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Lipidosis-like alterations in cultured macrophages exposed to local anaesthetics
Abstract:
In this ultrastructural study, the simple model of cultured rat peritoneal macrophages was used to examine whether local anaesthetics can induce lipidosis-like alterations. Exposure (24h) of macrophages to 1 X 10(-5) M dibucaine, or to 5 X 10(-5) M tetracaine, quinidine, and quinine, respectively, led to the occurrence of lamellated cytoplasmic inclusions in most cells. This is interpreted as indicating lipidosis. Type and degree of alterations were similar to those induced by the reference compound chlorphentermine (5 X 10(-5) M) for which lipidosis has previously been shown by biochemical methods. Tocainide (5 X 10(-5) M) caused weak alterations only; procaine (5 X 10(-5) M) was without effect. The differential potencies presently observed are paralleled by differential affinities of the local anaesthetics towards polar lipids as determined by other authors. The present results support the hypothesis that the lipidosis-inducing potency inherent to an amphiphilic cationic drug can be tentatively predicted on the basis of its affinity to polar lipids, although it may be obscured by secondary factors when the drug is administered to intact organisms. The present communication emphasizes the advantage of cell cultures over animal experiments for studying the structure-response relationships underlying drug-induced lipidosis, and to reliably ascertain that a given drug has only low lipidosis-inducing potency or none at all as found for tocainide and procaine, respectively.
Insights
Local anesthetics like dibucaine and tetracaine can cause lipidosis-like changes in macrophages. Drug affinity for polar lipids may predict this drug-induced lipidosis potential.
Area of Science:
- Cell Biology
- Pharmacology
- Toxicology
Background:
- Lipidosis, characterized by lipid accumulation, can be induced by certain drugs.
- Understanding the mechanisms of drug-induced lipidosis is crucial for drug safety.
- Cultured cells offer a simplified model for studying drug-induced cellular alterations.
Purpose of the Study:
- To investigate whether local anesthetics induce lipidosis-like alterations in cultured rat peritoneal macrophages.
- To explore the relationship between the chemical properties of local anesthetics and their potential to induce lipidosis.
- To evaluate the utility of cell cultures for predicting drug-induced lipidosis.
Main Methods:
- Cultured rat peritoneal macrophages were exposed to various local anesthetics (dibucaine, tetracaine, quinidine, quinine, tocainide, procaine) and chlorphentermine.
- Ultrastructural analysis was performed to identify cellular alterations, specifically lamellated cytoplasmic inclusions indicative of lipidosis.
- The observed alterations were compared to those induced by a known lipidosis-inducing agent, chlorphentermine.
Main Results:
- Dibucaine, tetracaine, quinidine, and quinine induced lamellated cytoplasmic inclusions, interpreted as lipidosis, in macrophages.
- The observed alterations were comparable to those induced by chlorphentermine.
- Tocainide showed only weak alterations, while procaine had no effect.
- The differential potencies correlated with the known affinities of these drugs for polar lipids.
Conclusions:
- Local anesthetics can induce lipidosis-like changes in macrophages, suggesting a potential cellular toxicity mechanism.
- The lipidosis-inducing potency of amphiphilic cationic drugs may be predictable based on their affinity for polar lipids.
- Cell cultures provide an advantageous model for studying drug-induced lipidosis and assessing drug safety compared to animal experiments.