Host: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
Name : WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
Location : Kyoto
Date : July 01, 2018 - July 06, 2018
Since transporters and metabolic enzymes are expressed in various human tissues, variations in ADME genes significantly contribute to individual differences in PK/PD profiles of drugs. Epigenetic mechanisms, such as DNA methylation and microRNA, alter the expression of genes without changing DNA sequences, leading to above-mentioned variations. MATE1, which mediates the excretion of organic cations into bile and urine, has an approximately 20-fold interindividual variability in its hepatic expression. Hepatic mRNA expression levels negatively correlated with methylation levels of the CpG island in the 27 kb upstream of the TSS. Some evidences including the luciferase reporter assay indicated that the 5' CpG island of SLC47A1 acts as an enhancer for the expression, and the DNA methylation level is expected as a biomarker for MATE1 function. Recently, we found that hepatic and intestinal CYP3A4 expressions are also regulated by DNA methylation at the regions on the chromosome 7q21. BCRP, another important drug transporter, has functionally significant 421C>A mutation in the ABCG2 gene, which is a useful biomarker for describing large interindividual differences in the PK profile of sulfasalazine (SASP). However, large inter-genotypic variability still exists in spite of the incorporation of this mutation into the PK of SASP. Since miR-328 negatively regulates BCRP expressions (both mRNA and protein levels) in human tissues, we hypothesized that exosomal miR-328 in plasma, which leaks from the intestine, is a possible biomarker for estimation BCRP activity in the human intestine. We established an immunoprecipitation-based quantitative method for circulating intestine-derived miR-328 in plasma using an anti-glycoprotein A33 antibody. Interestingly, intestine-derived exosomal miR-328 levels positively correlated (p < 0.05) with SASP AUC, suggesting that subjects with high miR-328 levels have low intestinal BCRP activity, resulting in the high AUC of SASP. This is the first study to show circulating tissue-specific exosomal microRNA in plasma has potential as a possible biomarker for estimating transporter function in an organ.
