Red wine's health benefits may be due in part to 'estrogen' in grape skin

Moderate consumption of red wine has been widely reported to reduce risk for cardiovascular disease. Some researchers have attributed this cardioprotective quality to the significant amounts of resveratrol naturally present in grape skin.

Resveratrol protects grapes and some other plants against fungal infections. It has been shown previously to have a number of potentially beneficial properties, including antioxidant, anticoagulant, anti-inflammatory and anti-cancer effects.

Resveratrol has a molecular structure similar to that of diethylstilbestrol, a synthetic estrogen. This prompted Barry D. Gehm, J. Larry Jameson, M.D., and colleagues at Northwestern to investigate whether resveratrol might have pharmacologic properties similar to those of estradiol, the major natural human estrogen.

As reported in the Dec. 9 issue of the Proceedings of the National Academy of Sciences, the group's laboratory studies showed that resveratrol is estrogenic. (Specifically, it is a phytoestrogen, from the Greek word for "plant.") At concentrations similar to those required for its other biological effects, resveratrol activated expression of both artificially introduced "reporter" genes and naturally occurring estrogen-regulated genes in cultured human cells.

The researchers also found that resveratrol could replace estradiol in supporting the proliferation of certain breast cancer cells that require estrogen for growth.

"Estrogen" is not a specific compound but a category of substances defined by their biological effect. Originally named for their ability to induce estrus ("going into heat") in animals, estrogens act on cells by binding to a protein called estrogen receptor, which then causes certain genes to be expressed, or "turned on." In addition to the body's sex hormones, a number of other natural and artificial estrogens are known.

In studying gene expression, many laboratories use artificial reporter genes. The reporter gene used in these studies is the gene for the enzyme luciferase, which makes fireflies light up. It was connected to a piece of DNA that the estrogen receptor "recognizes." When this reporter gene was put into cells, luciferase production increased in those treated with estrogen. Then, when mixed with certain chemicals, the enzyme was measured easily by the light it gave off.

In some cells, resveratrol caused more expression of the reporter gene than estradiol. This was surprising, Gehm said, since estradiol has always been thought to produce maximal activation of the estrogen receptor. The group found that the most effective dose of resveratrol produced two to four times more light as the most effective dose of estradiol. However, estradiol is effective at much lower doses.

"The estrogenic properties of resveratrol may play a role in the beneficial cardiovascular effects of red wine and the so-called 'French paradox,'" Gehm said.

Estrogen is known to provide some protection against heart disease, and red wine also appears to. Their specific effects are similar, most notably, increasing high-density lipoprotein (HDL), the "good cholesterol." This effect of red wine may be mediated by resveratrol.

But Gehm cautioned that it is not yet known if the body absorbs enough resveratrol from wine to make this plausible. The same can be said of resveratrol's other effects, described earlier.

Some researchers have previously suggested that it would be beneficial to supplement people's diets with resveratrol because of its anticarcinogenic and anti-arteriosclerotic properties.

"The discovery that resveratrol is estrogenic means that such supplementation might have undesirable side effects," Gehm said.

Nevertheless, the observation that reseveratrol produces greater expression of some estrogen-regulated genes than estradiol may ultimately lead to the development of new, more selective estrogenic drugs. Selective estrogens currently available are used in the treatment of breast cancer (tamoxifen) and postmenopausal osteoporosis (raloxifene).

Barry D. Gehm is a research assistant professor of medicine; J. Larry Jameson, M.D., is the C. F. Kettering Professor of Medicine and chief of endocrinology at Northwestern University Medical School. Also collaborating on this study were Joanne M. McAndrews and Pei-Yu Chien.