The ability of the novel water-soluble provitamin E, alpha-tocopherol-6-O-phosphate, to protect against ultraviolet B-induced damage in cultured mouse skin was investigated and compared with the protectiveness of alpha-tocopherol acetate in cultured mouse skin. Pretreatment of skin with 0.5% (9.4 mM) alpha-tocopherol-6-O-phosphate in medium for 3 h significantly prevented such photodamage as sunburn cell formation, DNA degradation, and lipid peroxidation, which were induced in control cultured skin by a single dose of ultraviolet B irradiation at 0 to 40 kJ per m2 (290-380 nm, maximum 312 nm). This protection was greater than that seen with alpha-tocopherol acetate, the most common provitamin E that is used in commercial human skin care products. The concentration of alpha-tocopherol in cultured skin pretreated with 0.5% alpha-tocopherol-6-O-phosphate rose to approximately two to three times that found in the control skin and the reduction in cutaneous alpha-tocopherol that was induced by ultraviolet irradiation was significantly inhibited. In the group pretreated with 0.5% alpha-tocopherol acetate, however, conversion of alpha-tocopherol acetate to alpha-tocopherol was not observed, although the level of provitamin incorporated into the cultured skin was the same as that for alpha-tocopherol-6-O-phosphate. These findings indicated that the enhanced ability of alpha-tocopherol-6-O-phosphate to protect against ultraviolet B-induced skin damage compared with alpha-tocopherol acetate may have been due to alpha-tocopherol-6-O-phosphate's conversion to alpha-tocopherol. Moreover, following pretreatment with a 0.5% alpha-tocopherol-6-O-phosphate, alpha-tocopherol-6-O-phosphate was incorporated into the human skin in a three-dimensional model and 5% of the incorporated alpha-tocopherol-6-O-phosphate was converted to alpha-tocopherol. These results suggest that treatment with the novel provitamin E, alpha-tocopherol-6-O-phosphate may be useful in preventing ultraviolet-induced human skin damage.

Melanin plays an important role in preventing ultraviolet (UV) light-induced skin damage. On the other hand, overexposure to UV radiation can lead to a pathological increase in melanin production. Epidermal hyper-pigmentation results from the increased activity of melanogenic enzymes such as tyrosinase. [1][2][3] Tyrosinase oxidizes the conversion of L-tyrosine to 3,4-dihydroxyphenylalanine (DOPA) and DOPA to DOPA quinone, which are the first two rate limiting steps in the melanin synthesis pathway. 3,4) As such, inhibitors of this enzyme suppress melanogenesis in the epidermal layer of skin, a fact that has led to the development of skin-lightening tyrosinase inhibitors by the cosmetics and pharmaceutical companies.4-7) While several melanin-inducing compounds have also been investigated for their possible use as UV protectants, few have actually reached the consumer market because of safety concerns.Data suggest that in addition to tyrosinase, factors released by keratinocytes and/or melanocytes stimulate melanin production by melanocytes. These factors include histamine, 8) a-MSH (melanocyte-stimulating hormone), 9) ET-1 (Endothelin-1), 10) and PGE2 (Prostaglandin E2), 11) which have all been reported to enhance melanin production in response to UV radiation. Nitric oxide (NO) was also suggested to influence skin pigmentation. 12)Tocopherol has four homologs i.e., a, b, g and d which differ in the number and position of methyl groups in their chroman ring. a-Toc is a well known scavenger of reactive oxygen species (ROS) such as hydroxyradical.13) a-tocopherol (a-Toc) was reported to be an effective treatment for facial hyperpigmentation.14,15) More recently, g-Toc and its metabolite g-carboxyethyl hydroxychroman (g-CEHC) were found to be natriuretic factors, [16][17][18] to inhibit prostate cancer cell proliferation [19][20][21][22] and the activity of the proinflammatory enzyme cyclooxygenase-2, [23][24][25] and to scavenge peroxyl radicals and peroxynitrite.26-28) g-Toc was also found to suppress the expression of tyrosinase and tyrosinase related protein-2 in B16 melanoma cells. 29)g-Toc is nearly insoluble in water and is readily oxidized by atmospheric oxygen. The phenolic functional group in gToc is easily esterified and some of its ester derivatives have shown improved water-solubility and resistance to oxidation. Tocopheryl-dimethyl-glycinate (TDMG) is a novel Toc derivative developed by Takata et al. 30) in which dimethylglycine is ester-linked to the sixth position of the chromanoxyl ring of Toc. We previously reported that the chromanoxyl ring of g-TDMG scavenges ROS generated by ultraviolet rays and that it exhibited greater bioavailability than g-Toc in mouse skin. 31)In this study, we examined whether the topical application of g-TDMG could reduce UV-induced hyper-pigmentation of the skin. We also examined its mechanism of action and compared it to that of the fungal metabolic product kojic acid, which is a skin-lightening agent. MATERIALS AND METHODSChemicals g-TDMG and g-Toc were kindly supp...

We investigated whether the topical application of a novel, water-soluble gamma-tocopherol (gamma-Toc) derivative, gamma-tocopherol-N,N-dimethylglycinate hydrochloride (gamma-TDMG), could protect against UV-induced skin damage in hairless mice. Topical pre- or post-application of a 5% (93 mM) gamma-TDMG solution in water/propylene glycol/ethanol (2:1:2) significantly prevented sunburn cell formation, lipid peroxidation and edema/inflammation that were induced by exposure to a single dose of UV irradiation of 5 kJ/m2 (290-380 nm, maximum 312 nm). This effect was greater than that seen with two alpha-Toc derivatives, alpha-tocopherol acetate (alpha-TA) and alpha-tocopherol-N,N-dimethylglycinate (alpha-TDMG). When a 5% solution of gamma-TDMG was applied to mouse skin for 1 h, cutaneous gamma-Toc increased by 25-fold after 24 h; levels of cutaneous alpha-Toc increased by only two- and eight-fold in alpha-TDMG and alpha-TA treated skins, respectively. These findings indicated that gamma-TDMG immediately converted to gamma-Toc in the skin and suggest that ability of gamma-TDMG to protect the skin from the damaging effects of irradiation was due to its conversion to gamma-Toc. When a 5% solution of gamma-Toc was applied to mouse skin for 1 h, cutaneous gamma-Toc rapidly increased by 25-fold, but fell to baseline levels by 24 h. In contrast, the concentration of gamma-Toc in skin that was treated with gamma-TDMG similarly increased, but these high levels were maintained after 24 h. These results suggest that gamma-TDMG may be a more effective source of gamma-Toc in skin. Thus, the topical application of gamma-TDMG may be efficacious for the prevention of UV-B-induced skin damage.

We investigated whether the topical application of a novel, water-soluble gamma-tocopherol (gamma-Toc) derivative, gamma-tocopherol-N,N-dimethylglycinate hydrochloride (gamma-TDMG), could protect against UV-induced skin damage in hairless mice. Topical pre- or post-application of a 5% (93 mM) gamma-TDMG solution in water/propylene glycol/ethanol (2:1:2) significantly prevented sunburn cell formation, lipid peroxidation and edema/inflammation that were induced by exposure to a single dose of UV irradiation of 5 kJ/m2 (290-380 nm, maximum 312 nm). This effect was greater than that seen with two alpha-Toc derivatives, alpha-tocopherol acetate (alpha-TA) and alpha-tocopherol-N,N-dimethylglycinate (alpha-TDMG). When a 5% solution of gamma-TDMG was applied to mouse skin for 1 h, cutaneous gamma-Toc increased by 25-fold after 24 h; levels of cutaneous alpha-Toc increased by only two- and eight-fold in alpha-TDMG and alpha-TA treated skins, respectively. These findings indicated that gamma-TDMG immediately converted to gamma-Toc in the skin and suggest that ability of gamma-TDMG to protect the skin from the damaging effects of irradiation was due to its conversion to gamma-Toc. When a 5% solution of gamma-Toc was applied to mouse skin for 1 h, cutaneous gamma-Toc rapidly increased by 25-fold, but fell to baseline levels by 24 h. In contrast, the concentration of gamma-Toc in skin that was treated with gamma-TDMG similarly increased, but these high levels were maintained after 24 h. These results suggest that gamma-TDMG may be a more effective source of gamma-Toc in skin. Thus, the topical application of gamma-TDMG may be efficacious for the prevention of UV-B-induced skin damage.

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