Overview of The Biological Activities of Isoflavones

Phytoestrogens are a group of heterogeneous herbal substances; they are called non-steroidal estrogens or estrogen-like molecules, as their structure is comparable to 17-β-estradiol structure, phytoestrogens are diphonelic compounds however they are non-steroidal substance despite their structural resemblance with estradiol, Presently phytoestrogens group contains more than 100 molecules, which are divided into isoflavones, coumestans, and lignans, Isoflavones is a natural plant compound, a subgroup of phytoestrogen, with a structure comparable to 17 estradiol that can bind to estrogenic receptors (ERs) as mentioned in figure 1, isoflavones have a greater affinity to bERs more than aERs, and might have a potency to stimulate both non-genomic and genomic signaling pathways of estrogen, furthermore; isoflavones can interact with steroid hormones metabolism, hence; the activity of isoflavones are somewhat complex, lately, isoflavones showed a several positive result on human health, especially in age related cognitive decline, osteoporosis, hormone dependent caner, adverse menopausal manifestations, and cardiovascular diseases.

Isoflavones are found naturally in more than 300 plants types, frequently in the seeds and roots, they can be found in linseed, red clover, red wine extracts, and alfalfa germs, as biologically inactive glucoconjugates which are further hydrolyzed into the active form (aglycone) by intestinal bacteria action, Isoflavones degradation takes place in liver, where they can be conjugated with glucuronic acid and sulfates, then they expelled from the body in bile or urine.

Isoflavones and the cardiovascular system

Besides genetic factors, disparity within the incidence of cardiovascular diseases is supposed to be triggered by nutritional factors, thus long term intake of isoflavones may exert a protective action on the cardiovascular system via many mechanisms, these include lipid metabolism and vaso-activity regulation, isoflavones influence the vascular tone through several mechanisms combination like endothelial independent and endothelial dependent blood vessels widening systems, and constrictor mechanisms blocking, these mechanisms include both non genomic and classical genomic mechanism. Nuclear ERs initiation by isoflavones was found to elevate endothelial NO-synthase expression (eNOS), increase NO bioavailability and reduce oxidative stress, through a quick non-genomic mechanism.

Also isoflavones help to prevent the formation of atherosclerosis through three mechanisms, the first mechanism is plasma lipids enhancement through alterations in the metabolism of liver, the second mechanism is that isoflavones have antioxidant action which reduces LDL particles size and protects LDL from peroxidation, making LDL less likely take up by the artery wall, and hence less atherogenic, the third mechanism is the inhibition of proliferation and migration of cells of smooth muscle, which are significant in the progression and promotion of the process of atherosclerosis, isoflavones also inhibit activation and aggregation of platelet, and decreasing platelet serotonin uptake hence suppressing thrombus formation.

Osteoporosis is a disorder is characterized by bone microarchitecture deterioration and low bone mass, leading to increased risk of fracture and fragility of bones, Reduced calcium bone resorption-accelerating cytokines (IL-1, IL-6, IL-11 and TNF) activation and availability are related to Low 17-β-estradiol serum levels, resulting in bone resorption ascendancy over synthesis of bone and consequent decalcification of bones, thus isoflavones long term intake was found to positively influence bone metabolism by two mechanisms, the first is apoptosis activation which impacts osteoclasts, and the second mechanism is tyrosine-kinase action inhibition through ERs membrane modulation with sequential changes in alkaline phosphatase action.

Regarding breast cancer; Tumors in postmenopausal women are developed by contribution of environmental factors, also it has been found that exogenous and endogenous estrogens have the ability to trigger breast cancer cell growth, Accordingly, these cells are called estrogenreceptor positive or estrogen-dependent, and they have estrogen-receptors in large quantity, thus it has been found that phytoestrogens particularly flavones or isoflavones consumption is associated with decreasing breast cancer occurrence, mammary gland proliferation ability, and mammary gland density as they have considered to have a protective action on progression or initiation of breast cancer By blocking estrogens local production by the circulating precursors in tissue of breast as illustrated in figure 3, these actions are related to isoflavones ability to increase the concentration of serum SHBG, thus reducing sexual hormones bioavailability in hormone-dependent tissues. Furthermore, in peripheral tissues, isoflavones block enzymes contributing in cell proliferation processes for example tyrosine kinase, and decrease the availability of estradiol via the inhibitory action on aromatase P540 an enzyme which convert androgens to estrogens, hence causing a reduction in the concentration of circulating estrogen, isoflavones also showed an inhibitory actions on 17β-hydroxysteroid dehydrogenase (17β- HSD) type 1, this enzyme converts estrone to estradiol in cells of breast cancer.

Isoflavones modulate oxidative stress, fatty acid b-oxidation, and lipid synthesis in liver, thus it have attracted significant attention for fatty liver disease prevention as it is a growing public health problem worldwide, also isoflavones showed a potent inhibitory effect on aldose reductase, an enzyme that has been reported to be involved in fatty liver disease by modulating peroxisome proliferator-activated receptor (PPAR) α activity, release of gut bacterial endotoxin-induced cytokines, expression of P450 (CYP) 2E1, and production of hepatic fructose hence it prevents consequent accumulation of fats in liver.

Effect of isoflavones on nervous system

Microglial are the brain primary immune cells that are stimulated in case of brain injury that have an important role in neurodegenerative diseases by producing nitric oxide (NO) and numerous proinflammatory cytokines. A recent study conducted by Park et al. (2006) showed that 3 types of Isoflavones and their metabolite suppress tumor necrosis factor (TNF), and lipopolysaccharide (LPS) induced NO release in primary cultured cell lines of microglial and BV2 microglial, the inhibitory action of the metabolite of isoflavones (aglycone form) was more effective than isoflavones (glycoside form).

In conclusion, isoflavones biological activity are various, and contain numerous physiological systems, isoflavones influence many signaling pathways via stimulation of both membrane and intracellular β estrogen receptors, in addition to interaction with steroid hormone metabolism, hence isoflavones impact on physiological processes seems to be so complex and might be associated with huge number of factors, Isoflavones have a protective effect on cardiovascular system through lipid metabolism and regulation of vasoactivity, also they aid in preventing atherosclerosis via reducing LDL level, also isoflavones were found to prevent osteoporosis by activation of apoptosis and TK inhibitory effect, isoflavones increase the concentration of serum SHBG and inhibit aromatase P540 an enzyme thus preventing breast cancer imitation, also isoflavones inhibit aldose reductase an enzyme involved in Fatty liver disease, also they have a positive effect on nervous system by suppressing TNF.