title: A possible mechanism of toxicity by the antidepressant amoxapine based on its effects in three in vitro models.
abstract: When the antidepressant amoxapine is taken in overdose, it can cause metabolic acidosis, brain damage and sometimes death. In previous studies, biochemical evidence has been presented that amoxapine disrupts reactions of membrane-associated multi-enzyme complexes, and mitochondrial energy conservation may be one of the first systems affected. Three in vitro systems were investigated to determine whether general membrane disruption or more specific mitochondrial effects of amoxapine could be responsible for toxicity and for lactic acid accumulation. In Saccharomyces cerevisiae, increased amoxapine concentrations led to decreased oxygen uptake associated with decreased survival of cells. In Chinese hamster ovary cells in culture, an initial increase in oxygen uptake was observed up to 10 mug amoxapine/ml and a decrease thereafter. At drug levels that caused an increased oxygen uptake, there was increased lactic acid output by cells, but no observable toxicity. At higher drug levels, the decreased oxygen uptake was accompanied by cell death, reduced lactic acid output and a change in the mitochondrial cristae configuration. Cell death in both of the above systems was attributed to interference with energy conservation. Isolated, beating guinea-pig hearts perfused with 5 mug amoxapine/ml stopped after 13 min, but no lactic acid accumulated. This may be explained by the membrane-stabilizing activity of the drug. In an arrested perfused heart, increased concentrations of amoxapine stimulated oxygen consumption and lactic acid production. Hence, membrane-stabilizing activity alone is not adequate to explain the action of amoxapine on isolated cells, and on the perfused arrested heart, or the clinical pattern of overdose, and disruption of energy conservation in cells is likely to be involved also.
authors.affiliation: Cancer Research Laboratory, University of Auckland School of Medicine, Private Bag, Auckland, New Zealand.
authors.forename: L R
authors.initials: LR
authors.lastname: Ferguson
authors.forename: G J
authors.initials: GJ
authors.lastname: Cooper
authors.forename: D S
authors.initials: DS
authors.lastname: Loiselle
authors.forename: A M
authors.initials: AM
authors.lastname: Roberton