Comparison of tacrine-induced cytotoxicity in primary cultures of rat, mouse, monkey, dog, rabbit, and human hepatocytes.
Tacrine is the first drug approved for the treatment of Alzheimer's disease. Approximately 50% of patients treated with tacrine develop elevated serum aminotransferase levels, an indication of potential hepatotoxicity. The mechanism of human hepatoxicity has been difficult to study, because of the absence of an animal model. Therefore, this study compared the cytotoxicity induced by tacrine in primary rat, mouse, monkey, dog, rabbit and human hepatocytes to determine differences in response to tacrine between species in vitro. Cytotoxicity was assessed by determination of extra- and intracellular lactate dehydrogenase. The ratio of intracellular enzyme to total enzyme (i.e. intracellular and extracellular) was used to represent the viabilities of the cultures. Concentration-dependent cytotoxicity occurred after four and 24-hour exposure over a tacrine concentration range of 0 to 380 micrograms/ml. Cytotoxic potency of tacrine in hepatocytes from human, dog, mouse and rat was not significantly different; monkey hepatocytes appeared slightly more sensitive, while rabbit hepatocytes appeared slightly less sensitive than human hepatocytes. Increased time of exposure to tacrine decreased the concentration necessary to induce a cytotoxic response. This in vitro model suggests only minimal differences in sensitivity to tacrine-induce cytotoxicity; therefore, cytotoxicity in primary cultures of hepatocytes from various species would appear to be related to common metabolite(s) and/or mechanism of cellular injury.
Monteith
D K
DK
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Theiss
J C
JC
D000410:Alanine Transaminase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008875:Middle Aged; D018697:Nootropic Agents / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013619:Tacrine / Q000633:toxicity*
D018697:Nootropic Agents; D013619:Tacrine; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase