# Comprehensive, context-aware, functional analysis of Cytochrome P450 variants

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $521,033

## Abstract

ABSTRACT
Subject-to-subject variability in response to drugs and environmental agents creates a significant challenge for
the safe and effective treatment of many human diseases. Pharmacogenomics seeks to address this challenge
by linking drug response to patient genotypes at important loci, termed pharmacogenes, in order to better
customize patient treatments. Cytochrome P450 (CYP) gene variation is a major contributor to adverse drug
reactions resulting from alterations in a subject's ability to metabolize therapeutic agents and environmental
toxins, relative to the population at large. Genetic variation in CYPs is extensive. For example, amongst 12 of
the most important cytochrome P450 (CYP) genes, 10% of people carry at least one rare, potentially
deleterious variant. Further complexity is introduced via complex alleles consisting of common variation plus
linked rare variants, and by extensive copy number variation and gene fusions at these loci. Unfortunately,
only a small number of variants have been unambiguously linked to alterations in drug/xenobiotic response.
Clearly, new approaches are needed to annotate the consequences of the huge pool of variants of unknown
significance, including those already identified by existing large-scale sequencing programs, and those that will
be discovered as clinical sequencing becomes routine. We have developed a suite of methods to test all
possible single substitutions at all amino acid residues in several CYP genes. In order to accomplish this, we
use deep mutational scanning, a method we have developed that allows parallelized, quantitative
measurements to be performed on libraries of genetic variants. We are in the midst of applying this approach
to single site variants of CYP2C9 and CYP2D6. We propose to extend our work to include CYP2C19, the third
prototypic CYP pharmacogene, CYP3A4, quantitatively the most important human liver drug metabolizing
enzyme, CYP2A6, which metabolizes nicotine and modulates smoking behaviors and lung cancer risk, and
CYP1A1, which bioactivates polycyclic heteroaromatic carcinogens. These efforts, which span the major
xenobiotic metabolizing CYP families (CYP1-3), constitute Aim 1. In Aim 2, we will evaluate more complex
alleles, including novel chimeras, and in Aim 3 we will dissect the substrate-dependency of genetic variation,
both efforts focusing on the drug-metabolizing CYP2 family. The result of this project will be a comprehensive,
context aware, functional analysis of CYP variants that will lead to a deeper understanding of the
consequences of genetic variation in these key pharmacogenes. We will also develop new, generalizable
methods for generating complex variant libraries and for directly assessing the effects of enzyme variants in a
multiplex fashion.

## Key facts

- **NIH application ID:** 10375437
- **Project number:** 5R01GM132162-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Maitreya J Dunham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $521,033
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375437

## Citation

> US National Institutes of Health, RePORTER application 10375437, Comprehensive, context-aware, functional analysis of Cytochrome P450 variants (5R01GM132162-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10375437. Licensed CC0.

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