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.
Rech
Virginia Cielo
VC
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Rua Ramiro Barcelos 2600, CEP 90.035-003, Porto Alegre, Rio Grande do Sul, Brazil.
Feksa
Luciane Rosa
LR
Fleck
Rochele Marisa Müller
RM
Athaydes
Genaro Azambuja
GA
Dornelles
Paula Karina Barcelos
PK
Rodrigues-Junior
Valnes
V
Wannmacher
Clovis Milton Duval
CM
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002540:Cerebral Cortex / Q000201:enzymology* / Q000503:physiopathology; D003402:Creatine Kinase / Q000378:metabolism*; D003543:Cysteamine / Q000494:pharmacology / Q000627:therapeutic use; D003553:Cystine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D003554:Cystinosis / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008247:Lysosomes / Q000201:enzymology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011770:Pyruvate Kinase / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000975:Antioxidants; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D003553:Cystine; D003543:Cysteamine; D011770:Pyruvate Kinase; D003402:Creatine Kinase; C034582:cystine dimethyl ester