Cultured corneal fibroblasts as a model system for the demonstration of drug-induced mucopolysaccharidosis

Abstract

The purpose of the present investigation was to establish a cell culture system suitable for demonstrating the drug-induced lysosomal storage of sulfated glycosaminoglycans (GAGs). This is a drug side-effect which was previously studied in animals treated with the di-cationic amphiphilic compound tilorone and congeners, and which is likely to occur in humans, too. Cultured corneal fibroblasts of rats were exposed to tilorone for 72 h. They developed histochemical and cytochemical alterations indicative of mucopolysaccharidosis and resembling those occurring in vivo. The threshold drug concentration was found to be below 0.7 microM. The reversibility of the lysosomal GAG storage was low. An increase in the drug concentration to 10 microM produced additional unspecific lysosomal alterations, while the mucopolysaccharidosis-like lesions became less prominent. Concentrations of 40 microM and 80 microM caused unspecific cytoplasmic vacuolation and cell death, respectively. The present model system appears suitable for screening investigations of newly developed drugs with respect to their mucopolysaccharidosis-inducing potential and for investigating the structure-activity relationships underlying this adverse drug effect. Care should be taken not to use too high drug concentrations which cause unspecific lysosomal lesions.