PROCESSING OF EPIDERMAL GLUCOSYLCERAMIDES IS REQUIRED FOR OPTIMAL MAMMALIAN CUTANEOUS PERMEABILITY BARRIER FUNCTION

The interstices of the mammalian stratum corneum contain lipids in a s ystem of continuous membrane bilayers critical for the epidermal perme ability barrier. During the transition from inner to outer stratum cor neum, the content of polar lipids, including glucosylceramides, decrea ses while ceramide content increases. We investigated whether inhibiti on of glucosylceramide hydrolysis would alter epidermal permeability b arrier function. Daily topical applications of bromoconduritol B epoxi de (BrCBE) to intact murine skin selectively inhibited beta-glucocereb rosidase, increased glucosylceramide content of stratum corneum with c eramide content remaining largely unchanged, and caused a progressive, reversible decrease in barrier function. Histochemistry of inhibitor- treated epidermis revealed persistence of periodic acid-Schiff-positiv e staining in stratum corneum cell membranes, consistent with retentio n of hexose moieties. Electron microscopy of inhibitor-treated samples revealed no evidence of toxicity or changes in the epidermal lipid de livery system. However, immature membrane structures persisted in the intercellular spaces throughout the stratum corneum, with reappearance of mature membrane structures progressing outward from the lower stra tum corneum upon termination of BrCBE. Finally, the induced barrier ab normality was not reversed by coapplications of ceramide. These data d emonstrate that glucosylceramide hydrolysis is important in the format ion of the epidermal permeability barrier, and suggest that accumulati on of glucosylceramides in stratum corneum intercellular membrane doma ins leads to abnormal barrier function.