Volume 36, Issue 11, Pages 22-23 (November 2005)

LESLIE S. BAUMANN, M.D.

DR. BAUMANN is director of cosmetic dermatology at the University of Miami. To respond to this column, or to suggest topics for future columns, write to Dr. Baumann at our editorial offices via e-mail at This e-mail address is being protected from spambots. You need JavaScript enabled to view it .

The isoflavone genistein (4',5,7-trihydroxyisoflavone) occurs naturally as the major active constituent of soybeans, and its potent antioxidant and chemopreventive activities are well documented (Acta Pol. Pharm. 2000;57:135–55; Photochem. Photobiol. 2005;81:32–7; Skin Pharmacol. Appl. Skin Physiol. 2001;14:373–85; Nutr. Cancer 1993;20:1–12; J. Biol. Chem. 1994;269:3529–33; Nutr. Cancer 1996;25:1–7; Proc. Soc. Exp. Biol. Med. 1995;208:124–30; Carcinogenesis 1998;19:649–54; Carcinogenesis 1998; 19:1509–14).

Genistein was first isolated from the soybean in 1931 (J. Nutr. 2003;133[11 suppl. 1]:3811S-19S; J. Chromatogr. 1978;150:266–8). This isoflavone, which is characterized as a phytoestrogen, has diverse biologic activities. Studies have shown that genistein has the following effects:

It inhibits protein tyrosine kinase (Adv. Exp. Med. Biol. 2004;546:121–65; J. Nutr. 2003;133[11 suppl. 1]:3811S-19S; Carcinogenesis 1998;19:1509–14; Biochem. Biophys. Res. Commun. 1993;194:944–50).

It influences cell cycles.

It is associated in animals and humans with preventive and therapeutic effects on several cancers, including breast, skin, and prostate cancer (Am. J. Clin. Nutr. 2005;81[suppl.]:284S-91S; Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 2003;147:137–45; J. Nutr. 2003;133[11 suppl. 1]:3811S-19S; Biochim. Biophys. Acta 2002;1556:187–96; Carcinogenesis 1998;19:1509–14; Carcinogenesis 1996;17:73–7).

It can help in the prevention and treatment of postmenopausal syndrome, osteoporosis, and certain cardiovascular conditions (J. Nutr. 2003;133[11 suppl. 1]:3811S-19S).

It enhances the effects of radiation in the treatment of breast and prostate cancers (Adv. Exp. Med. Biol. 2004; 546:121–65).

In addition, a recent study showed that genistein can reverse or affect alopecia areata in C3H/HeJ mice. Normal-haired mice were first treated to become susceptible to alopecia development via grafting with skin from mice that spontaneously developed alopecia. When the mice were fed diets of 1%, 5%, or 20% soy oil that contained genistein, alopecia development was suppressed in a dose-dependent manner.

In a related study by the same investigative team, mice on a 1% soy oil diet were injected with genistein or administered a control. Genistein again showed a suppressive tendency, with only 4 of 10 mice receiving treatment developing alopecia, whereas 9 of 10 controls developed the condition (Exp. Dermatol. 2003;12:30–6).

Antineoplastic Action

However, the preponderance of research on genistein has focused on animal, human, and culture studies of its effectiveness in cancer inhibition.

In fact, a literature review revealed that nearly one-fifth of the more than 4,500 peer-reviewed studies of genistein dealt with its antitumorigenic capacity (Adv. Exp. Med. Biol. 2004;546:121–65).

In human renal cell carcinoma, genistein has recently been found to have the capacity to inhibit cell proliferation and induce apoptosis in vitro, as well as suppress angiogenesis in vivo, suggesting it is a potentially significant agent in the anticancer armamentarium (Urology 2004;64:389–93).

Indeed, when genistein was orally administered to TRAMP mice, it reduced the incidence of advanced-stage prostate tumors in a dose-dependent manner (Am. J. Clin. Nutr. 2005[suppl.];81:284S-91S; Cancer Res. 2001;61:6777–82).

Human bladder cancer cells have also been treated with genistein, resulting in impaired CDC2 kinase activity and arrest of the G2/M phase of the cell cycle (Am. J. Clin. Nutr. 2005;81[suppl.]:284S-91S; Clin. Cancer Res. 2000;6:230–6).

Moreover, in human epidermoid carcinoma A432 cells, genistein has been demonstrated to downregulate, in a dose-dependent manner, UVB-mediated phosphorylation of tyrosine phosphokinase-dependent epidermal growth factor receptor (J. Biol. Chem. 1994;269:3529–33).

Genistein's ability to halt many processes—particularly cell growth, proliferation, invasion, and angiogenesis—is also shown by its inhibition of protein tyrosine kinase, topoisomerase II, and matrix metalloprotein (MMP9), as well as its downregulation of multiple genes, including the vascular endothelial growth factor gene (Adv. Exp. Med. Biol. 2004;546:121–65).

Sun Protection

Genistein has been demonstrated to inhibit photocarcinogenesis and photoaging in mice, as well as photodamage (particularly UVB-induced skin burns) in humans, via potent antioxidant action, the protection of oxidative and photodamaged DNA, and downregulation of UVB-induced signal transduction cascades (J. Nutr. 2003;133[11 suppl. 1]:3811S-19S).

Perhaps not surprisingly, then, genistein, along with N-acetylcysteine, has also been found to inhibit the expression of tropoelastin—a main component of elastic fibers—when used to pretreat skin subsequently exposed for 24 hours to heat treatment (J. Invest. Dermatol. 2005;124:70–8).

In a study focusing on the generation of reactive oxygen species and the capacity of genistein (and N-acetylcysteine) to inhibit UV effects that lead to in vivo photoaging in humans, pretreatment with the isoflavone impaired UV-induced epidermal growth factor receptor tyrosine kinase activity, as well as UV-induced activities of extracellular signal-regulated kinase and cJun N-terminal protein kinase.

Genistein also inhibited UV induction of cJun protein, cJun-driven enzyme, and collagenase (J. Invest. Dermatol. 2003;120:835–41).

The researchers concluded that these results support the notion that genistein's antioxidant activities are consistent with the prevention of photoaging.

Furthermore, genistein has been found to enhance melanin production. That ability, combined with the compound's known capacity to spur tyrosinase activity, has led some authors to conclude that genistein shields melanocytes from UVB-induced melanoma in whites (Adv. Exp. Med. Biol. 2004;546:121–65).

Equol, a gastrointestinal metabolite of genistein, was recently found to significantly protect the skin of hairless mice against carcinogenesis resulting from chronic exposure to solar-simulated UV, topical treatments with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), or a combination of the two.

Equol lotion was applied daily, and tumor development was monitored for 40 weeks. The results revealed significant delays in tumor appearance and lower tumor number in the groups treated with the genistein derivative. Furthermore, in the groups treated with solar-simulated UV alone or combined with the carcinogen, the proportion of tumors progressing from benign papillomas to malignant squamous cell carcinomas was significantly reduced, as was the average diameter of the carcinomas (Photochem. Photobiol. 2005;81:32–7).

And in a short-term experiment, the authors noted that equol inhibited, in a dose-dependent manner, the simulated solar UV induction of ornithine decarboxylase—a tumor-promotion biomarker enzyme—in the skin.

In an earlier experiment using genistein and its metabolites, UVB-induced hydrogen peroxide production, contact hypersensitivity, and inflammatory edema in hairless mice were mitigated by topically applied equol, isoequol, and dehydroequol, with equol as the most effective (Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 2003;147:137–45; Photochem. Photobiol. 2001;74:465–70).

In two experiments performed in the same laboratory, investigators found that topical genistein confers skin protection from psoralen plus ultraviolet A-induced (PUVA-induced) photodamage. Specifically, SKH-1 female mice were administered genistein in a dimethyl sulfoxide/acetone solution 1 hour post 8-methoxypsoralen dosing and 1 hour before UVA exposure. PUVA-induced skin thickening, erythema, and ulceration were significantly diminished in a dose-dependent fashion (Carcinogenesis 2002;23:317–21).

Recently, the pretreatment of mice with genistein 1 hour before UVB exposure was shown to significantly suppress hydrogen peroxide and malondialdehyde in skin as well as 8-hydroxy-2-deoxyguanosine in the epidermis and internal organs. The authors concluded that genistein can directly scavenge reactive oxygen species spawned by UVB, or indirectly reverse the photoinduced oxidative trends through its anti-inflammatory activity, thus displaying distinct antiphotocarcinogenic characteristics (Cancer Lett. 2002;185:21–9).

In one of the more pivotal animal studies of the chemopreventive effects of the soy isoflavone performed by the same team, investigators showed in a two-stage mouse carcinogenesis model that genistein significantly inhibited skin tumorigenesis initiated by DMBA and promoted by 12-O-tetradecanoylphorbol-13-acetate. In the female SENCAR mice studied, topically applied genistein lowered tumor incidence by 20% and multiplicity by 50% (Carcinogenesis 1998;19:1509–14).

Genistein also consistently and significantly inhibited tissue-plasminogen activator-promoted (TPA-promoted) skin tumorigenesis in two additional promotion studies performed by the same lab on CD-1 and SENCAR mice. In these experiments, tumor multiplicity was markedly reduced, whereas tumor incidence was reduced to a lesser extent.

In the Diet

Dietary administration of genistein has previously been shown to significantly promote antioxidant enzymes in SENCAR mouse skin (Nutr. Cancer 1996;25:1–7). An earlier in vivo study published just over a decade ago demonstrated that genistein strongly inhibits TPA-induced oxidant formation, edema, and polymorphonuclear leukocyte infiltration in a CD-1 mouse skin model (J. Biol. Chem. 1994;269:3529–33).

Oral administration of genistein has also been shown to significantly accelerate catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities in a mouse skin model (Skin Pharmacol. Appl. Skin Physiol. 2001;14:373–85; Nutr. Cancer 1996;25:1–7; Proc. Soc. Exp. Biol. Med. 1995;208:124–30).

Genistein works synergistically with several agents, including the drugs tamoxifen, cisplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea, dexamethasone, daunorubicin, and tiazofurin, as well as bioflavonoid ingredients such as quercetin, green tea catechins, and black tea thearubigins used in food supplements. However, some researchers caution that, given the biphasic bioactivity—inhibiting at high concentrations and sometimes promoting at low ones—of this potent antioxidant, great care must be used to ascertain optimal genistein doses alone or combined with radiation therapy, chemotherapy, and/or immunotherapy (Adv. Exp. Med. Biol. 2004;546:121–65).

It is worth noting, however, that in another recent study, organ cultures of human skin incubated for 8 days with 14-all-trans-retinoic acid exhibited a hyperplastic response, whereas those treated with 14-all-trans-retinoic acid and, subsequently, varying concentrations of soy extract showed dose-dependent reductions in hyperplasia and suppressed proliferation of fast-growing keratinocytes.

The same concentrations of genistein showed the same results as the soy extracts, reducing epidermal hyperplasia and inhibiting keratinocyte proliferation, but they differed in that the genistein treatment affected fibroblast growth (soy extract stimulated proliferation and type I procollagen synthesis). The researchers concluded that combining topical retinoid therapy with soy extract or genistein might prove effective in reducing therapeutic side effects without compromising the intended cutaneous benefits of therapy (Exp. Mol. Pathol. 2004;77:176–83).

A study of the effects of topically applied genistein and daidzein on hyaluronic acid (HA) production in a transformed human keratinocyte culture, as well as on hairless mouse skin in vivo, revealed that both isoflavones effectively enhanced HA production in culture and murine skin. The authors added that these topically applied compounds may prevent or ameliorate the adverse effects that result from HA depletion in skin (Skin Pharmacol. Appl. Skin Physiol. 2002;15:175–83).

At the Store

Genistein is included in dietary supplements, such as those sold under the Nutrilite brand and marketed in the United States, Japan, and Australia.

Of particular interest when considering the hype that often is associated with botanical ingredients are reports that genistein is more bioavailable than green tea polyphenols and curcumin (Am. J. Clin. Nutr. 2005[suppl.];81:284S-91S; Int. J. Cancer 1997;72:860–4; Adv. Exp. Med. Biol. 1998;439:237–48).

Moreover, an in vivo evaluation of the transdermal absorption of daidzein and genistein has revealed that both are captured in the skin, with the excretion rate of the isoflavones in urine and their concentration in plasma significantly reduced after repeated transdermal applications (Pharmazie 2001;56:711–7).

An up-and-coming product is Bifidobacterium-fermented soy milk extract (BE), which contains genistein and daidzein. When it was topically applied for 6 weeks to the skin of mice, elasticity and viscoelasticity were significantly ameliorated, HA content was raised, and the skin was found to be hydrated and thickened. In another experiment by the same researchers, the decrease in skin elasticity was significantly lowered after a gel containing 10% BE was topically applied to the human forearm over a 3-month period (J. Cosmet. Sci. 2004;55:473–9).

Given such results, the authors anticipate the imminent inclusion of BE as a new cosmetic ingredient to boost HA production, thereby protecting the skin against lost elasticity.

Conclusion

The isoflavone genistein has been the subject of keen medical interest, particularly during the past decade. Early indications that this potent phytoestrogen possesses significant anticancer activities have been largely substantiated. Although more research is necessary to ascertain how applications of genistein might be effectively expanded into additional medical subspecialties, the potent antioxidant, supported by a wealth of data, has already begun to carve a niche in the medical armamentarium.

I'd like to see randomized, head-to-head trials between genistein and various therapies, but I think there is already ample reason to expect to see much more of this potent soy isoflavone.

PII: S0037-6337(05)70803-2

doi:10.1016/S0037-6337(05)70803-2

© 2005 Elsevier Inc. All rights reserved.