Ascorbyl-6-palmitate is not ascorbic acid.

The skin protects itself from oxidative stress, generated by sunlight and pollution, with enzymic and nonenzymic antioxidants. The major nonenzymic antioxidants include L-ascorbic acid, glutathione, a-tocopherol, and ubiquinone/ubiquinol. Lascorbic acid protects the aqueous space and is the most plentiful antioxidant in skin. Glutathione protects the intracellular £uid space. a-Tocopherol and, to a lesser extent, ubiquinone/ubiquinol protect lipid membranes. The nonenzymic antioxidants work together in tissue like a symphony (Podda and GrundmannKollmann, 2001).When a reactive oxygen species attacks a membrane structure, it can be reduced by tocopherol, which in turn can be regenerated by ubiquinol or ascorbic acid. Reduced ascorbic acid can be regenerated by glutathione, which in turn can be reduced by the NADPH pool. By applying ascorbic acid and a-tocopherol topically to skin, it has been possible to bypass limiting mechanisms for systemic tissue distribution and, in eiect, increase the reservoir of antioxidants in skin. By increasing skin L-ascorbic acid (Darr et al, 1992) and a-tocopherol (Burke et al, 2000) stores, added photoprotective eiects can be achieved. Antioxidants are inherently unstable molecules. In order to produce more stable molecules, antioxidants such as ascorbic acid and a-tocopherol are commonly esteri¢ed at their active site. When they are administered orally, the esters are hydrolyzed in the stomach and the now active antioxidants are distributed to tissue stores. Esters are commonly used in antioxidant products for topical application to skin because they are more stable. It is hypothesized that these esters will be converted in skin by esterases to active antioxidant. Studies show, however, that this conversion is not e⁄cient for esters of ascorbic acid (Pinnell et al, 2001) or of a-tocopherol (Alberts et al, 1996). Despite creative labeling and advertising, these derivatives are not very eiective when applied topically to skin. In this issue of the journal, Meves et al report that ascorbyl-6palmitate, in comparison to L-ascorbic acid, is toxic to keratinocytes in the presence of ultraviolet B. Ascorbyl-6-palmitate is different from most esters of antioxidants. Instead of esterifying the essential active-center hydroxyl groups at position C3,4, esteri¢cation occurs at C6.The ester itself is active as an antioxidant, and because of its hydrophobic palmitate side chain the molecule positions itself into cell membranes. It is not entirely clear how ascorbyl-6-palmitate is toxic to cells. Ultraviolet B irradiation generates oxidative stress. In the cell membrane, ascorbyl-6-palmitate may be oxidized, generating the corresponding ascorbyl free radical. In the aqueous phase, ascorbyl free radical is relatively weak as a free radical and would be readily reduced by other aqueous phase antioxidants. In the membrane, however, it may cause irreversible damage before it is reduced. Damage to membranes is a serious cellular event and may lead to apoptotic or direct cell death. Alternatively, the active center of ascorbic acid, the 3-4 enediol, can participate in the Fenton reaction in the presence of free copper or iron, with the generation of highly reactive hydroxyl radical (Darr and Fridovich, 1994). This rarely occurs in the body because copper and iron are tightly bound by chelating proteins. Any leakage that would take place in an aqueous environment would probably be reduced by soluble enzymic or nonenzymic antioxidants. If ultraviolet B, however, released free iron or copper in the vicinity of ascorbyl-6-palmitate in a cell membrane, generation of hydroxyl ion could produce damage at the site where it was generated, destroying the membrane and the cell. It is clear from the study reported by Meves et al that ascorbyl6-palmitate is not ascorbic acid. If applied to the surface of skin, its lipid nature may allow it to penetrate the stratum corneum. The stratum corneum is the outermost defense against free radical damage. It has its own antioxidant barrier provided by a-tocopherol delivered in sebum (Thiele, 2001).Would ascorbyl-6-palmitate interfere with this antioxidant defense and disrupt the lipid barrier or could it penetrate deeper and harm cellular layers of skin? Only additional in vivo studies will allow us to assess its potential harm to skin.