# Cellular Signaling in Drug Induced Toxicity

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $114,000

## Abstract

Drug-induced hepatotoxicity is a leading cause of both the withdrawal of approved drugs from the market and
the attrition of new chemical entities during the drug development process; however, the mechanisms
underlying drug-induced hepatotoxicity are not fully understood. We have used efavirenz, an antiretroviral
drug that is hepatotoxic in certain patients, as a model compound to investigate cellular signaling mechanisms
that may play a causal role in drug-induced hepatocyte death. Previously, using primary human hepatocytes, we
demonstrated that efavirenz and the major oxidative metabolite of efavirenz, denoted as 8-hydroxyefavirenz (8-
OHefavirenz), stimulate cell death in a manner that is dependent upon activation of the stress kinase c-Jun N-
terminal kinase and upregulation of the proapoptotic protein BimEL (Bcl-2 interacting mediator of cell death extra
long). Subsequently, we have reported that efavirenz can also activate inositol requiring enzyme 1α (IRE1α), a
key regulator of cell stress that lies upstream of JNK and BimEL. The goal of this proposal is to determine the
mechanism by which efavirenz and 8-OHefavirenz activate BimEL and IRE1α, while also gaining a mechanistic
understanding of how genetic variation in IRE1α might impact efavirenz and 8-OHefavirenz-induced cell death.
Importantly, we will leverage the insights we have gained through using efavirenz as a model compound and
employ prototypic hepatotoxic drugs beyond efavirenz, namely carbamazepine, diclofenac and isoniazid, in order
to establish BimEL and IRE1α as central regulators of drug-induced hepatotoxicity across a range of drug
classes. The aims are as follows: (1) to test the hypothesis that BimEL acts as an executioner of cell death in
response to efavirenz and other prototypic hepatotoxic drugs: BimEL null mice will be used to determine whether
the absence of BimEL prevents hepatotoxicity stimulated by the hepatotoxic drugs being investigated here;
CRISPR/Cas9 systems will be used to determine the role of effector proteins, Bax and Bak, that are downstream
of BimEL in modulating hepatocyte death; CRISPR/Cas9 and reporter gene assays will be used to define the
mechanism by which efavirenz, 8-OHefavirenz and other hepatotoxic drugs regulate the transcription of BimEL;
efavirenz analogs will be employed in order to elucidate the structure-activity relationship of BimEL activation by
efavirenz; (2) to test the hypothesis that IRE1α is a central upstream regulator of drug-induced hepatotoxicity
that is stimulated by several classes of drugs: we will determine whether efavirenz, 8-OHefavirenz, and other
hepatotoxic drugs stimulate formation of the IRE1α/TRAF2/ASK1/JNK complex that results in IRE1α-dependent
activation of JNK; we will test the impact of naturally occurring genetic variants of IRE1α on activity and cell
death. It is expected that these studies will define BimEL and IRE1α activation as important molecular
mechanisms by which a range of drugs induce-hepatotox...

## Key facts

- **NIH application ID:** 10132448
- **Project number:** 3R01GM103853-07A1S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Namandje N Bumpus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $114,000
- **Award type:** 3
- **Project period:** 2013-04-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132448

## Citation

> US National Institutes of Health, RePORTER application 10132448, Cellular Signaling in Drug Induced Toxicity (3R01GM103853-07A1S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10132448. Licensed CC0.

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