# The role of lncRNAs in P450-mediated drug metabolism and drug-induced liver injury

> **NIH NIH R35** · UNIVERSITY OF CONNECTICUT STORRS · 2022 · $402,500

## Abstract

ABSTRACT
The aim of the project is to determine the roles of long non-coding RNAs (lncRNAs) of HNF1a-AS1 and
HNF4a-AS1 in the regulation of cytochrome P450 (CYP) gene expression. Drug-metabolizing CYP
enzymes are responsible for therapeutic outcomes of 60-70% drugs. Understanding all key factors in
the regulation of expression of the CYP enzymes is critical to predict outcomes of drug therapy.
Transcription factors (TFs) of hepatocyte nuclear factor 1a (HNF1a), 4a (HNF4a), pregnane X receptor
(PXR), and constitutive androstane receptor (CAR) are the key factors. After binding to their response
elements, the TFs facilitate transcriptional regulation through alterations of histone modification status
of the CYP genes, the major epigenetic mechanism. A remaining question is how the TFs trigger
alterations of histone modifications to facilitate the regulation of CYP expression. lncRNAs may be the
key components. Increasing evidence has shown that antisense lncRNAs next to TFs on chromosomal
locations are involved in the functions of the TFs in regulation of gene expression. We identified two
lncRNAs next to the TFs of HNF1a and HNF4a, which are HNF1a-AS1 and HNF4a-AS1. Several
fundamental challenge questions need to be addressed. (1) Whether HNF1a-AS1 and HNF4a-AS1 are
the two key factors in maintaining homeostasis of P450 enzymes in liver in a dynamic process, such as
drug induction, through enhancing by HNF1a-AS1 or repressing by HNF4a-AS1 in the transcriptional
regulation of P450 gene expression? (2) Whether HNF1a-AS1 and HNF4a-AS1 are the two key factors
in sensitizing susceptibility of drug induced liver injury (DILI) and following process of liver regeneration?
(3) How HNF1a-AS1 and HNF4a-AS1 participate in the regulation of P450 gene expression, directly or
indirectly through the regulation of PXR or CAR by alteration of histone modifications? These
fundamental questions are so critical for deeply understanding molecular mechanisms in the regulation
of CYP-mediated drug metabolism and DILI. In the past five years, we have determined the role of
lncRNAs in drug metabolism. Our recent progress has placed us into an appropriate position to provide
answers to these fundamental questions. We have developed a comprehensive plan to address these
challenge questions with both in vitro and in vivo models in the next five years. After completion of the
proposed studies, we expect to provide answers to address the challenge questions. The proposed
work will elucidate the epigenetic regulatory mechanisms by lncRNAs that control homeostasis of drug-
metabolizing CYP expression in a positive and negative feedback loop after exposure to drugs. The
proposed work will determine the roles of lncRNAs in P450-mediated drug metabolism and susceptibility
to DILI. The generated knowledge will help to identify novel key factors for predicting therapeutic efficacy
and DILI.

## Key facts

- **NIH application ID:** 10371142
- **Project number:** 5R35GM140862-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** XIAO-BO ZHONG
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371142

## Citation

> US National Institutes of Health, RePORTER application 10371142, The role of lncRNAs in P450-mediated drug metabolism and drug-induced liver injury (5R35GM140862-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10371142. Licensed CC0.

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