RWJ-50353, a serine protease inhibitor that reduced melanosome uptake in culture, is shown to have a dose-dependent depigmenting activity in vivo with no irritation or other side effects. Treatment with increasing concentrations of RWJ-50353 did not affect tyrosinase mRNA levels. Interestingly, this treatment led to decreased levels of TRP-1 and increased levels of TRP-2 mRNAs (49). The downregulation of TRP-1 by RWJ-50353 should lead to reduced tyrosinase activity and reduced pigment production.
RWJ-50353 inhibits melanosome transfer from melanocytes to keratinocytes by its inhibitory effect on the keratinocyte PAR-2 signaling pathway. RWJ-50353-treated keratinocytes are unable to actively take or receive melanosomes from the presenting dendrites. Electron microscopy studies illustrated an accumulation of immature
melanosomes inside melanocytes and abnormal dendrite dynamics in RWJ-50353-treated epidermal equivalents.
In vivo RWJ-50353 (up to 10mM, twice-daily treatment to swine skin) could not completely inhibit melanogenesis or pigment transfer, and the transferred melanosomes are of poor quality (50). Treatment of dark skinned Yucatan swine for eight weeks with RWJ-50353 induced visible skin lightening. Histological analysis of treated sites at eight weeks shown only minimally stained melanin granules dispersed in the basal layer of epidermis (50).