Tetrahydroaminoacridine-induced apoptosis in rat hepatocytes

Toxicology in Vitro : an International Journal Published in Association with BIBRA
M W FarissL P Walton

Abstract

Tacrine (tetrahydroaminoacridine, THA) is currently administered to thousands of patients for the treatment of Alzheimer's disease. Unfortunately, THA therapy is often limited by this drugs' propensity to induce reversible hepatotoxicity. In the present study we investigated the mechanism of THA cytotoxicity by measuring the effect of THA on cell viability, protein synthesis activity and the induction of apoptosis in suspensions of freshly isolated rat hepatocytes. Our experimental findings indicate that THA-mediated apoptosis is responsible for the acutein vitro hepatotoxicity observed with this aminoacridine derivative. We found that THA-treated hepatocytes (0.1, 0.25 and 0.5 mm) demonstrated a significant and dose-dependent reduction in cellular protein synthesis activity (84, 55 and 5% of control activity, respectively) after 1 hr of incubation. However, in hepatocytes exposed to 0.1 and 0.25 mm THA, the inhibition of protein synthesis was short-lived. In these treated cells, protein synthesis activity returned to control levels (100%) by the fifth hr of incubation without a significant increase in cellular lactate dehydrogenase (LDH) leakage or the induction of apoptosis. In hepatocytes exposed to 0.5 mm THA, the near comp...Continue Reading

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Citations

Dec 14, 2007·Pharmacogenetics and Genomics·Daniel F CarrB Kevin Park
Jul 28, 2011·Medicinal Research Reviews·Rafael LeónJosé Marco-Contelles
Jun 18, 2010·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·M Tolulope OlaleyeAfolabi A Akindahunsi
Feb 16, 1999·Journal of Applied Toxicology : JAT·D R Plymale, F A de la Iglesia
Aug 15, 2017·European Journal of Medicinal Chemistry·Leili Jalili-BalehAlireza Foroumadi

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis