Binding properties of an orally active platinum anti-tumor drug JM216 withmetallothionein in vivo

The abilities of the orally active platinum anti-tumor drug JM216 [trans-bi s-acetato-cis-dichloroammine (cyclohexylamine) platinum (IV)] to induce the biosynthesis of metallothionein (MT) were investigated in rabbits given or al administrations or injections s. c. It is revealed that oral administrat ion of JM216 can induce the MT synthesis in the liver but not in the kidney . The hepatic MT contained 7.11 +/- 0.11 Zn and only little Pt or Cu. Injec tions of JM216 to rabbits can greatly elevate the MT levels in the liver, b ut increase the renal MT levels only slightly. The MT content as well as Pt concentration in the liver was much higher than that in the kidney. The me tal stoichiometry in the purified renal MT was determined to be 4.41 +/- 0. 04 Zn, 0.36 +/- 0.11 Pt and 2.50 +/- 0.18 Cu per mole protein. The hepatic MT was still characterized as Zn7MT. Both the treatment with oral administr ation and injections s.c. cannot lead to the increase of Pt content in the kidney. The oxidation state of platinum in the MT from the kidney was deter mined to be +2 by X-ray photoelectron spectroscopy. As compared with zinc c ompounds, JM216 was a very poor stimulator for MT biosynthesis in vivo. Pre -injections with Zn(NO3)(2) significantly enhanced the MT levels as well as the Pt concentration compared with that resulting from injections with JM2 16 alone. Based on the experimental data, the role of MT in relation to its involvement in the metabolism and the mechanism of detoxification of Pt(IV ) complexes are discussed.