Pantetheinase activity and cysteamine content in cystinotic and normal fibroblasts and leukocytes

Abstract

Cysteamine is the most effective agent known for the reduction of the elevated cystine content of cells from patients with cystinosis. A defect in endogenous cysteamine generation could account for many of the metabolic features of this disorder. To test this hypothesis, we have developed improved methods for measuring pantetheinase (cysteamine-generating) activity and intracellular cysteamine levels and used these methods to measure such parameters in cystinotic and normal leukocytes and cultured skin fibroblasts. Pantetheinase activity as defined in the text was similar in extracts of cystinotic and normal cells [leucocytes, normal, 78 ± 15 (S.E.), cystinotic, 56 ± 6.4; fibroblasts, normal, 9.4 ± 1.5; cystinotic, 7.7 ± 1.7]. Cysteamine levels were normal in leukocytes from cystinotics receiving no cysteamine or doses of oral cysteamine too low to reduce leukocyte cystine content. The results indicate that the cause of cystinosis is unlikely to be related to a failure to generate or sustain normal intracellular cysteamine levels. Speculation: Cysteamine is an extremely effective cystine depleting agent for cystinotic fibroblasts in vitro and can greatly reduce cystinotic leukocyte cystine content in vivo. Its pharmacologic properties suggest that it might prove to be of value in the therapy of cystinosis. However, we do not believe that a defect in endogenous cysteamine generation is a characteristic of cystinotic cells. The eventual elucidation of the cystinotic defect may require analysis of the permeability characteristics of cystinotic lysosomes or the discovery of presently unidentified pathways for lysosomal metabolism of cystine. © 1981 International Pediatric Research Foundation, Inc.