| Abstrakt: |
This review deals with drug-induced lipidoses and the possible underlying mechanisms. A variety of drugs, widely differing in their main pharmacological actions, but closely resembling each other with respect to particular physiochemical properties, have been found to cause in animals and man cytological alterations that are reminiscent of the inherited lipid-storage diseases of man. Ultrastructurally, the alterations are characterized by multilamellated or crystalloid cytoplasmic inclusions, i.e., residual bodies resulting from an intralysosomal accumulation of polar lipids. Biochemically, some of the most severely affected tissues have been demonstrated to contain increased amounts of phospholipids and of the drug applied. All drugs hitherto found to induce such alterations are cationic amphiphilic (amphipathic) compounds; they possess a highly apolar ring system and a cationic hydrophilic side chain (e.g., triparanol, chloroquine, chlorzyclizine, 4,4′′-diethylaminoethoxyhexestrol, chlorphentermine, iprindole, imipramine). Nuclear magnetic resonance spectrographic measurements have revealed strong interaction of some of these compounds with phospholipids in vitro. As to the mechanisms underlying the adverse drug action, it is suggested that phospholipids, when associated with the drug, are less readily degraded by phospholipases and gradually accumulate within lysosomes. A strong lipid-drug interaction in vitro does not necessarily imply pronounced lipidosis-like alterations in vivo, since pharmacokinetics and drug metabolism may introduce modifying factors. |
