Interactions of bismuth complexes with metallothionein(II)

Abstract

Bismuth complexes are widely used as anti-ulcer drugs and can significantly reduce the side effects of platinum anti-cancer drugs. Bismuth is known to induce the synthesis of metallothionein (MT) in the kidney, but there are few chemical studies on the interactions of bismuth complexes with metallothionein. Here we show that Bi3+ binds strongly to metallothionein with a stoichiometry bismuth:MT = 7:1 (Bi7MT) and can readily displace Zn2+ and Cd2+. Bismuth is still bound to the protein even in strongly acidic solutions (pH 1). Reactions of bismuth citrate with MT are faster than those of [Bi(EDTA)]-, and both exhibit biphasic kinetics. 1H NMR data show that Zn2+ is displaced faster than Cd2+, and that both Zn2+ and Cd2+ in the β-domain (three metal cluster) of MT are displaced by Bi3+ much faster than from the α-domain (four metal cluster). The extended x-ray absorption fine structure spectrum of Bi7MT is very similar to that for the glutathione and N-acetyl-L-cysteine complexes [Bi(GS)3] and [Bi(NAC)3] with an inner coordination sphere of three sulfur atoms and average Bi-S distances of 2.55 Å. Some sites appear to contain additional short Bi-O bonds of 2.2 Å and longer Bi-S bonds of 3.1 Å. The Bi3+ sites in Bi7MT are therefore highly distorted in comparison with those of Zn2+ and Cd2+.