KINETICS OF THE REACTION OF PLATINUM(II) COMPLEXES WITH METALLOTHIONEIN

Properties of the reactions of cis-dichlorodiammineplatinum (II)(cis-DDP) and related complexes with rabbit liver zinc-+ or apo-thionein have been investigated. A similar product containing 7.0 mol Pt(II) per mol of protein is obtained when excess cis-DDP or other Pt(II) complexes were reacted with Zn(7)MT(2) at neutral pH. The kinetics of reactions are triphasic as monitored by the formation of Pt-thiolate. The pseudo first-order rate constants k(I), k(II), and k(III) corresponding to three rate-limiting steps are determined, respectively. The results show that the first rate step is sensitive to the nature of the ligands occupying the other two coordination sites in diammine-Pt(II), whereas k(II) and k(III) do not change markedly toward different conditions. Significantly, trans-DDP has a strong kinetic preference for MT compared with cis-DDP. A mechanism for these reactions is proposed in which all of the hydrolysis species of platinum(II) complexes react directly with metallothionein followed by the loss of ammine ligands as the product is formed. The obtained kinetic data are discussed in relation to the antitumor activity and toxicity of platinum(II) complexes.