EXPERIMENTAL STUDIES
Phytoestrogens and vascular therapy*
James D. Marsh, MD, FACCa
a Cardiology Division, Department of Internal Medicine, Wayne State University, School of Medicine, Detroit, Michigan, USA
Reprint requests and correspondence: Dr. James D. Marsh, Cardiology Division, Wayne State University, Elliman Building, 421 E Canfield, Room 1107, Detroit, Michigan 48201.
marsh{at}intmed.harper.wayne.edu
Phytoestrogens are a group of plant-derived natural products which include lignans, isoflavones, coumestans, and resorcyclic acid lactones. Dietary consumption of lignans and isoflavones has been postulated to play a role in the protection of humans against development of coronary heart disease (1). In order for some of these plant-derived compounds to be biologically active, they must be modified by intestinal bacteria. For instance, isoflavones, including biochanin A, are found in soybeans and chick peas, and have direct biological activity, whereas other isoflavones are modified by the gut flora to produce biologically active compounds such as genistein. Lignans are found in high concentrations in oil seeds and cereals. The most abundant mammalian lignan is enterolactone, which is dependent on the intestinal bacteria for its synthesis from the plant precursor. Flavanoids are often found in a glycoside form. There are structural similarities between phytoestrogens and 17ß-estradiol (2). It is well established that 17ß-estradiol has vasodilating properties (3).
There is growing evidence from epidemiologic studies that consumption of phytoestrogens has a beneficial effect on the risk of acute coronary events. Vanharanta et al. (4) recently reported a case-control study relating the serum enterolactone concentration (a marker for phytoestrogen dietary consumption) with risk for acute coronary events in men. Men in the highest enterolactone quartile had a 65% lower risk than did men in the lowest quartile for acute coronary events over 7.7 years (4). The investigators concluded that dietary consumption of plant-derived fiber-rich food lowers the risk for coronary heart disease substantially.
In this issue of Journal, Figtree et al. (5) provide useful and novel insights into the mechanism of action of phytoestrogens on coronary artery vascular tone. They use the combination of classic vascular smooth muscle contractility studies, cardiac myocyte studies of calcium current and contractility and human studies to define relevant serum concentrations of a phytoestrogen-derived product in plasma. These authors clearly demonstrate that several phytoestrogens, including biochanin A and genistein, relax precontracted rabbit coronary artery rings. Through a series of carefully designed and conducted experiments, they exclude several candidate mechanisms of action for the vasodilator effects. The highly efficacious vasodilator effects of genistein are not dependent on nitric oxide and are independent of endothelium. This is of therapeutic interest, as conceivably these compounds might be used in patients with diseased and dysfunctional endothelium. They also demonstrate that the vasodilator effects are not dependent on the estrogen receptor ER-alpha, although they cannot exclude an effect of ER-beta. The authors establish that the isoflavone, genistein, appears to function as a calcium channel blocker in vascular smooth muscle and in cardiac myocytes. The pharmacologic effects of genistein in vascular smooth muscle are as one might expect from an organic calcium channel blocker. In isolated guinea pig myocytes, genistein decreases calcium current and cell contractility in a concentration-dependent manner. Of considerable importance, the plasma concentration found in normal humans after consuming a soy liquid supplement (Supro), 2 µmol/liter, is associated with significant inhibition of the calcium current in myocytes. Thus, concentrations achievable in humans taking phytoestrogen dietary supplements correspond with important biological effects in vitro.
Exactly how does genistein block the L-type calcium channel? Additional, more detailed molecular pharmacologic and biophysical work will need to be done to define this more fully. The work by Figtree et al. (5) reported in this issue of the Journal begins to explore the mechanism. Genistein is a tyrosine kinase antagonist. However, it is unlikely that this is important for its calcium channel blocking effects. Of note, the precursor of genistein, biochanin A (which is not a tyrosine kinase antagonist), is a more potent inhibitor of vascular smooth muscle tone than is genistein.
Phytoestrogens hold therapeutic potential for cardiovascular disease. Of note, in the recent study by Vanharanta et al. (4), there appeared to be an association between increased dietary consumption of phytoestrogens (using the serum enterolactone concentration as a marker) and lower systolic and diastolic blood pressure. Are phytoestrogens "natural" calcium channel blockers that may have therapeutic benefit for coronary artery disease and hypertension? Possibly. However, caution is warranted in adopting phytoestrogens as home remedies. Synthesis of some mammalian phytoestrogens is dependent on gut flora, and synthesis is abolished for three weeks by a course of oral antibiotics. Thus, the bioavailability of phytoestrogens will likely be highly variable. It is not a wise therapeutic strategy for hypertension or angina to have the effect of a natural product (a phytoestrogen) abolished when a patient takes a course of antibiotics for a urinary tract infection. Moreover, there may be important interactions with other drugs, including warfarin. At this time, we do not know which member(s) of the phytoestrogens may have the greatest potential for therapeutic benefit.
Will phytoestrogens be the "vascular glycosides" of the 21st century, just as digitalis glycoside extracts of the foxglove leaf were the "cardiac glycosides" of the past two centuries? Physicians no longer prescribe the pill, digitalis leaf, with its host of glycosides possessing varying therapeutic and toxic effects. It is likely that our patients will be best served, just as in the case of cardiac glycosides, by investigators carefully defining, purifying, standardizing, and determining the mechanism of action of the plant-derived natural products. Phytoestrogens do have the potential to be useful agents for prevention and treatment of vascular disease, but we have a great deal to learn about their safe and effective use.
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Footnotes
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* Editorials published in Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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- Hertog MG, Kronhout D, Aravonis C, et al. Flavanoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch Intern Med. 1995;155:381–386[Abstract]
- Miksicek RJ. Commonly occurring plant flavanoids have estrogenic activity. Mol Pharmacol. 1993;44:37–43[Abstract]
- Jiang C, Sarrel PM, Lindsay DC, Poole-Wilson PA, Collins P. Endothelium independent relaxation of rabbit coronary artery by 17ß-estradiol in vitro. Br J Pharmacol. 1991;104:1033–1037[Medline]
- Vanharanta M, Voutilainen S, Lakka TA, VanderLee M, Adlercreutz H, Salonen JT. Risk of acute coronary events according to concentration of enterolactone: a prospective population-based case-control study. Lancet. 1999;354:2112–2115[CrossRef][Medline]
- Figtree GA, Griffiths H, Lu Y-A, Webb CM, MacLeod K, Collins P. Plant–derived estrogens relax coronary arteries in vitro by a calcium antagonistic mechanism. J Am Coll Cardiol 2000;35:1977–85.
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