PHARMACOLOGICAL ACTIVITIES:
Genistein belongs to the isoflavone class of flavonoids. It is also classified as a phytoestrogen. Phytoestrogens are plant-derived nonsteroidal compounds that possess estrogen-like biological activity. Genistein has been found to have both weak estrogenic and weak anti-estrogenic effects.
Genistein is the aglycone (aglucon) of genistin. The isoflavone is found naturally as the glycoside genistin and as the glycosides 6"-O-malonylgenistin and 6"-O-acetylgenistin. Genistein and its glycosides are mainly found in legumes, such as soybeans and chickpeas. Soybeans and soy foods are the major dietary sources of these substances. Nonfermented soy foods, such as tofu, contain higher levels of the genistein glycosides, while fermented soy foods, such as tempeh and miso, contain higher levels of the aglycone.
Genistein has weak estrogenic activity as measured in in vivo and in vitro assays. In vivo, its estrogenic activity is one-third that of glycitein and four times greater than that of daidzein.
Genistein has been found to have a number of antioxidant activities. It is a scavenger of reactive oxygen species and inhibits lipid peroxidation. It also inhibits superoxide anion generation by the enzyme xanthine oxidase. In addition, genistein, in animal experiments, has been found to increase the activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, catalase and glutathione reductase.
Several mechanisms have been proposed for genistein's putative anticarcinogenic activity. These include upregulation of apoptosis, inhibition of angiogenesis, inhibition of DNA topoisomerase II and inhibition of protein tyrosine kinases. Genistein's weak estrogenic activity has been suggested as another mechanism for genistein's putative anti-prostate cancer activity. In addition to the above mechanisms, other mechanisms of genistein's putative anti-prostate cancer activity include inhibition of nuclear factor (NF)-Kappa B in prostate cancer cells, downregulation of TGF (transforming growth factor)-beta and inhibition of EGF (epidermal growth factor)-stimulated growth. Genistein's anti-estrogenic action may be another possible mechanism to explain its putative anti-breast cancer activity. In the final analysis, the mechanism of genistein's putative anticarcinogenic activity is unclear.
The possible anti-atherogenic activity of genistein may be attributed, in part, to its antioxidant activity. Genistein may have some lipid-lowering activity, but the mechanism of this is unclear. The weak estrogenic activity of genistein may also contribute to its possible anti-atherogenic action.
Genistein's weak estrogenic effect may help protect against osteoporosis by preventing bone resorption and promoting increased bone density. Genistein has been found to maintain trabecular bone tissue in rats. However, the mechanism of genistein's possible anti-osteoporotic effect is unclear.
The pharmacokinetics of genistein in humans is complex and not well understood. The major dietary and supplemental form of genistein is the glycoside genistin. Some genistin may be hydrolyzed by hydrochloric acid in the stomach to genistein and some may be hydrolyzed by beta-glucosidases in food to genistein. Most of ingested genistin, however, is delivered to the large intestine intact. In the large intestine, bacterial beta-glucosidases hydrolyze genistin to genistein. Genistein is either absorbed or further metabolized in the large intestine to dihydrogenistein and 6'-hydroxy-O-desmethylangolensin. Genistein, which is absorbed from the large intestine and small intestine, is eventually transported to the liver. There, it undergoes conjugation with glucuronate and sulfate via hepatic phase II enzymes (UDP-glucuronosyltransferases and sulfotransferases). The glucuronate and sulfate conjugates of genistein are excreted in the urine and in the bile. The genistein conjugates may be deconjugated to release genistein, which may be reabsorbed via the enterohepatic circulation.
There is considerable individual variation in the absorption and metabolism of ingested genistin and genistein. There are some data suggesting that genistein may be more bioavailable than genistin. However, other data suggest that the extent of absorption of genistein is similar for the aglycone and the glucoside forms. There are little data available on the tissue distribution of genistein.
There is a growing body of in vitro and animal studies suggesting that genistein may be helpful in preventing and treating some cancers, principally breast and prostate cancers. The clinical studies that might support or refute claims that genistein has anti-atherogenic properties and that it can safely and effectively be used as "natural" estrogen-replacement therapy have not been conducted. There are, however, preliminary data suggesting that soy isoflavones, including genistein, may be helpful in some problems associated with menopause, including osteoporosis and "hot flashes." See Soy Isoflavones.
Epidemiological data have long suggested that dietary isoflavones may confer protection against various cancers, especially breast and prostate cancer. High dietary intake of soy products in parts of Asia significantly correlated with reduced incidence of both breast and prostate cancers. Epidemiological data have not been entirely consistent in this regard, but most studies suggest protective effects. Some studies have shown, moreover, that this protection is lost in the second generation of those Asians emigrating to the United States.
These data led to experimental animal studies demonstrating protective effects. In one study, genistein perinatally fed to rats significantly protected offspring from subsequent chemically induced mammary cancers. These researchers concluded that adequate perinatal exposure to genistein can confer permanent protective effects against breast cancer. They have further speculated that protective effects in humans, with respect to breast cancer specifically, may depend upon exposure to genistein early in life. More research is needed to clarify this issue.
A number of studies have shown that genistein can inhibit prostate cancer-cell growth in vitro. Some recent in vitro studies suggest that genistein may be both chemopreventive and therapeutic in prostate cancers regardless of androgen responsiveness. Clinical trials are needed.
