Elucidation of mitochondrial effects by tetrahydroaminoacridine (tacrine) in rat, dog, monkey and human hepatic parenchymal cells

Abstract

Tetrahydroaminoacridine (tacrine) causes morphological and functional changes in the endoplasmic reticulum, ribosomes, and mitochondria in the liver of humans and animals. In order to investigate species differences as well as to understand the morphological changes, we examined the effects of tacrine on respiration and electron transport in mitochondria isolated from rat, dog, monkey, and human liver. Tacrine produced significantly decreased respiratory control ratios (RCR) in all species at concentrations ranging from 5 to 25 microg/ml. Human mitochondria were more sensitive to tacrine effects with RCR decreased 24% at 5 microg/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 humans. Mitochondria from aged rats were more sensitive to the effects of tacrine than mitochondria from young animals, with significantly decreased RCR at 10 microg/ml in aged rats while mitochondria from young rats were unaffected at this concentration. Concomitant with the respiratory changes, mitochondrial DNA synthesis was impaired. Since tacrine undergoes extensive biotransformation, we also explored the possibility that 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 microg/ml. In vivo administration of 20 mg/kg tacrine to rats for up to 20 days caused a paradoxical increase in RCR and 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 on mitochondria at different sites in the electron transport chain that differ among species. These effects are exacerbated in mitochondria from older animals and humans appear to be more sensitive than the laboratory animals studied.

In-vitro stability and metabolism of a tacrine–silibinin codrug

“…The mechanism of tacrine's toxicity is not yet fully understood. A possible role of mitochondrial dysfunction and uncoupling is discussed in the literature . One such mechanism is the onset of mitochondrial permeability transition caused by opening of permeability transition pores in the inner mitochondrial membrane.…”

Drug-Associated Mitochondrial Toxicity and its Detection

“…The RCR is determined by the rate of respiration in the presence of ADP (state 3 or phosphorylating respiration) divided by the rate obtained after the expenditure of ADP, or state 4. Typical RCR values in isolated control mitochondria can range from 4 -6.5 depending upon the age of the donor, species, substrate choice, and organ source [76][77][93][94]. Contaminating organelles can include microsomes and peroxisomes [83] or in brain preparations, synaptosomes.…”

“…Rat brain and liver mitochondria differ in the baseline behavior of the MPT and responses to modifiers of PT [76]. Human mitochondria are more sensitive to the effects of tacrine on respiration rate than rat, dog, or monkey mitochondria [77]. These examples demonstrate the diversity of mitochondrial toxicants, the variety of mitochondrial targets, variability in sensitivity depending upon the source, and some of the organ or organ system toxicities initiated by them.…”

Animal Models of Human Disease in Drug Safety Assessment

“…Again, it can be surmized that certain drugs, which are used to treat such neurodegenerative diseases (e.g., tolcapone or tacrine) and that themselves are known to potentially impair mitochondrial function (Berson et al, 1996;Robertson et al, 1998;Haasio et al, 2002;Smith et al, 2003), might exacerbate the underlying mitochondrial injury. This could become toxicologically relevant under two conditions; first, in tissues or cells with a high energy demand and a high mitochondrial density, and second, and importantly, in cells which have the capacity to enzymatically bioactivate the drug to a reactive metabolite that is ultimately responsible for the mitochondrial functional damage.…”