Abstract
Previous studies have reported that estrogen hormone promotes melanogenesis while progesterone inhibits it. A selective estrogen receptor modulator (SERM), tamoxifen, has been shown to promote melanogenesis; however, to date, there have been no reports on the effects of a selective progesterone receptor modulator (SPRM) on melanogenesis. In the present study, we hypothesized that asoprisnil (AP), a SPRM, inhibits melanogenesis. AP was tested for cytotoxicity to B16F10 mouse melanoma cells for screening the nontoxic concentrations using MTS cytotoxicity assay. Extracellular and intracellular melanin levels were estimated at nontoxic concentrations of AP. To evaluate the direct effect of AP on tyrosinase enzyme, tyrosinase activity and copper chelating activities were measured. Next, the effects of AP on melanogenesis were tested in normal human melanocytes, neonatal, darkly pigmented (HEMn-DP). Our results demonstrate that AP was nontoxic at a concentration range of 10–50 μM in B16F10 cells; AP at 50 μM significantly suppressed extracellular melanin levels comparable to kojic acid at 500 μM, with no significant effect on intracellular melanin levels. The mechanism of melanogenesis inhibition was studied to assess if AP downregulated tyrosinase activity in cell lysates or in a cell-free system. However, AP was found to increase intracellular tyrosinase activity without any effect on tyrosinase enzyme activity or copper chelating activity in a cell-free system, indicating that AP inhibits melanogenesis by mechanisms other than direct effects on tyrosinase enzyme activity. The capacity of AP to inhibit melanosome export was further validated in HEMn-DP cells; AP significantly suppressed dendricity at concentrations of 20 and 30 μM in the absence of effects on melanin synthesis or intracellular tyrosinase activity. In addition, AP was nontoxic to human keratinocytes (HaCaT) at these concentrations, validating its safety for topical use. Taken together, our preliminary results demonstrate that AP might be repurposed as a candidate therapeutic for treatment of hyperpigmentation disorders via a unique mechanism, which encompasses a selective inhibition of melanosome export.
Highlights
Melanin pigment is synthesized in melanocytes located in the basal layers of the epidermis and is exported via dendrites to keratinocytes where it accumulates perinuclearly and causes skin coloration
Our results demonstrate that the selective progesterone receptor modulator (SPRM) AP demonstrates the capacity to inhibit melanogenesis by selectively inhibiting one or more subsequent steps of melanosome export in the absence of the effect on melanin biosynthesis in both B16F10 mouse melanoma cells and primary human melanocytes
The possibility that SPRMs such as AP might function by the non-classical pathway not involving progesterone receptor (PR) binding cannot be ruled out, and future studies to assay for changes in the transcription level of genes involved in melanogenesis are warranted
Summary
Melanin pigment is synthesized in melanocytes located in the basal layers of the epidermis and is exported via dendrites to keratinocytes where it accumulates perinuclearly and causes skin coloration. The most popular skin-depigmenting compounds are tyrosinase inhibitors such as hydroquinone and kojic acid (KA), which exhibit serious side effects; KA causes contact allergy [5] and tumorigenesis [6], while hydroquinone exhibits carcinogenicity [7] Due to these limitations, there is an active interest in the search for novel compounds for the reduction in skin pigmentation that do not exhibit adverse effects and that have a relatively safe profile. As several of the skin-whitening compounds are tyrosinase inhibitors, alternative targets to inhibit melanogenesis have been actively researched Some of these are directed to later steps in the melanogenesis cascade, such as the export of melanin pigment via dendrites, as after synthesis in the cells, melanin is secreted by melanocytes and taken up by keratinocytes via various pathways [8,9]. Dendrites are actin and microtubule-containing structural features of melanocytes and are key conduits of the export of melanin pigment to keratinocytes [10]; compounds that can promote or inhibit dendricity can be used to control pigmentation disorders
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