title: Cysteamine prevents inhibition of thiol-containing enzymes caused by cystine or cystine dimethylester loading in rat brain cortex.
abstract: 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.
authors.affiliation: 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.
authors.forename: Virginia Cielo
authors.initials: VC
authors.lastname: Rech
authors.forename: Luciane Rosa
authors.initials: LR
authors.lastname: Feksa
authors.forename: Rochele Marisa Müller
authors.initials: RM
authors.lastname: Fleck
authors.forename: Genaro Azambuja
authors.initials: GA
authors.lastname: Athaydes
authors.forename: Paula Karina Barcelos
authors.initials: PK
authors.lastname: Dornelles
authors.forename: Valnes
authors.initials: V
authors.lastname: Rodrigues-Junior
authors.forename: Clovis Milton Duval
authors.initials: CM
authors.lastname: Wannmacher
mesh_terms: 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
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D003553:Cystine; D003543:Cysteamine; D011770:Pyruvate Kinase; D003402:Creatine Kinase; C034582:cystine dimethyl ester