Related Experiment Videos
Acridine-induced subcellular and functional changes in isolated human hepatocytes in vitro
D R Plymale1, F A de la Iglesia
1Pathology and Experimental Toxicology Department, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Journal of Applied Toxicology : JAT
|February 16, 1999
Summary
Other acridines, like tacrine (Tetrahydroaminoacridine), cause mitochondrial dysfunction and cellular damage in human liver cells. These findings suggest acridine compounds share similar toxic effects on hepatocytes.
Area of Science:
- Hepatology
- Toxicology
- Molecular Biology
Background:
- Acridines, including Tetrahydroaminoacridine (tacrine), are known nucleic acid intercalators used clinically for Alzheimer's disease.
- Tacrine causes sporadic aminotransferase elevations and in vitro hepatocyte alterations, but the link to liver damage is unclear.
- Previous studies identified subcellular changes in hepatocytes exposed to tacrine, but it was unknown if other acridines induced similar effects.
Purpose of the Study:
- To investigate whether other acridine compounds, similar to tacrine, induce comparable subcellular changes and mitochondrial dysfunction in primary human hepatocytes.
- To compare the effects of various acridines and their metabolites on hepatocyte structure and function.
Main Methods:
- Primary human hepatocytes were exposed in vitro to tacrine, acridine orange, 9-aminoacridine, quinacrine, and proflavin.
- The effects of tacrine metabolites (1-hydroxy and 7-hydroxy tacrine) and acridine derivatives (acridine hydrochloride, acridine 9-carboxylic acid) were also assessed.
- Mitochondrial membrane potential, ultrastructural changes, and cytotoxicity were evaluated.
Main Results:
- Acridine orange, 9-aminoacridine, quinacrine, and proflavin induced mitochondrial membrane potential reduction and ultrastructural changes in human hepatocytes, mirroring tacrine's effects.
- Tacrine metabolites and eserine, while not causing characteristic ER changes, damaged mitochondria, reduced membrane potential, and were cytotoxic.
- These acridines consistently demonstrated mitochondrial dysfunction and cytotoxic effects in human hepatocytes.
Conclusions:
- Subcellular changes observed with tacrine in hepatocytes are reproducible with other acridine compounds.
- Acridines, as a class, can induce mitochondrial dysfunction in human hepatocytes.
- The study highlights shared toxic mechanisms among acridine derivatives impacting liver cell mitochondria.