogens isolate beverage powder for 28 days, that showed a for 6 weeks showed improvements in lipid and dramatic rise in plasma isoflavone concentrations, lipoprotein level, and blood pressure.e detected no significant effect on platelet aggregation.l2 Therefore, more sfirdies will need to be conducted to clariff the exact mechanism by, which phytoestrogens MECHANISMS FOR THE CARDIOVASCULAR affect various platelet responses.' PROTECTWE EF'FECTS OF PHYTOESTROGENS

The mechanisms for the cardiovascular protective Phytoestro gens' hypocholesterolemic effect effect ofphytoestrogens are shown by several studies. Several human clinical tials with phytoeshogens have reported inconsistent serum lipid effects,r with a bigger Phytoestrogens' effect on atherosclerosis tendency to favorable effects. The dose needed to get a hypocholesterolemic effect is shown in Table 2. A study showed that isoflavone phytoestrogens reduced tipid peroxidation in vivo and increased the The mechanisms for the hypocholesterolemic effect of resistance of low-density lipoprotein (LDL) to be p- oxidation. Isoflavones (genistein, daidzein and ) lor of were also shown as antioxidants in vitro. These facts Tof Lignans may be a significant mechanism in reducing jhe risk particular significance for hyperlipidemics. I 0 may also affect cholesterol homeostasis, as they have of atherosc leros is and cardiovascular' disease. been shown to inhibit the activity of cholesterol'7a- the Furthermore, various studies have suggested that hydroxylase, the rate-limiting enzyme in genistein acts as a protein tyrosine kinase inhibitor. An fàrmation of primary bite acids from cholesterol,r increase in tyrosine phosphorylation at tyrosine residues of platelet proteirs is associated with thrombin-induced Phytoestrogens' effects on arteries platelet's activation. Therefore, genistein as a tyrosine i.inus" inhibitor is though to be responsible for a Soy phytoestrogens favorably influence coronary reduction in the deposition and aggregation ofplatelets, reactivity. In a study on the effect of phytoestrogens and a decrease in the progression of atherosclerosis. (genistein, , and zearalanone) This thought is however opposed by other workers who on isolated rabbit coronary artery rings showed that observed that concentrations of genistein up to genistein, phloretin and biocha"rin A induced

Table 2. The dosage needed to get beneficial effect in various condition

Subject Phytoestrogens Dose/duration lmprovement tevel, blood Perimenopausa[ women Phytoestrogens tn soY 34 mg in single dose or split into Lipid and tipoprotein protetn 2 doses for 6 weeks pressuret

Healthy, noffno- Conjugated isoflavones in 45 mglday TotaI cholesterolt cholesterolemic, soy product premenopausal women Vol I I, No 2, April-June 2002 Phytoestrogens 123

significant gender-independent relaxation in rings Wildman REC, Medeiros DM. Nutrition supplement and with and without endothelium. This study demonstated nutraceuticals. [n: Wildman REC, Medeiros Divt. Advanced human Nutrition. Boca Raton: CRC Press; that phy-toestrogens induce endothelium-independent 2000. p. 367-398. placebo- rela,xation of coronary arteries.la'15 A 6 Nlessina MJ. Legumes and soybeans: overview of their controlled crossover trial tested the effects of nuhitional profiles and health effects. Am J Clin Nutr phytoestrogens in the form of soy-isoflavones in 1999;70(suppl):43 9S-50S. peri- and post-menopausal women, and found that Izumi T, Piskula MK, Osawa S, Obata A, Tobe K, Saito the systemic arterial compliance (arterial elasticity) M, et al. Soy isoflavone aglycones are absorbed faster and in higher amounts than their glucosides in humans. J Nutr was significantly improved those taking soy- in 2000; I 30:1695-9. isoflavones.l6 Phytoestrogens also inhibit the Goodman-Gruen D. Kritz-Silverstein D. Usual dietary progression of atherosclerosis in the coronary, iliac isoflavone intake is associated with cardiovascular disease and common carotid arteries. The cardiovascular risk factors in postmenopausal women. J Nutr 2001; benefits of soy phytoestrogens appear to be equal for 13l:1202-1206. 9 Washburn S, Burke GL, Morgan T, Anthony M. Effect of males and females.la soy protein supplementation on serum lipoprotein, blood pressure, and menopausal symptoms inperimenopausal In another study on human aortic smooth muscle cells women. Menopause 1999;6(l):7-13. (SMC), phytoestrogens may confer protective effects t0 Wiseman H, O'Reilly JD, Adlercreutz H, Mallet AI, on the cardiovascular system by inhibiting vascular Bowey EA, Rowland IR. Isoflavone phytoestrogens remodeling and neointima formation. consumed in soy decrease F2-isoprostane concentrations and increase resistance of low-densify lipoprotein to oxidation in human. Am J Clin Nutr 2000;72(2):395-400. In conclusion, phytoestrogens are strongly believed to ll Nakashima S, Koike T, Nozawa Y. Genistein, a protein have a potential role in the reduction ofcardiovascular tl,rosine kinase inhibitor, inhibits thromboxane A2- mdiated disease. The mechanisms of actions might be through human platelet responses. MoI Pharmacol 1990;39:475-80. blood pressure reduction, inhibition of lipid l2 Gooderham MJ, Adlercreutz H, Ojala ST, Wahala K, protein genistein and peroxidation and platelet aggregation, thus prevgnting Holub BJ. A soy isolate rich in daidzein and its effect on plasma isoflavone concentration, atherosclerosis, increasing arterial compliance and/or platelet aggregation, blood lipids and fatty acid hypocholesterolemic effect. composition of plasma phospholipid in normal men. J Nutr 1996;126:2000-6. t3 Sirtori CR. Lovati MR, lvlanzoni C, Monetti M, Pazzuconi REFER.ENCES F, Gatti E. Soy and cholesterol reduction: clinical experienco. J Nutr 1995;125(Suppl):5985-605S. l4 Clarkson TB, Anthony MS. Phy4oestrogens and coronary l. Tham DM, gardner CD, Haskel WL. Potential health heart disease. Baillieres Clin Endocrinol Metab 1998; benefits of dietary phytoestrogens: a review of the 12:589-604. clinical, epidemiological, and mechanistic evidence. J l5 Figtree GA, Griffiths H, Lu YQ, Webb ClvI, Iv{acteod K, Cl in Endocrino I lvletab 1998;83 (7) :2223 -3 5. Collins P. Plant-derived relax coronary arteries 2. Artaud-Wild SM, Connor SL, Sexton J, Connor WE. mechanism. J Am Colt Differences in coronary mortality can be explained by in-vitro by a calcium antagonistic Cardiol 2000;35: 1977-85. differences in cholesterol and saturated fat intakes in 40 countries but not in France and Finland. A paradox. l6 Nestel PJ, Yamashita T, Sasahara T, Pomeroy S, Dart A, Komesaroff P, et al. Soy isoflavones improve systemic C irculation 1993 ;88:227 l -9. 3. Keys A, Menotti { Aravanis C, et al. The seven countries arterial compliance but not plasma lipids in menopausal perimenopausal 1997;17: shrdy:2,289 deaths in l5 years. Prev Med 1984;13:141-54. and women. Arteriosclerosis 4. van der Schouw YT, de Klein MJ, Peeters PH, Grobbee 3392-8. DE. Phy,to-oeshogens and cardiovascul.ar disease risk. Nutr Metab Cardiovasc Dis 2000;10(3):154-67.

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