Drug-induced Liver Steatosis and Phospholipidosis: Cell-Based Assays for Early Screening of Drug Candidates
M. Teresa Donato and M. Jose Gomez-Lechon
Affiliation: Unidad de Hepatologia Experimental, Centro de Investigacion, Hospital La Fe, Avda de Campanar 21, 46009-Valencia, Spain.
Keywords: Steatosis, phospholipidosis, drug, cell-based assay, hepatotoxicity, Drug, Liver Steatosis, Screening, Fat Metabolism , steatohepatitis, phospholipidosis, lesions, prognosis.
The liver plays a key role in fat metabolism, and excessive lipid accumulation in liver cells is characterised by a large spectrum
of lesions, e.g., steatosis and phospholipidosis. Steatosis is increased lipid accumulation, mainly as triglycerides, in the liver, while phospholipidosis
is a lysosomal storage disorder characterised by intracellular accumulation of phospholipids. These alterations can be induced
by several factors, including exposure to certain drugs. Drug-induced steatosis is often reversible, and prolonged exposure to certain
drugs can cause macrovacuolar steatosis, a benign hepatic lesion, that can evolve into steatohepatitis and cirrhosis in some patients.
Some drugs may acutely induce microvesicular steatosis which, despite having a good short-term prognosis, can lead to chronic lipid
peroxidation and to the development of steatohepatitis lesions with time. Over 50 marketed drugs have been reported to induce phospholipidosis
in different tissues, including the liver. Although drug-induced phospholipidosis is often reversible and there is no definitive evidence
for its toxicological implications, it is considered an adverse side finding by regulatory agencies. As developing new drugs is a
complex, lengthy and expensive process that aims to identify pharmacologically active, low-toxicity drug candidates among closely related
compounds, it could be advantageous to determine which drugs are able to induce lipid metabolic disorders in early developmental
stages. To this end, in vitro predictive screening assays, particularly cell-based approaches in which many drug candidates are evaluated,
have been developed to identify and rule out compounds with a strong liver steatosis and/or phospholipidosis-inducing potential.
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