protein binding can determine the ability of a cell to take up retinoids has been considered. (The influence of protein binding on metabolism is discussed later.)
Hodam and Creek (15) studied the uptake of retinol, either free (in ethanol) or bound to RBP, in cultured human keratinocytes. Utilizing radiolabeled compounds, they demonstrated that the retinol uptake was much greater in the free than in the bound form. Free retinol added to the culture medium had a maximum uptake of 35% of the applied dose within 3 h of incubation, falling to 20% by 12 h. In contrast, RBP retinol had a peak uptake of 7.5% of the applied dose, detected at 24 h. Therefore, keratinocytes demonstrated a much slower uptake of RBP retinol compared to free retinol.
The metabolism of vitamin A and its derivatives in the skin is considered important to the understanding of their pharmacological effect. It has been hypothesized that the effects of ROL and RAL may result from their cutaneous metabolism to RA. While some investigators have shown that this metabolism may occur, pharmacological effects have also been seen in the absence of measurable RA. This section discusses the evidence that RA is an essential metabolite in the activity of ROL and RAL.
In vitro, metabolism of ROL, RAL, and RA was studied utilizing human skin and dermal fibroblasts (16). Radiolabeled ROL, RAL, and RA were applied either topically to the skin biopsies or to the culture media of the fibroblast suspensions and the metabolites were identified by HPLC after 24 h of incubation. The skin cultures demonstrated a gradient distribution of the retinoids within the skin: 75% of absorbed activity was in the epidermis, 20% in the dermis, and 2 to 6% in the culture medium for the three retinoids tested. Of the epidermal extracts, 60% of applied ROL remained unmetabolized. The main ROL metabolites in the epidermis were retinyl esters (18.5%), a finding that has also been demonstrated in keratinocyte cultures. RA (2%), RAL (1.6%), 13-cis-retinoic acid (1%), and polar compounds were also found. The dermis yielded similar metabolites, but a higher proportion of polar compounds.
RAL was also metabolized in the epidermis: 43% of the absorbed radioactivity was RAL, 9% retinyl esters, 14% ROL, and 0.8% RA. When RA itself was applied, 66% of the epidermal radioactivity was from RA, 17% from 13-cis-RA, and 10% from polar compounds. RA was not metabolized to ROL or RAL. -g
Dermal fibroblasts also metabolized ROL, RAL, and RA in culture medium, 1
but the significance of this in vivo is not yet clear. It is possible that these cells may contribute to the role of the dermis in the kinetics and dynamics of these substances.
These skin studies demonstrate the capacity for topical ROL, RAL, and 4
RA to penetrate the skin in a gradient manner from the epidermis to the dermis.
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