ELUCIDATION OF MITOCHONDRIAL EFFECTS BY TETRAHYDROAMINOACRIDINE (TACRINE) IN RAT, DOG, MONKEY AND HUMAN HEPATIC PARENCHYMAL-CELLS

Tetrahydroaminoacridine (tacrine) causes morphological and functional changes in the endoplasmic reticulum, ribosomes, and mitochondria in t he liver of humans and animals. In order to investigate species differ ences as well as to understand the morphological changes, we examined the effects of tacrine on respiration and electron transport in mitoch ondria isolated from rat, dog, monkey, and human liver. Tacrine produc ed significantly decreased respiratory control ratios (RCR) in all spe cies at concentrations ranging from 5 to 25 mu g/ml. Human mitochondri a were more sensitive to tacrine effects with RCR decreased 24% at 5 m u g/ml while other species were unaffected at this concentration. The tacrine effects were characterized by increased hepatic mitochondrial State 4 respiration in rats and decreased State 3 respiration in human s. Mitochondria from aged rats were more sensitive to the effects of t acrine than mitochondria from young animals, with significantly decrea sed RCR at 10 mu g/ml in aged rats while mitochondria from young rats were unaffected at this concentration. Concomitant with the respirator y changes, mitochondrial DNA synthesis was impaired. Since tacrine und ergoes extensive biotransformation, we also explored the possibility t hat metabolites could exert detrimental effects. The ranking order of potency for decreasing RCR caused by monohydroxylated metabolites was: tacrine > 4-OH and 7-OH > 2-OH, 1-OH, and velnacrine with the latter group of metabolites having no effect on mitochondrial respiration at concentrations up to 50 mu g/ml. In vivo administration of 20 mg/kg ta crine to rats for up to 20 days caused a paradoxical increase in RCR a nd P/O on Day 1 and decreased RCR on Days 9 and 20, the later findings being consistent with in vitro data. From these data we propose that tacrine does not necessarily have to be metabolized to exert effects o n mitochondria at different sites in the electron transport chain that differ among species. These effects are exacerbated in mitochondria f rom older animals and humans appear to be more sensitive than the labo ratory animals studied.