Biological regulation of copper and selective removal of copper: Therapy for Wilson disease and its molecular mechanism

Copper (Cu) is an essential trace element and constitutes the active center of the redox Cu enzymes such as Cu, Zn-superoxide dismutase (Cu, Zn-SOD), ceruloplasmin and cytochrome c oxidase. Among hereditary diseases due to a defect in the metabolism of Cu, Menkes disease (caused by a Cu deficiency) and Wilson disease (caused by the excessive accumulation of Cu) have been s hown to be caused by the mutation of genes encoding Cu-binding ATPase for t he efflux of Cu, ATP7A and ATP7B, respectively. Following the identificatio n of these causative genes, intracellular Cu transporters (Cu chaperones) s pecific for the Golgi apparatus, mitochondria and Cu, Zn-SOD were discovere d, and these findings have facilitated the study of the underlying mechanis ms of the biological regulation of Cu. Apart from these physiological and b iochemical studies, toxicological studies have elucidated the underlying me chanisms of the occurrence of acute hepatitis caused by the accumulation of Cu accumulating in the liver of an animal model for Wilson disease, LEC ra ts. In these toxicological studies, two biological aspects of metallothione in (MT), i.e., antioxidant and prooxidant depending on the Cu/Zn ratio in C u-containing MT have been proposed. The present article overviews the recen t findings on the biological regulation of Cu and on the toxicological aspe ct of Cu. It is known that Cu forms a stable ternary complex with molybdenu m and sulfur under reductive conditions in the body. On the basis of this o bservation, tetrathiomolybdate (TTM) has been applied to remove Cu from the liver of Long-Evans rats with a cinnamon-like coat color (LEC) rats. Preci se mechanisms underlying the complex formation between Cu bound to MT and T TM were presented, and an appropriate protocol for the chelation therapy wa s also proposed together with the mechanisms underlying the occurrence of s ide-effects.