Genetic Polymorphism (Asian) • • • • • • CYP2D6 SNP C188T (70%T) CYP2A6*4 (27%) CYP3A5*3 (72%) OATP2 SNP A388G (78%G) MRP1 SNP C218T (1%T), G2168A (2%A) MRP2 SNP G1249A (7%A), C2366T (1%T) Nuclear Proteins • Nuclear orphan receptors • Transcriptional factors Nuclear Orphan Receptors • PPARa: ligand- fibrates, lower blood lipid • PPARγ: ligand- traglitazone etc., lower blood sugar in NIDDM • PPARδ, LXRα, LXRβ • PXR: ligand- rifampin etc., induce CYP3A4, and P-glycoprotein • CAR: ligand- phenobarbital, induce CYP2B6 and other genes Transcriptional regulatory elements in Mrp3 promoter AP2 IRF-2 c-Myc AP1 c-Ets-1/PEA3 Sp1 C/EBP -19 -2723 c-Myb COUP GATA-1 HiNF-A Pit-1 NF-1 CCAAT HNF-1 CREB NF-E Tissue Distribution of Sp1/Sp3 and C/EBP protein family Liver L1 L2 L3 L4 Intestine H I I1 I2 Sp1 Sp3 C/EBPa C/EBP LAP-FL LAP LIP C/EBP C/EBP as a inducible factor, shows no constitutive expression in liver and hepatoma cell lines (H, H4IIE). Proteomics in Drug Development and Review • Xenobiotic affects transcriptional factors • Example xenobiotic A → C/EBP → MRP3 → clearance of substrates • drug-drug interaction study proteomic design, for example, xenobiotic A and MRP3 substrates
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