Cysteamine prevents inhibition of thiol-containing enzymes caused by cystine or cystine dimethylester loading in rat brain cortex.

Cystinosis is a systemic genetic disease caused by a lysosomal transport deficiency accumulating cystine in the lysosomes of all tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are still obscures. Considering that thiol-containing enzymes are critical for several metabolic pathways, our main objective was to investigate the effects of cystine or cystine dimethylester load on the thiol-containing enzymes creatine kinase and pyruvate kinase, in the brain cortex of young Wistar rats. The animals were injected twice a day with 1.6 micromol/g body weight of cystine dimethylester or 1 micromol/g body weight of cystine and/or 0.46 micromol/g body weight of cysteamine from the 16th to the 20th postpartum day and sacrificed after 12 h. Cystine or cystine dimethylester administration inhibited the two enzyme activities. Co-administration of cysteamine, the drug used to treat cystinotic patients, normalized the two enzyme activities. Lactate dehydrogenase activity, a nonthiol-containing enzyme was not affected by cystine dimethylester administration. Cystine inhibits creatine kinase and pyruvate activities possibly by oxidation of the sulfhydryl groups of the enzymes. Considering that creatine kinase and pyruvate kinase, like other thiol-containing enzymes, are crucial for energy homeostasis and antioxidant defenses, the enzymes inhibition caused by cystine released from lysosomes could be one of the mechanisms of tissue damage in patients with cystinosis.

Inhibition of creatine kinase activity by cystine in the kidney of young rats.

Nephropathic cystinosis is a lethal genetic disease caused by a lysosomal transport disorder leading to intralysosomal cystine accumulation in all tissues. Cystinosis is the most common inherited cause of Fanconi syndrome, but the mechanisms by which cystine causes tissue damage are not fully understood. Thiol-containing enzymes are critical for renal energy metabolism and may be altered by disulfides like cystine. Therefore, in the present study our main objective was to investigate the in vivo and in vitro effects of cystine on creatine kinase, which contains critical thiol groups in its structure, in the kidney of young Wistar rats. We observed that cystine inhibited in vivo and in vitro the enzyme activity and that this inhibition was prevented by cysteamine and glutathione. The results suggest oxidation of essential sulfhydryl groups necessary for creatine kinase function by cystine. Considering that creatine kinase and other thiol-containing enzymes are crucial for renal energy metabolism, and programmed cell death occurs in situations of energy deficiency, the enzyme inhibition caused by cystine released from lysosomes might be a mechanism of tissue damage in patients with cystinosis.