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Metallothionein (MT)1 is an intriguing, low molecular mass (ϳ7 kDa), cysteine-and metal-rich protein. It was first isolated from equine renal cortex 40 years ago (1) and contains 61 amino acids, of which 20 are cysteine residues. Since then, similar proteins have been isolated from the kidney, liver, and intestines of a variety of animal species (2), fungi (3, 4), plants (5), and metal-resistant bacteria (6 -8). The two major isoforms of mammalian MT (MT(I) and MT(II)) differ only in minor sequence changes and overall charge. Recently, the discovery of a growth inhibitory factor (GIF) from human brain tissue and nerve and its characterization as a metallothionein (MT-III) has stimulated new interests in studying this small protein (9, 10).The functions of metallothionein are still not fully understood. It appears to play a fundamental role in the metabolism of copper and zinc ions under various physiological conditions (11, 12), including its ability to donate metal ions to apo-Zn 2ϩ enzymes (13,14 (18,19), thereby preventing reactions with other cellular targets in mammals and other higher organisms (20). Metallothionein also appears to play a role in radical scavenging, stress response, and the pharmacology of metallodrugs and alkylating agents (12,21,22).The best characterized mammalian metallothioneins contain a single polypeptide chain with seven bound metal ions (either Zn 2ϩ or Cd 2ϩ ). The x-ray crystal structure of rat liver Zn 2 Cd 5 -MT(II) (23) and NMR solution structures of rabbit liver Cd 7 -MT(II) (24), rat liver Cd 7 -MT(II) (25), and human liver Cd 7 -MT (26) show that metallothionein contains two structurally independent ␣ (C-terminal) and  (N-terminal) domains, which are linked in the protein via two amino acids. The seven metal ions are present in clusters of four and three metals bound to bridging and terminal cysteine thiolate ligands, with metal-tothiolate ratios of M 4 S 11 and M 3 S 9 for the ␣-and -domains, respectively (23). When both Zn 2ϩ and Cd 2ϩ are present, Cd 2ϩ binds preferentially to the ␣-domain, whereas Zn 2ϩ is found preferentially in the -domain (23, 28). A Zn 2 Cd three-metal cluster ( domain) in MT has the same structure as a Cd 3 cluster (23). The ␣-domain binds Cd 2ϩ ions cooperatively (29). All 20-cysteine residues participate in metal binding, and each of the seven Zn 2ϩ or Cd 2ϩ ions is tetrahedrally coordinated to four cysteine thiolate sulfur atoms (30,31).Bismuth is known to induce the synthesis of renal metallothionein (32), and it has been shown that pretreatment with bismuth complexes can prevent the toxic side effects of the anti-cancer drug cisplatin without compromising its anti-tumor activity (33)(34)(35)(36)