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Relative cytotoxicity of psychotropic drugs in cultured rat hepatocytes

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Abstract

The relative cytotoxic effects of ten psychotropic drugs were assessed in rat hepatocyte monolayer cultures. Clear concentration-related toxicity was seen in the narrow range of 10−5M to S × 10−5M. The four cytotoxicity endpoints chosen were: release of the cytosolic enzyme, lactate dehydrogenase, and impairment of biosynthesis and secretion of proteins, bile acids and glycerolipids. LDH leakage and inhibition of protein secretion into the culture medium proved to be the parameters which allowed the best differentiation between the test compounds. The inhibition of glycerolipid secretion was the most sensitive test in relation to concentration and time of exposure. Based on the effects of these endpoints, the following ranking of relative in vitro toxicity, using equimolar drug concentrations, could be established: clomipramine > imipramine = thioridazine > chlorpromazine > amitriptyline = fluperlapine > haloperidol > promazine > clozapine ≫ sulpiride. This ranking order of in vitro cytotoxicity correlated well with the potential of the drugs to impair liver function in man. Only clozapine had to be classified as a false negative. There was, however, no correlation between the cytotoxicity and the intracellular accumulation of the test drugs. Furthermore, the comparison of the data obtained with psychotropics with the data from five other amphiphilic cationic drugs was consistent with the widely accepted concept of a direct toxic interaction of the drugs with cytomembranes. This nonspecific toxicity of the membrane-active drugs was further corroborated by a positive correlation between their potential to induce LDH leakage in hepatocytes and their ability to induce hemolysis in red cells. In conclusion, the results obtained in our study strongly suggest that it is possible to assess the relative cytotoxicity of psychotropic drugs in rat hepatocyte cultures. It is proposed that this in vitro system provides a useful tool to evaluate new drugs at an early stage of their development, and to identify the most promising candidates within a class of structurally related compounds. In addition, it allows information to be obtained on possible mechanisms of cytotoxicity.

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Abbreviations

AIB:

aminoisobutyric acid

AMT:

amitriptyline

BSA:

bovine serum albumin

CLP:

clomipramine

CLZ:

clozapine

CPZ:

chlorpromazine

FLU:

fluperlapine

HAL:

haloperidol

HC50 :

dose causing 50% hemolysis

IMP:

imipramine

LDH:

lactate dehydrogenase

PZ:

promazine

SUL:

sulpiride

TCA:

trichloroacetic acid

TRZ:

thioridazine

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Authors and Affiliations

  1. Preclinical Research, Sandoz Ltd., Basel, Switzerland

    Urs A. Boelsterli, Patrick Bouis & Peter Donatsch

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  1. Urs A. Boelsterli
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  2. Patrick Bouis
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  3. Peter Donatsch
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Boelsterli, U.A., Bouis, P. & Donatsch, P. Relative cytotoxicity of psychotropic drugs in cultured rat hepatocytes. Cell Biol Toxicol 3, 231–250 (1987). https://doi.org/10.1007/BF00117862

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