FUNCTIONAL AND SUBCELLULAR ORGANELLE CHANGES IN ISOLATED RAT AND HUMAN HEPATOCYTES INDUCED BY TETRAHYDROAMINOACRIDINE

Tacrine (tetrahydroaminoacridine) is a reversible cholinesterase inhib itor used for the treatment of Alzheimer's disease. This drug causes a n elevation of serum aminotransferases in a limited population of pati ents. Several in vivo studies failed to elucidate the mechanism for th e enzyme elevation but previous in vitro studies have indicated defect s in mitochondrial function. Zn this study, electron microscopic, hist ochemical, and confocal microscopy techniques were used with primary h epatocyte cultures from humans and rats to examine the sequence of ear ly cellular changes after tacrine exposure. Changes included ribosome alterations as early as 1-2 h following tacrine exposure at concentrat ions ranging between 0.1 and 1.0 mM. Mitochondrial membrane potential was also altered as indicated by decreased rhodamine 123 uptake with t ime. Cellular lysosome content increased as indicated by increased sta ining of fluorescein isothiocyanate (FITC)-conjugated dextran. The res ults of acid phosphatase histochemistry correlated with the FITC-dextr an findings. Additionally, tacrine-related degranulation and vesiculat ion of the endoplasmic reticulum paralleled the ribosomal and mitochon drial changes. These subcellular changes were reproducible in rat and human hepatocytes, showing for the first time that human hepatocytes c an be altered by tacrine. The molecular mechanism of the organelle cha nges is unknown at this time. Also, the relationship between these sub cellular changes in isolated hepatocytes and the transaminase elevatio n noted in human populations treated with tacrine needs to be clarifie d.