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Inter-individual Differences in the Expression of ABC and SLC Family Transporters in Human Skin: DNA Methylation Regulates Transcriptional Activity of the Human(MRP3) Gene.

著者 Takechi T , Hirota T , Sakai T , Maeda N , Kobayashi D , Ieiri I
Drug Metab Dispos.2018 Feb 02 ; ():.
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The identification of drug transporters expressed in human skin and inter-individual differences in gene expression are important for understanding the role of drug transporters in human skin. In the present study, we evaluated the expression of ABC and SLC transporters using human skin tissues. In skin samples, ABCC3 was expressed at the highest levels, followed by SLCO3A1, SLC22A3, SLC16A7, ABCA2, ABCC1, and SLCO2B1. Among the quantitated transporters, ABCC3 accounted for 20.0% of the total mean transporter mRNA content. The expression of ABCC3 mRNA showed large inter-individual variability (9.5-fold). None of the SNPs tested (-1767G>A, - 1328G>A, - 1213C>G, - 897delC, - 260T>A, and - 211C>T) in the promoter region of thegene showed a significant change in ABCC3 mRNA levels. ABCC3 expression levels negatively correlated with the methylation status of the CpG island (CGI) located approximately 10 kbp upstream of(: - 0.323,< 0.05). The reporter gene assay revealed a significant increase in transcriptional activity in the presence of CGI. ABCC3 mRNA was up-regulated in HaCaT cells by the demethylating agent 5-aza-2'-deoxycytidine. Furthermore, the deletion of the region surrounding CGI using the CRISPR/Cas9 system resulted in significantly lower ABCC3 mRNA levels than those in control clones in HaCaT cells. We herein demonstrated that large inter-individual differences in the expression of drug transporters in human skin. CGI may function as an enhancer of the transcription ofand methylation levels in CGI contribute to the variability ofexpression in human skin.
PMID: 29437875 [PubMed - as supplied by publisher]
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