Pharmacogenomic regulation of CYP transcription by TSPYL genes

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Variation in drug response could affect both the efficacy and toxicity of virtually all drugs. Adverse drug reactions are the 4th leading cause of death in the United States. Therefore, to understand factors that might contribute to this variation and to use that information to help maximize drug efficacy and to minimize side effects would represent a major advance. Host genetics, among many factors, contributes significantly to variation in drug response. Genetic variation within genes encoding proteins determining drug concentrations, so called pharmacokinetic pathways, and proteins determining the effect of the drug, so called pharmacodynamics, can both influence drug response. The well-studied Phase I metabolism enzymes, the cytochromes P450 (CYPs), are highly genetically polymorphic. Many CYP genes contain variants with known clinical utility and have been incorporated into FDA drug labeling or relabeling. Among the CYP family genes, CYP3A4, CYP2C9 and CYP2C19, taken together, metabolize more than 50% of all drugs. The regulation of these genes is of great interest and importance from both basic scientific and clinical points of view. Even though SNPs and copy number variation (CNV) that cis-regulate CYP gene function have been well-studied, they do not explain all of the inter-individual variability in the function of these genes. Previous evidence indicates the functional significance of the trans-regulation of CYPs through genetic variation in transcription factors, microRNAs or epigenetic regulation. These findings serve to emphasize the crucial need to identify mechanisms underlying the transcriptional regulation of CYP genes and to identify genomic alterations responsible for variation in these regulatory mechanisms which, in turn, contribute to variation in CYP gene function and—ultimately--drug response. As a result, enhancing our basic knowledge of the transcription of CYPs would help to us build more comprehensive regulatory networks for CYP gene expression and function, and this knowledge would enhance our ability to individualize drug therapy. In this application, our extensive preliminary data have shown that a novel family of proteins, the TSPYL family, can function as transcription factors, contributing significantly to regulation of the expression of CYP2C and 3A family members. Our Preliminary Data showed that a functional SNP in TSPYL1 can influence in vitro level and clinical response of abiraterone, a drug that is metabolized by CYP 3A4. Here, we propose to study mechanisms by which TSPYL family members might regulate CYP gene expression as well as the contribution of genetic variation that either cis or trans-regulates TSPYL genes to inter-individual variation in CYP gene expression and in drug response phenotypes. We believe that our novel finding could add another comprehensive layer to our understanding of the transcription regulation of CYPs, which could, in turn, contribute significantly to understanding of variation in drug response.