Inhibition of phospholipid degradation and changes of the phospholipid-pattern by desipramine in cultured human fibroblasts

Abstract

Cationic amphiphilic drugs produce profound changes in phospholipid metabolism when administered in high doses over an extended period of time [l]. In a variety of tissues of animals and man and also in cultured cells they form microscopically visible lamellar bodies within the cell. These bodies have been identified as lysosomes containing excess membrane phospholipids. Analyses of the accumulated individual phospholipids have shown a disproportionally high content of acidic phospholipids. It has been speculated that cationic drugs including tricyclic antidepressants change the physico-chemical properties of phospholipids in biological membranes by complex formation which alters their turnover rates. Thus, these drugs could interfere with membrane-linked phenomena such as fusion of vesicles, permeability and receptor functions [2]; e.g. tricyclic antidepressants have been shown to reduce the number of beta-adrenergic receptor sites in brain and peripheral organs of rats as part of their regular drug effects [3]. Two different mechanisms have been discussed to explain lysosomal phospholipid accumulation in drug-treated cells. One involves storage of drugphospholipid complexes in the lysosomes as the result of a decreased breakdown of these phospholipids [l, 4, 51. The other hypothesis suggests a drug-induced increase of the selective synthesis of acidic phospholipids together with an inhibition of lysosomal phospholipid degradation [6,7]. In the present paper the effect of desipramine (DMI) on the phospholipid metabolism in cultured human skin fibroblasts was studied using [14C]-glycerol and [3H]-inositol as markers for phospholipids. The aim of the study was to differentiate between possible hypothetic mechanisms of drug effects leading to phospholipid accumulation in living cells.