A novel butyrate derivative, zinc dibutyroyllysinate, blunts MITF expression and up-regulates retinol and differentiation pathway mRNAs in a full-thickness human skin model

Lysine, butyric acid and zinc play important roles in skin homeostasis that involve aging, inflam-mation and prevention of skin barrier disruption. This bioactivity spectrum is not replicated by any one topical compound currently in use. Our purpose in this study was to characterize a novel compound, zinc dibutyroyllysinate (ZDL), consisting of zinc with lysine and butyric acid moieties. We used RNA-seq to evaluate its effect on gene expression in a full-thickness skin model. We show that lysine alone has minimal effects on gene expression, whereas ZDL had greater transcriptional bioactivity. Effects of ZDL included increased expression of genes promoting epidermal differenti-ation and retinol metabolism, along with decreased expression of microphthalmia-associated transcription factor (MITF) and other melanogenesis genes. These effects were not replicated by an alternative salt compound (i.e., calcium dibutyroyllysinate). ZDL additionally led to a dose-dependent increase of extracellular matrix proteins in skin fibroblasts, including collagen I, collagen IV and prolidase. Loss of melanin secretion was also seen in ZDL-treated melanocytes. These results provide an initial characterization of ZDL as a novel topical agent. Our findings support a rationale for development of ZDL as a skincare ingredient, with potential applications for diverse conditions involving melanocyte hyperactivity, pigmentation, inflammation, or aging.