Retinoid-induced epidermal hyperplasia in human skin organ culture: inhibition with soy extract and soy isoflavones

Organ cultures of human skin were incubated for 8 days with 1 microg/ml 14-all trans retinoic acid (14-all trans RA) and concomitantly treated with varying concentrations of soy extract. The epidermis of organ cultures treated with 14-all trans RA alone underwent a hyperplastic response. In cultures treated with a combination of 14-all trans RA and soy extract (4-40 microg/ml), hyperplasia was reduced by 16-41%. The same concentrations of soy extract that reduced epidermal hyperplasia in organ culture also suppressed proliferation of rapidly growing keratinocytes in monolayer culture (approximately 25% reduction at 20 and 40 microg/ml). On the other hand, soy extract did not further inhibit proliferation of quiescent keratinocytes; rather, it stimulated growth (50-52% increase relative to control). When dermal fibroblasts were examined for a response to soy extract (i.e., proliferation and synthesis of type I procollagen), both responses were stimulated (proliferation: 75% increase and collagen production 114% increase relative to control). Genistein, the major isoflavone in extracts of soy also inhibited epidermal hyperplasia in organ culture (34-40% reduction relative to control). The same concentrations that reduced epidermal hyperplasia (0.5-1.0 microg/ml) also inhibited keratinocyte proliferation in monolayer culture but had little effect on fibroblast growth. Two other isoflavones (daidzein and glycetein) were also inhibitory, but were less effective than genistein. Taken together, these data suggest that use of soy extract or its constituent isoflavones in conjunction with 14-all trans RA may provide a way to mitigate unwanted epidermal effects of topical retinoid therapy without compromising beneficial retinoid effects in the dermis.