Pharmacogenetics of Nuclear Receptors/Hepatic transport

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Variability in drug metabolism has long been appreciated to be a major factor in interindividual differences in drug responsiveness and, more recently, a role for efflux membrane transporters has been recognized. Molecular determinants related to the regulation of such proteins? activities and functions are, however, poorly understood. Genetic variability may, for example, be present in the coding region of the gene or in the genes/proteins responsible for transcriptional regulation involving the 5?-promoter region of the gene of interest. Specific Aim 1 focuses on single nucleotide polymorphism (SNP) discovery in such regions. Of particular interest are human orphan nuclear receptors, PXR, CAR and FXR, along with their heterodimer partner RXR-alpha (cis-retinoic acid receptor). This is because these regulatory proteins appear to be important in the transcription of both cytochrome P4503A (CYP3A) - a major drug metabolizing enzyme of the liver and intestine - and certain hepatic transporters like MDR1, MRP2 and BSEP. Genetic variability will also be investigated in the transporters, themselves, since they appear to function in concert with cytochrome P450s to eliminate xenobiotics and endogenous compounds. Subsequent to the identification of common SNPs and definition of allelic frequency, the functional consequence of the allelic variants will be investigated in Specific Aim 2 by DNA-expression and/or protein function studies, in vitro. For genetic variants that affect either of these characteristics, studies will be performed in Specific Aim 3 using in vivo probes of CYP3A and MDR1 to determine their functional relevance in humans. Such a systematic approach will define the role and importance of genetic variability in orphan nuclear receptors and efflux transporters relative to important processes in drug disposition that contribute to interindividual differences in drug responsiveness.