TY - JOUR T1 - Interindividual Differences in the Expression of ATP-Binding Cassette and Solute Carrier Family Transporters in Human Skin: DNA Methylation Regulates Transcriptional Activity of the Human ABCC3 Gene JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 628 LP - 635 DO - 10.1124/dmd.117.079061 VL - 46 IS - 5 AU - Tomoki Takechi AU - Takeshi Hirota AU - Tatsuya Sakai AU - Natsumi Maeda AU - Daisuke Kobayashi AU - Ichiro Ieiri Y1 - 2018/05/01 UR - http://dmd.aspetjournals.org/content/46/5/628.abstract N2 - The identification of drug transporters expressed in human skin and interindividual differences in gene expression is important for understanding the role of drug transporters in human skin. In the present study, we evaluated the expression of ATP-binding cassette (ABC) and solute carrier (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 interindividual variability (9.5-fold). None of the single nucleotide polymorphisms tested (–1767G>A, –1328G>A, –1213C>G, –897delC, –260T>A, and –211C>T) in the promoter region of the ABCC3 gene 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 kilobase pairs upstream of ABCC3 (Rs: −0.323, P < 0.05). The reporter gene assay revealed a significant increase in transcriptional activity in the presence of CGI. ABCC3 mRNA was upregulated in HaCaT cells by the demethylating agent 5-aza-2′-deoxycytidine. Furthermore, the deletion of the region surrounding CGI using the clustered regularly interspaced short palindromic repeat/Cas9 system resulted in significantly lower ABCC3 mRNA levels than those in control clones in HaCaT cells. Herein, we demonstrated large interindividual differences in the expression of drug transporters in human skin. CGI may function as an enhancer of the transcription of ABCC3, and methylation levels in CGI contribute to the variability of ABCC3 expression in human skin. ER -