Psychotropic drugs as inhibitors of glycerolipid biosynthesis and secretion in primary rat hepatocyte cultures

Abstract

Glycerolipid synthesis and secretion in rat hepatocyte monolayer cultures have been studied as possible endpoints in cytotoxicity assays. Ten psychotropic drugs of different structural classes were incubated with the hepatocytes at concentrations ranging from 10 −6 m to 5 × 10 −5 m and their effects on the incorporation of [ 3H]glycerol into glycerolipids and on the subsequent lipid secretion into the medium were measured. After 2-hr exposures to eight of the ten drugs, glycerolipid secretion was inhibited as a function of the drug concentration. The integrity of the plasma membrane, however, was still preserved, as no leakage of the cytosolic enzyme, lactate dehydrogenase, occurred. The incorporation of [ 3H]glycerol into the total cell-associated glycerolipid fraction was much less affected by the drugs than was the medium-associated fraction. In this model, the tricyclic antidepressants, imipramine, clomipramine and amitriptyline caused a marked inhibition of in vitro glycerolipid secretion. Chlorpromazine, thioridazine, fluperlapine, haloperidol and promazine were of intermediate potency, and clozapine and sulpiride had no inhibitory effect on glycerolipid secretion. A significant inhibition of glycerolipid secretion was also seen after exposure to low concentrations (10 −5 m) of the non-psychotropic drugs, amiodarone, perhexiline and chloroquine, indicating that the cationic amphiphilic nature of all of the drugs studied accounted for the toxic effect. The results suggest that the assessment of the inhibitory effect on glycerolipid secretion is a sensitive endpoint for cytotoxicity which, in combination with other in vitro tests (e.g. determination of protein and bile acid biosynthesis and secretion, and enzyme leakage), allows a ranking of the relative toxicity of psychotropic drugs.