Tacrine inhibits topoisomerases and DNA synthesis to cause mitochondrial DNA depletion and apoptosis in mouse liver.
After several weeks of treatment, levels of alanine aminotransferase (ALT) increase in 50% of patients treated with tacrine for Alzheimer's disease. We looked for progressive effects on DNA to explain delayed toxicity. We first studied the in vitro effects of tacrine on DNA replication and topoisomerase-mediated DNA relaxation. We then treated mice with doses of tacrine reproducing the human daily dose on a body area basis and studied the effects of tacrine administration for up to 28 days on hepatic DNA, mitochondrial function, and cell death. In vitro, tacrine impaired DNA polymerase gamma-mediated DNA replication and also poisoned topoisomerases I and II to increase the relaxation of a supercoiled plasmid. In vivo, administration of tacrine markedly decreased incorporation of [(3)H]thymidine into mitochondrial DNA (mtDNA), progressively and severely depleted mtDNA, and partly unwound supercoiled mtDNA into circular mtDNA. Incorporation of [(3)H]thymidine into nuclear DNA (nDNA) was barely decreased, and nDNA levels were unchanged. After 12 to 28 days of treatment, administration of tacrine increased p53, Bax, mitochondrial permeability transition, cytosolic cytochrome c, and caspase-3 activity and triggered hepatocyte apoptosis and/or necrosis. In conclusion, the intercalating drug tacrine poisons topoisomerases and impairs DNA synthesis. Tacrine has been shown to accumulate within mitochondria, and it particularly targets mtDNA. After several weeks of treatment, the combination of severe mtDNA depletion and a genotoxic stress enhancing p53, Bax, and permeability transition trigger hepatocyte necrosis and/or apoptosis.
Mansouri
Abdellah
A
INSERM Unité 481, Faculté de Médecine Xavier Bichat, Paris, France.
Haouzi
Delphine
D
Descatoire
Véronique
V
Demeilliers
Christine
C
Sutton
Angela
A
Vadrot
Nathalie
N
Fromenty
Bernard
B
Feldmann
Gérard
G
Pessayre
Dominique
D
Berson
Alain
A
D000818:Animals; D017209:Apoptosis; D004247:DNA / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D053938:DNA Fragmentation; D000074002:DNA Polymerase gamma; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology; D004270:DNA, Circular / Q000096:biosynthesis; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism*; D004278:DNA, Superhelical / Q000187:drug effects / Q000502:physiology; D004259:DNA-Directed DNA Polymerase / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000506:poisoning; D008099:Liver / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D009336:Necrosis; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000187:drug effects; D010539:Permeability; D013619:Tacrine / Q000008:administration & dosage / Q000494:pharmacology* / Q000506:poisoning; D013936:Thymidine / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D004270:DNA, Circular; D004272:DNA, Mitochondrial; D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D013619:Tacrine; D004247:DNA; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; D013936:Thymidine