Isoflavonoid Compounds from Red Clover (Trifolium pratense) Protect from Inflammation and Immune Suppression Induced by UV Radiation¶

Abstract

Isoflavones derived from many edible plants have been reported to possess significant antioxidant, estrogenic and tyrosine kinase inhibitory activity. Genistein has been found previously to provide protection from oxidative damage induced by UV radiation both in vitro and following dietary administration. We have therefore examined the potential of a number of isoflavones from red clover (Trifolium pratense) and some metabolically related compounds to offer protection from UV irradiation in hairless mice by topical application after UV exposure. We show that whereas the primary isoflavones, daidzein, biochanin A and formononetin, were inactive, 20 microM lotions of genistein and the metabolites equol, isoequol and the related derivative dehydroequol had powerful potential to reduce the inflammatory edema reaction and the suppression of contact hypersensitivity induced by moderate doses of solar-simulated UV radiation. For equol the protection was concentration dependent and 5 microM equol markedly reduced the UV-induced inflammation but abrogated the UV-induced immunosuppression. Equol protected similarly from immunosuppression induced by the putative epidermal mediator, cis-urocanic acid (UCA), indicating a potential mechanism of action involving inactivation of this UV-photoproduct. Since immunosuppression induced by both UV radiation and by cis-UCA appears to be an oxidant-dependent response our observations support the actions of these topically applied isoflavones and their metabolites as antioxidants. They also indicate that lotions containing equol, unlike topical UV sunscreens, more readily protect the immune system from photosuppression than from the inflammation of the sunburn reaction, even when applied after exposure, and thus such compounds may have a future role as sun-protective cosmetic ingredients.

Flavonoids as Anti-Inflammatory and Analgesic Drugs: Mechanisms of Action and Perspectives in the Development of Pharmaceutical Forms

“…Studies have shown that topically applied isoflavones and their metabolites may offer protection from UV-induced inflammation and immunosuppression [191]. The topical administration may also be a suitable route for soy isoflavones to obtain systemic bioavailability because of their rapid clearance from the plasma [192].…”

“…Studies that have focused on equol ([S]-4 0 ,7-dihydroxyisoflavane) because it was shown that its contribution to the protection against solar-simulated UVR-induced erythemal-associated edema and immunosuppression [190] showed a potential role in the prevention of human skin cancer [190] by acting as a sunscreen and, thus, inhibiting DNA photodamage [191] when topically applied as a lotion.…”

Estrogen receptor signaling protects against immune suppression by UV radiation exposure

“…Consistent with this observation, it was found that topical application to humans of an equol-related synthetic isoflavonoid, NV-07␣, also protected against the UV radiation-induced suppression of the elicited Mantoux reaction (2). In mice it was shown that the immunoprotective mechanism of topically applied equol involved inactivation of the downstream actions of cis-urocanic acid, a major UV-induced immunosuppressive photoproduct produced in the skin (1). Because chronic photoimmune suppression is a prerequisite for the promotion of UV radiation-initiated tumors (3), and because topically applied equol was also demonstrated to have antiphotocarcinogenic properties in mice (4), the photoprotective effects of equol offer the opportunity to identify critical pathways linking the UV-induced immune defect with the development of skin cancer.…”

MLK3 is a direct target of biochanin A, which plays a role in solar UV-induced COX-2 expression in human keratinocytes

“…Although many groups have demonstrated the beneficial effects of biochanin A, including an anti-proliferation effect on squamous cell carcinoma [41], anti-inflammatory, immune suppressive [42], and LDL cholesterol-lowering effects [43], the direct mechanisms of action of biochanin A are not fully understood. Several proteins and signaling pathways have been suggested to mediate the mechanism of biochanin A's actions.…”