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Titolo:
ELUCIDATION OF MITOCHONDRIAL EFFECTS BY TETRAHYDROAMINOACRIDINE (TACRINE) IN RAT, DOG, MONKEY AND HUMAN HEPATIC PARENCHYMAL-CELLS
Autore:
ROBERTSON DG; BRADEN TK; URDA ER; LALWANI ND; DELAIGLESIA FA;
Indirizzi:
PARKE DAVIS PHARMACEUT RES,DEPT PATHOL & EXPT TOXICOL,2800 PLYMOUTH RD ANN ARBOR MI 48106
Titolo Testata:
Archives of toxicology
fascicolo: 6, volume: 72, anno: 1998,
pagine: 362 - 371
SICI:
0340-5761(1998)72:6<362:EOMEBT>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
ALZHEIMERS-DISEASE; LIVER-MITOCHONDRIA; HUMAN HEPATOCYTES; CONTROLLED TRIAL; CHAIN FUNCTION; INHIBITION; DECLINE; HEPATOTOXICITY; CYTOTOXICITY; RESPIRATION;
Keywords:
TETRAHYDROAMINOACRIDINE; TACRINE HEPATOTOXICITY; TACRINE METABOLITES; MITOCHONDRIAL RESPIRATION; AGE-RELATED EFFECTS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
41
Recensione:
Indirizzi per estratti:
Citazione:
D.G. Robertson et al., "ELUCIDATION OF MITOCHONDRIAL EFFECTS BY TETRAHYDROAMINOACRIDINE (TACRINE) IN RAT, DOG, MONKEY AND HUMAN HEPATIC PARENCHYMAL-CELLS", Archives of toxicology, 72(6), 1998, pp. 362-371

Abstract

Tetrahydroaminoacridine (tacrine) causes morphological and functionalchanges 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 examinedthe 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 mu g/ml. Human mitochondria were more sensitive to tacrine effects with RCR decreased 24% at 5 mu g/ml while other species were unaffected at this concentration. Thetacrine effects were characterized by increased hepatic mitochondrialState 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 mu g/ml in aged rats while mitochondria from young ratswere 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 ofpotency for decreasing RCR caused by monohydroxylated metabolites was: tacrine > 4-OH and 7-OH > 2-OH, 1-OH, and velnacrine with the lattergroup of metabolites having no effect on mitochondrial respiration atconcentrations up to 50 mu g/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 thattacrine 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 07/07/20 alle ore 14:25:52