Tetrahydroaminoacridine-induced ribosomal changes and inhibition of protein synthesis in rat hepatocyte suspensions.
Tacrine (tetrahydroaminoacridine) is currently the only drug approved for the treatment of Alzheimer's disease. Unfortunately, tetrahydroaminoacridine therapy is often limited by this drug's propensity to induce reversible hepatotoxicity. Using suspensions of freshly isolated rat hepatocytes, we investigated the mechanism of tetrahydroaminoacridine cytotoxicity by examining the effect of tetrahydroaminoacridine on hepatocyte viability, protein synthesis, protein, DNA and RNA levels and ultrastructure. Our experimental findings support the explanation that tetrahydroaminoacridine-induced hepatotoxicity results from tetrahydroaminoacridine's adverse effect on protein synthesis and ribosomal structure and function. We found that viable, tetrahydroaminoacridine-treated hepatocytes (1.0 to 2.0 mmol/L or 118 to 235 micrograms/10(6) cells) demonstrated a dose-dependent and dramatic aggregation of ribosomes on endoplasmic reticulum as well as the aggregation of other nucleic acids found in the nucleus (chromatin) and in mitochondria. These electron microscopy data suggest that tetrahydroaminoacridine treatment results in severe ribosomal dysfunction. This was confirmed by the observed rapid loss of cellular RNA content (but not DNA or protein) and the rapid and complete inhibition of protein synthesis in tetrahydroaminoacridine-treated cells (lowest concentration tested was 0.5 mmol/L or 58 micrograms/10(6) cells). Thus tetrahydroaminoacridine treatment appears to aggregate hepatocellular nucleic acids, and in doing so adversely affects ribosomal function and protein synthesis. We propose that these adverse effects of exposure to tetrahydroaminoacridine are responsible for tetrahydroaminoacridine-induced hepatotoxicity.
Fariss
M W
MW
Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0662.
Johnsen
S A
SA
Walton
L P
LP
Mumaw
V R
VR
Ray
S D
SD
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D003864:Depression, Chemical; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D014176:Protein Biosynthesis; D012313:RNA / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012270:Ribosomes / Q000187:drug effects / Q000648:ultrastructure; D013535:Suspensions; D013619:Tacrine / Q000633:toxicity*
D013535:Suspensions; D013619:Tacrine; D012313:RNA; D004247:DNA