Comparative Histologic Effects of Daily Topical Application of Creams Containing All-trans-Retinoic Acid or All-trans-Retinoyl β-Glucuronide on Pig Skin

Abstract

The efficacy of all-trans-retinoic acid (tRA) and all-trans-retinoyl β-glucuronide (RAG), a water-soluble metabolite of vitamin A, in the topical treatment of acne is comparable. However, whereas 3.3 mM tRA shows side effects, 3.3 mM RAG does not. To assess the relative toxic and histologic effects (dermal and epidermal changes) of long-term (24-week) daily applications of tRA and RAG on the skin, separate skin patches were measured and marked dorsally on the skin of six 21-day-old, castrated male pigs. Each skin patch area was treated daily with a cream formulation containing either 3.3 mM RAG, 16.5 mM RAG, 33 mM RAG, 3.3 mM tRA, 16.5 mM tRA or blank cream. To serve as controls, one patch received no treatment, one patch received blank cream only and for 5.3 weeks one ‘washed’ patch was given daily application of 33 mM RAG with routine cleansing using a mild soap typical of skin care. The amount of cream used per square centimeter remained the same during the course of the study. Biopsy tissue was collected at –1, 0, 2, 4, 8, 12 and 24 weeks from 7 test patches. The ‘washed’ patch was biopsied once at the 5.3-week mark. Topically applied RAG cream (3.3 mM) resulted in significantly lower histologic scores when compared with scores from tissue treated with an equimolar concentration of tRA. The highest concentration of RAG tested (33.3 mM) resulted in a response comparable to that observed in the lowest tRA (3.3 mM) treated patch area. Daily cleansing of the test area receiving 33.3 mM RAG completely eliminated any clinical signs or negative histologic changes. In conclusion, long-term topical tRA treatment in young pigs, as in humans, showed dose-dependent adverse effects on the skin, whereas RAG treatment had significantly lower histologic changes and less irritation and/or inflammation.