# Pharmacogenomic regulation of CYP transcription by TSPYL genes

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $309,982

## Abstract

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 variatio...

## Key facts

- **NIH application ID:** 9823883
- **Project number:** 5R01GM125633-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Liewei Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $309,982
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9823883

## Citation

> US National Institutes of Health, RePORTER application 9823883, Pharmacogenomic regulation of CYP transcription by TSPYL genes (5R01GM125633-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9823883. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*