Evidence that Thiosulfate Inhibits Creatine Kinase Activity in Rat Striatum via Thiol Group Oxidation.

ABSTRACT

Sulfite oxidase, molybdenum cofactor, and ETHE1 deficiencies are autosomal recessive disorders that affect the metabolism of sulfur-containing amino acids. Patients with these disorders present severe neurological dysfunction and basal ganglia abnormalities, accompanied by high levels of thiosulfate in biological fluids and tissues. Aiming to better elucidate the pathophysiology of basal ganglia damage in these disorders, we evaluated the in vivo effects of thiosulfate administration on bioenergetics, oxidative stress, and neural damage in rat striatum. The in vitro effect of thiosulfate on creatine kinase (CK) activity was also studied. In vivo findings showed that thiosulfate administration decreased the activities of CK and citrate synthase, and increased the activity of catalase 30 min after administration. Activities of other antioxidant enzymes, citric acid cycle, and respiratory chain complex enzymes, as well as glutathione concentrations and markers of neural damage, were not altered by thiosulfate 30 min or 7 days after its administration. Thiosulfate also decreased the activity of CK in vitro in striatum of rats, which was prevented by the thiol reducing agents dithiothreitol (DTT), the antioxidants glutathione (GSH), melatonin, trolox (hydrosoluble analogue of vitamin E), and lipoic acid. DTT and GSH further prevented thiosulfate-induced decrease of the activity of a purified CK in a medium devoid of biological samples. These data suggest that thiosulfate inhibits CK activity by altering critical sulfhydryl groups of this enzyme. It may be also presumed that bioenergetics impairment and ROS generation induced by thiosulfate are mechanisms underlying the neuropathophysiology of disorders in which this metabolite accumulates.