Targeting the pregnane X receptor in liver injury

Abstract

Introduction: The nuclear receptor pregnane X receptor (PXR) is a well-characterized hepatic xenobiotic sensor whose activation by chemically diverse compounds results in the induction of drug clearance pathways that rid the body of potentially toxic substances, thus conferring protection from foreign chemicals and endobiotics.

Areas covered: PXR activities are implicated in drug-drug interactions and endocrine disruption. Recent evidence supports a hepatoprotective role for PXR in chronic liver injury, inhibiting liver inflammation through suppression of the NF-κB pathway. However, PXR-mediated induction of CYP3A enhances APAP-induced acute liver injury by generating toxic metabolites. While these observations implicate PXR as a therapeutic target for liver injury, they also caution against PXR activation by pharmaceutical drugs.

Expert opinion: While evidence of PXR involvement in acute and chronic liver injuries identifies it as a possible therapeutic target, it raises additional concerns for all drug candidates. The in vitro and in vivo tests for human PXR activation should be incorporated into the FDA regulations for therapeutic drug approval to identify potential liver toxicities. In addition, PXR pharmacogenetic studies will facilitate the prediction of patient-specific drug reactivities and associated liver disorders.

Figure 1

Model depicting the central role of the nuclear receptor PXR in the liver response to endobiotic and xenobiotic compounds. Activation of PXR by structurally and functionally diverse ligands induces the transcription of drug metabolizing enzymes and transporters. Compound modifications facilitate their removal (detoxicification), or conversely, increase their toxicity, resulting in systemic disorders such as endocrine disruption and chemo-resistance.