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Human sebaceous cells, isolated from adult human skin, were cultured on either bovine type I collagen or mitomycin-C-treated 3T3 fibroblasts. Sebaceous cells, termed "sebocytes", were determined to be epithelial in nature by positive staining with monoclonal antikeratin antibodies BG2 and BG12. However, sebocyte colonies were also negative for keratins found in differentiated cells of keratinocyte colonies, as defined by monoclonal antikeratin antibodies CC2 and CC6. Sebocytes did not produce cornified envelopes in vitro and could only be induced to produce small quantities (less than 5%) of envelopes with a calcium ionophore. Sebocyte growth characteristics in a variety of serum, dexamethasone, and hydrocortisone combinations were significantly different from those of human facial keratinocytes. Sebocytes also displayed a growth curve and plating efficiency that were different from those of keratinocytes. Large lipid droplets within growing sebocytes could be visualized with oil red o staining. Additionally, squalene and wax/cholesterol esters were made by sebocytes in vitro in greater amounts than by facial keratinocytes, as determined by thin-layer chromatography of organic extracts of 3H2O-labeled sebocytes. Sebocytes synthesized greater quantities of lipid, on a per-cell and protein basis, than did keratinocytes.

A conformationally defined retinoic acid analog (1) which contains a dimethylene bridge to maintain the 6-s-trans orientation for two terminal double bonds in the polyene chain was synthesized. A Reformatsky reaction was utilized to extend the polyene chain of the starting enone, which provided exclusively the 9Z-configuration for the intermediate aldehyde. A Horners-Emmons condensation with this aldehyde then produced retinoic acid analogs with both 9Z- and 9Z,13Z-configurations. An I2-catalyzed isomerization of the intermediate 9Z-aldehyde yielded the all-E-aldehyde, which was olefinated as above to yield the (all-E)- and (13Z)-retinoic acid analogs of 1. Each configurational isomer of 1 was evaluated for its ability to inhibit the binding of retinoic acid to CRABP (chick skin) and to inhibit the chemical induction of ornithine decarboxylase in mouse skin. In each assay (all-E)-1 was the most active isomer, and this activity was comparable to or better than that for (all-E)-retinoic acid. (all-E)-1 and (13Z)-1 were both shown to be equally effective as (13Z)-retinoic acid in suppressing the proliferation of human sebaceous cells in vitro. (all-E)-1 was further evaluated for its ability to prevent the induction of mouse skin papillomas and to induce signs of vitamin A toxicity in mice. The cancer chemopreventive activity of (all-E)-1 was comparable to that of (all-E)-retinoic acid, and the toxicity was comparable to or slightly better than that of the natural vitamin.

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