SKIN DELIVERY OF VITAMIN E 253 stemming from one primary process, lipid peroxidation (11). Figure 4 contains the oxidation products of tx-tocopherol. tx-Tocopherol loses hydrogen with its electrons from the hydroxyl group at the 6-po- sition in the chromanol nucleus to give the radical. It is further oxidized to a quinone, which is devoid of antioxidant activity. The chroman group is important not only for the antioxidant activity of vitamin E, but it also imparts lipophilic properties. The phytyl chain, on the other hand, has no effect on the chemical reactivity of vitamin E antioxi- dants but, due to its highly lipophilic nature, is important for proper positioning within biomembranes. The flexible phytyl chain is thought to be rotated or bent to pack closely with the phospholipid acyl chains (4). Further structural requirements for a good chain- breaking tocopherol analog for in vivo autooxidation are summarized in other reviews (12-15). REGENERATION OF a-TOCOPHEROL ot-Tocopherol is the vitamin E homologue with the highest in vivo biological activity and is the major lipophilic antioxidant in many biological systems (16). The skin's antioxi- dants are interlinked in a network system. It has been demonstrated using pulse radi- olysis experiments that ascorbate can regenerate ot-tocopherol from the tocopheroxyl radical (17) and that such regeneration may occur in the skin (18). The resulting ascorbyl radical itself can be converted to the ascorbate by reduced glutathione (GSH) (19). This is illustrated in Figure 5. Vitamin E acts in concert with antioxidant enzymes such as Me HO•O • Me •C 16H33 I Me Me -w Me Me •C16H33 I Me Me Alpha-Tocopherol Alpha-Tocopherol radical Me HO• + 2H_ •C 16H33 •' 2H Me" T 'OHoHMe Me O ••C16H33 Me' • •'O olI_•Me Me Alpha-Tocopheryl hydroquinone Alpha-Tocopheryl quinone Figure 4. Oxidation products of o•-tocopherol. Adapted from reference 1.

254 JOURNAL OF COSMETIC SCIENCE LO0' • Vitamin E•.X//• GS' •GSSG NADPH • '•' Vitarnin C' •+H + LOOH Vitamin E'[• •Vitamin C, GSH NADP + F{gure 5. Regeneration ooe vitarn{n E oerom (x-chromanoxy] radical Dy g]urarh]one and vitamin C. _Adapted from reference 1. glutathione peroxidase, catalase, and superoxide dismutase, as well as with smaller molecules with antioxidant properties such as ascorbic acid, glutathione, and uric acid. Direct depletion of o•-tocopherol and formation of its radical would thus affect other endogenous antioxidant pools as well. MOLECULAR MODEL OF MEMBRANE STABILIZATION BY VITAMIN E Diplock and Lucy (20) have used molecular model building to hypothesize that vitamin E may stabilize membrane structure by virtue of a specific physicochemical interaction between its phytyl side-chain and the fatty acyl chains ofpolyunsaturated phospholipids, particularly those derived from arachidonic acid. Significant interactions of o•-tocopherol with unsaturated fatty acids occur less frequently when the acyl chains of the latter are curved than when they are straight. These authors have also proposed interactions between the methyl groups of the phytyl chain of o•-tocopherol and the cis double bond of arachidonyl residues of membrane phospholipids. Thus the methyl group at C4' of o•-tocopherol can fit into a pocket provided by the cis double bond nearest the carboxyl group. The methyl group at C8' then interacts with the third cis double bond. In this "complex," the hydroxyl group of the chromanol ring of o•-tocopherol and the polar groups of the phospholipids lie together at one end, where they would be expected to participate in polar interactions at the surface of any region of membrane having a lipid bilayer structure. The fit of the methyl groups in the pockets created by the cis double bonds permits the methylene groups in the backbones of both the phytyl and fatty acyl chains to associate closely, further promoting the stability of the complex through London-Van der Waals dispersion-attraction forces. Complex formation could have the following functional consequences: (a) an inhibition of the oxidative destruction of polyunsaturated fatty acids in cells and in cellular membranes, (b) a reduction in the permeability of biological membranes, containing relatively high levels of polyunsatu- rated fatty acids, particularly arachidonic acid, and (c) the prevention of the degradation of membrane phospholipids in vivo by membrane-bound phospholipases (21-23). Simu- lation modeling, which allows calculation of lipid peroxidation indices that describe the antioxidant protection against oxidation, is available (24). Figure 6 gives a diagrammatic representation of the proposed interaction of vitamin E and polyunsaturated phospho- lipids in a biological membrane. Urano et al. (25) using •9F NMR and fluorescence polarization techniques have summarized the molecular orientation of vitamin E in liposomal membranes. They found that the chromanol moiety of o•-tocopherol was tightly adapted to the space close to the surface of membranes formed by the unsaturated fatty acid molecules in phophatidyl choline, the phytyl chain had significant motional freedom for the maintenance of a physiological fluidity, and the hydroxyl group of