PXR-mediated idiosyncratic drug-induced liver injury: mechanistic insights and targeting approaches

ABSTRACT

Introduction

The human liver is the center for drug metabolism and detoxification and is, therefore, constantly exposed to toxic chemicals. The loss of liver function as a result of this exposure is referred to as drug-induced liver injury (DILI). The pregnane X receptor (PXR) is the primary regulator of the hepatic drug-clearance system, which plays a critical role in mediating idiosyncratic DILI.

Areas covered

This review is focused on common mechanisms of PXR-mediated DILI and on in vitro and in vivo models developed to predict and assess DILI. It also provides an update on the development of PXR antagonists that may manage PXR-mediated DILI.

Expert opinion

DILI can be caused by many factors, and PXR is clearly linked to DILI. Although emerging data illustrate how PXR mediates DILI and how PXR activity can be modulated, many questions concerning the development of effective PXR modulators remain. Future research should be focused on determining the mechanisms regulating PXR functions in different cellular contexts.

KEYWORDS:

• Adverse drug reaction
• drug-induced liver injury
• drug metabolism
• liver toxicity
• pregnane X receptor

Article highlights

• Idiosyncratic DILI is a rare, but life-threatening adverse drug reaction caused by unexpected interaction between the drug and environmental factors.

• PXR plays a critical role in mediating DILI because of its regulatory function in the hepatic drug metabolism.

• When PXR is activated by xenobiotics, it induces the expression of drug-metabolizing enzymes (DMEs), which may lead to the accumulation of reactive metabolites of parent drugs that are cytotoxic at high doses.

• PXR activation can also trigger DME-independent downstream events that cause cytotoxicity.

• PXR antagonists, which only inhibit agonist-induced PXR activity, may manage PXR-mediated DILI.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank ALSAC for support, and Cherise Guess, PhD, ELS, for editing the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM118041. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.