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Gastroenterology. 1996 Jun;110(6):1878-90.

Uncoupling of rat and human mitochondria: a possible explanation for tacrine-induced liver dysfunction.

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1
INSERM Unité 24, Hôpital Beaujon, Clichy, France.

Abstract

BACKGROUND & AIMS:

Tacrine administration (1-3 mg/kg) may lead to sinusoidal concentrations in the micromolar range and produce liver dysfunction in 50% of recipients. The aim of this study was to determine the cellular effects of tacrine that account for liver dysfunction.

METHODS:

The effects of tacrine on mitochondrial function were determined in isolated rat liver mitochondria, cultured rat hepatocytes, and isolated human lymphocytes.

RESULTS:

In vitro, tacrine was taken up by rat liver mitochondria, decreased their membrane potential, and stimulated their respiration. Ex vivo, respiration was increased in rat mitochondria isolated 30 minutes after the administration of 2 mg of tacrine per kilogram. After 7 days of culture, tacrine (2.5 mumol/L) decreased rat hepatocyte adenosine triphosphate levels. Ten micromolar decreased 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium reduction and neutral red uptake without modifying cell glutathione, the morphology of the endoplasmic reticulum, or protein synthesis. Tacrine (1.25 mumol/L) decreased levels of adenosine triphosphate in human lymphocytes.

CONCLUSIONS:

The weak base tacrine exerts a protonophoric effect in mitochondria that wastes energy and decreases levels of adenosine triphosphate in rat and human cells. These effects are visible after clinically relevant doses of tacrine and might be involved in tacrine-induced liver dysfunction.

PMID:
8964414
[Indexed for MEDLINE]

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