Preclinical liver toxicity models: Advantages, limitations and recommendations

Devaraj Ezhilarasan; Sivanesan Karthikeyan; Mustapha Najimi; Paramasivan Vijayalakshmi; Ganapathy Bhavani; Muthukrishnan Jansi Rani

doi:10.1016/j.tox.2024.154020

Preclinical liver toxicity models: Advantages, limitations and recommendations

Toxicology. 2024 Dec 3:511:154020. doi: 10.1016/j.tox.2024.154020. Online ahead of print.

Authors

Devaraj Ezhilarasan¹, Sivanesan Karthikeyan², Mustapha Najimi³, Paramasivan Vijayalakshmi⁴, Ganapathy Bhavani⁵, Muthukrishnan Jansi Rani²

Affiliations

¹ Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India. Electronic address: ezhilarasand.sdc@saveetha.com.
² Department of Pharmacology and Environmental Toxicology, Dr. A.L.M. Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India.
³ Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium.
⁴ Department of Pharmacology and Environmental Toxicology, Dr. A.L.M. Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India; Department of Pharmacology, Asan Memorial Dental College and Hospital, Chengalpattu, Tamil Nadu, India.
⁵ Department of Pharmacology and Environmental Toxicology, Dr. A.L.M. Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India; Department of Pharmacology, Meenakshi Ammal Dental College and Hospital, Meenakshi Academy of Higher Education and Research, Chennai, Tamil Nadu, India.

PMID: 39637935
DOI: 10.1016/j.tox.2024.154020

Abstract

Experimental animal models are crucial for elucidating the pathophysiology of liver injuries and for assessing new hepatoprotective agents. Drugs and chemicals such as acetaminophen, isoniazid, valproic acid, ethanol, carbon tetrachloride (CCl₄), dimethylnitrosamine (DMN), and thioacetamide (TAA) are metabolized by the CYP2E1 enzyme, producing hepatotoxic metabolites that lead to both acute and chronic liver injuries. In experimental settings, acetaminophen (centrilobular necrosis), carbamazepine (centrilobular necrosis and inflammation), sodium valproate (necrosis, hydropic degeneration and mild inflammation), methotrexate (sinusoidal congestion and inflammation), and TAA (centrilobular necrosis and inflammation) are commonly used to induce various types of acute liver injuries. Repeated and intermittent low-dose administration of CCl₄, TAA, and DMN activates quiescent hepatic stellate cells, transdifferentiating them into myofibroblasts, which results in abnormal extracellular matrix production and fibrosis induction, more rapidly with DMN and CCL₄ than TAA (DMN > CCl₄ > TAA). Regarding toxicity and mortality, CCl₄ is more toxic than DMN and TAA (CCl₄ > DMN > TAA). Models used to induce metabolic dysfunction-associated liver disease (MAFLD) vary, but MAFLD's multifactorial nature driven by factors like obesity, fatty liver, dyslipidaemia, type II diabetes, hypertension, and cardiovascular disease makes it challenging to replicate human metabolic dysfunction-associated steatohepatitis accurately. From an experimental point of view, the degree and pattern of liver injury are influenced by various factors, including the type of hepatotoxic agent, exposure duration, route of exposure, dosage, frequency of administration, and the animal model utilized. Therefore, there is a pressing need for standardized protocols and regulatory guidelines to streamline the selection of animal models in preclinical studies.

Keywords: Acetaminophen; Alcohol; Carbon tetrachloride; High fat diet; Sodium valproate; Thioacetamide.

Publication types

Review