# Regulation and Consequences of Cytochrome P450 2E1

> **NIH NIH R35** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $368,932

## Abstract

PROJECT SUMMARY
Cytochrome P450 2E1 (CYP2E1) is a unique, highly conserved, and highly regulated mammalian P450
monooxygenase. CYP2E1 undergoes extensive post-transcriptional and post-translational regulation, including
bimodal targeting to endoplasmic reticulum and mitochondria. There are no known loss of function mutations in
the human population, and no known polymorphic variants that change the coding region of the protein,
indicating an important endogenous role for CYP2E1. However, knockout of CYP2E1 in rodent models has not
yielded a dramatic phenotype, and has been reported to be protective against diet-induced obesity,
nonalcoholic fatty liver disease, and ethanol-induced toxicity. Therapeutic targeting of CYP2E1 has been
recommended for liver repair after alcoholic liver damage and to improve the efficacy of a ketogenic diet for the
treatment of epilepsy. However, there remain major gaps in our understanding of the endogenous function of
CYP2E1 that must be addressed before CYP2E1 can be safely inhibited in humans, particularly in the long-
term. This proposal addresses these challenges using the expertise of the Hartman lab, resources and
reagents we have generated to study CYP2E1, and the expertise of our collaborators. The overall goal of the
research program is to discover the endogenous function and regulation of CYP2E1 and the consequences of
CYP2E1 activity in mitochondria and endoplasmic reticulum. Overview of research and goals for the next five
years: The Hartman Lab opened at MUSC during the beginning of the pandemic. It pursues key questions like:
How does the cell decide how much CYP2E1 to send to mitochondria vs. the endoplasmic reticulum?
Mechanisms of nascent polypeptide targeting will be determined through genetic and pharmacological
approaches. What are the endogenous functions of CYP2E1 in multiple tissues? CYP2E1 is known to
metabolize acetone to acetol and methylglyoxal, and to hydroxylate fatty acids at the omega and omega-1
position, but these activities have not been studied in the context of overall cellular metabolism and have
generally only focused on liver. We are investigating the tissue-specific endogenous functions in multiple
tissues. What are the consequences of CYP2E1 expression in mitochondria and endoplasmic reticulum?
Emerging evidence in our lab suggests that for ethanol and acetaminophen, mitochondrial CYP2E1 is a liability
for drug-induced cellular damage, but for fatty acids, endoplasmic reticular CYP2E1 drives lipid stress.
Therefore, there are organelle-specific liabilities that must be further defined. Together this work will address
arising and long-standing fundamental questions about CYP2E1.

## Key facts

- **NIH application ID:** 10884292
- **Project number:** 5R35GM150843-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Jessica Helene Hartman
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $368,932
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884292

## Citation

> US National Institutes of Health, RePORTER application 10884292, Regulation and Consequences of Cytochrome P450 2E1 (5R35GM150843-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10884292. Licensed CC0.

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