University of Oulu

Itkonen, A., Hakkola, J. & Rysä, J. Adverse outcome pathway for pregnane X receptor-induced hypercholesterolemia. Arch Toxicol 97, 2861–2877 (2023).

Adverse outcome pathway for pregnane X receptor-induced hypercholesterolemia

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Author: Itkonen, Anna1; Hakkola, Jukka2; Rysä, Jaana1
Organizations: 1School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
2Research Unit of Biomedicine and Internal Medicine, Biocenter Oulu, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
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Language: English
Published: Springer Nature, 2023
Publish Date: 2023-11-03


Pharmaceuticals and environmental contaminants contribute to hypercholesterolemia. Several chemicals known to cause hypercholesterolemia, activate pregnane X receptor (PXR). PXR is a nuclear receptor, classically identified as a sensor of chemical environment and regulator of detoxification processes. Later, PXR activation has been shown to disrupt metabolic functions such as lipid metabolism and recent findings have shown PXR activation to promote hypercholesterolemia through multiple mechanisms. Hypercholesterolemia is a major causative risk factor for atherosclerosis and greatly promotes global health burden. Metabolic disruption by PXR activating chemicals leading to hypercholesterolemia represents a novel toxicity pathway of concern and requires further attention. Therefore, we constructed an adverse outcome pathway (AOP) by collecting the available knowledge considering the molecular mechanisms for PXR-mediated hypercholesterolemia. AOPs are tools of modern toxicology for systematizing mechanistic knowledge to assist health risk assessment of chemicals. AOPs are formalized and structured linear concepts describing a link between molecular initiating event (MIE) and adverse outcome (AO). MIE and AO are connected via key events (KE) through key event relationships (KER). We present a plausible route of how PXR activation (MIE) leads to hypercholesterolemia (AO) through direct regulation of cholesterol synthesis and via activation of sterol regulatory element binding protein 2-pathway.

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Series: Archives of toxicology
ISSN: 0340-5761
ISSN-E: 1432-0738
ISSN-L: 0340-5761
Volume: 97
Issue: 11
Pages: 2861 - 2877
DOI: 10.1007/s00204-023-03575-4
Type of Publication: A2 Review article in a scientific journal
Field of Science: 3111 Biomedicine
Funding: Open access funding provided by University of Eastern Finland (UEF) including Kuopio University Hospital. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 825762. The research work of Jukka Hakkola was also supported by a grant from the Academy of Finland (323706).
EU Grant Number: (825762) EDCMET - Metabolic effects of Endocrine Disrupting Chemicals: novel testing METhods and adverse outcome pathways
Academy of Finland Grant Number: 323706
Detailed Information: 323706 (Academy of Finland Funding decision)
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