Isoflavonoid Photoprotection in Mouse and Human Skin Is Dependent on Metallothionein

Abstract

Previous studies report that selected topical isoflavonoids are immunoprotective in both mice and humans, when applied following UV irradiation. Isoflavonoids have documented antioxidant activity, but their mechanism of immunomodulation remains unclear. This study examines whether photoimmunoprotection by the isoflavonoids might result from their interaction with one cutaneous antioxidant known to modulate UV photodamage, metallothionein (MT). In mice bearing a null mutation for MT-I and -II, we found that immunoprotection by the isoflavonoid 4',7-dihydroxyisoflavane (equol) against solar-simulated UV radiation (SSUV) or exogenous cis-urocanic acid was abrogated. Topical equol did not activate MT expression in normal mouse skin, but markedly enhanced the increase in MT expression in murine epidermis following SSUV irradiation. Normal human skin, unlike murine, expressed MT in the basal epidermis. Following SSUV irradiation, topical application of the related synthetic isoflavonoid NV-07alpha to human skin also markedly enhanced epidermal MT expression. The NV-07alpha has been reported previously to protect humans against the UV suppression of Mantoux reactions. Thus, epidermal MT expression appears to protect against photoimmunosuppression in both human and mouse skin. We speculate that equol and its related derivative NV-07alpha may activate the MT gene synergistically with SSUV, to produce the enhanced immunoprotective effect.

Estrogen receptor signaling protects against immune suppression by UV radiation exposure

“…However, cutaneous MT might have such a role, being a recognized antioxidant and a photoimmune protectant in both mice and humans, as well as a readily inducible factor by topical equol treatment in SSUVirradiated normal-haired mouse skin (9,10). There is now evidence from cultured human tumor cell lines that the MT gene is regulated by the ER (17) and that the zinc-finger domain of the ER is supplied with zinc by MT (18), demonstrating an intimate intracellular relationship between MT and estrogenic activity.…”

“…Oxidative radical scavenging by equol has been reported in numerous systems (6)(7)(8). Furthermore, both equol and NV-07␣ have the capacity to stimulate the solar-simulated UV radiation (SSUV) induction of metallothionein (MT) in the skin (9). In addition to its capacity for metal ion chelation, MT is one of the endogenous cutaneous antioxidants that have been identified as relevant for protection against oxidative photodamage (10).…”

Topical ‘Sydney’ Propolis Protects against UV-Radiation-Induced Inflammation, Lipid Peroxidation and Immune Suppression in Mouse Skin

“…The response of the skin to overexposure to UV radiation comprises inflammation, observed as the erythema and oedema of the sunburn reaction, the suppression of T-cell-mediated immune function both locally in the irradiated skin and systemically, the increased lipid peroxidation of cell membranes, and the depletion of the endogenous cutaneous antioxidants such as metallothionein, glutathione and the glutathione peroxidases and reductases [1,2,3,4]. Development of oxidative stress then stimulates the induction of a further redox-regulated stress enzyme, haem oxygenase-1, which plays an important protective role against immune suppression [5].…”

Equol’s Anti-Aging Effects Protect against Environmental Assaults by Increasing Skin Antioxidant Defense and ECM Proteins While Decreasing Oxidative Stress and Inflammation

“…Additionally, equol has been shown to stimulate the gene expression of the SH-rich detoxifying proteins, like metallothionein-1H and metallothionein-2H, that protect against metal toxicity [85,94]. Finally, Widyarini et al have shown that equol's photo-protective effect in mouse and human skin is dependent on metallothionein [96].…”