Interaction of sodium chloroplatinate and iproplatin with metallothionein in vivo.

The abilities of platinum(IV) complexes to induce the biosynthesis of metallothionein (MT) were investigated in rabbits given injections s.c. of sodium chloroplatinate (Na2PtCl6) and iproplatin (cis-dichloro-bis-isopropylamine-trans-dihydroxylplatinum IV). It is revealed for the first time that both complexes can induce MT synthesis in the liver and the kidney, but the induction ability was weaker compared to Zn2+ compounds. The induced MT was purified and identified. The hepatic MT resulting from Na2PtCl6 injection only contained Zn, whereas the hepatic MT from iproplatin injection and the renal MT from injection of both complexes contained 4-5 Zn and 1-2 Pt per mole of protein, and the renal MT also contained 1-2 Cu per mole of protein. The oxidation state of platinum in the MT is +2 as determined by X-ray photoelectron spectroscopic measurements. Pretreatment with Zn(NO3)2 elevated the levels of MT, but the binding of Pt to MT was significantly less compared to that without Zn(NO3)2 pretreatment. The data obtained from the amino acid composition analysis were consistent with the theoretical values. Upon these bases, the role of MT in relation to its involvement in the metabolism of Pt(IV) complexes and the mechanism of drug resistance to the Pt(IV) complexes as antitumor agents are discussed.