Effect of Genetic Polymorphisms of Human SLC22A3 in the 5′-flanking Region on OCT3 Expression and Sebum Levels in Human Skin

Background: Human organic cation transporter 3 (OCT3,SLC22A3) mediates the uptake of many important endogenous substances and basic drugs, and has been identified as one of the transporters that are highly expressed in human skin. However, the mechanisms responsible for variability in mRNA expression, and the role of SLC22A3 in human skin is not clear. Objective: We examined the effects of the single nucleotide polymorphisms ofSLC22A3 on the variability in SLC22A3 expression and sebum levels in humans. Methods: Immunostaining of OCT3 in human skin was performed. We analyzed the association of promoter variants with the SLC22A3 mRNA expression levels in human skins. Luciferase, knockdown, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay were employed to investigate transcriptional regulation of SLC22A3 expression. Effects of the identified variant on sebum levels were evaluated in healthy volunteers. Results: Immunohistochemistry revealed marked expressions of OCT3 in the basal epidermis, sebaceous glands, hair follicles, and sweat glands of human skin. SLC22A3 mRNA levels were significantly lower in skin samples with homozygotes for -1603A/A than in those for -1603 G/G. The analysis of p53 binding to -1603 G> A in the promoter ofSLC22A3 suggested that -1603 G> A down-regulates SLC22A3 gene expression by decreased p53 binding in the vicinity of the -1603 site. In humans, squalene levels in samples from the back at the baseline were significantly lower in homozygotes for -1603A/A than in those for -1603 G/G. Conclusion: These results suggest that the genetic variant contributes to the variability of expression and activities of OCT3 in human skin. (C) 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.