Date of Completion

4-28-2020

Embargo Period

4-28-2021

Keywords

lncRNA, P450, liver

Major Advisor

Xiao-bo Zhong

Associate Advisor

Theodore Rasmussen

Associate Advisor

Ronald S. Obach

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Hepatic cytochrome P450 (P450) mediated metabolism, which includes the metabolism of both endogenous and exogenous chemicals, is an important process in the maintenance of homeostasis and normal physiological function in humans. The expression and function of P450 genes are controlled by multiple regulatory factors and show great inter-individual differences. Understating the underlying regulatory mechanisms to P450 genes is critical to evaluate the metabolism capability and predict drug efficacy or toxicity. Long noncoding RNAs (lncRNAs) are a class of recently discovered regulatory molecules in gene expression and function, which are highly involved in multiple physiological activities across different species. Recent studies also suggest that lncRNAs are involved in metabolism activities in humans. However, there is a significant knowledge gap in understating how lncRNAs influences the expression and function of P450 genes and downstream drug metabolism. The research project in this thesis mainly focuses on understating the roles of two transcription factor neighborhood lncRNAs, HNF1α-antisense-1 (HNF1α-AS1) and HNF4α-antisense-1 (HNF4α-AS1), in the regulation of P450 expression and P450 mediated drug metabolism. My results demonstrate that lncRNAs HNF1α-AS1 and HNF4α-AS1 are able to regulate the expression of multiple P450 genes and P450 related transcription factors, including CAR and PXR. In addition, the manipulation of these lncRNAs further impacted P450 mediated drug metabolism and toxicity. Taken together, these studies indicate the critical regulatory roles of lncRNAs in drug metabolism through the regulation of hepatic P450s. A better understanding of how lncRNAs impact drug usage in clinical conditions is needed.

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