metallothionein and zinc-nitrate

The abilities of the orally active platinum anti-tumor drug JM216 [trans-bis-acetato-cis-dichloroammine (cyclohexylamine) platinum (IV)] to induce the biosynthesis of metallothionein (MT) were investigated in rabbits given oral administrations or injections s.c. It is revealed that oral administration 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. Injections of JM216 to rabbits can greatly elevate the MT levels in the liver, but 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 metal 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 administration 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 determined to be +2 by X-ray photoelectron spectroscopy. As compared with zinc compounds, 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 JM216 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.

Topics: Animals; Antineoplastic Agents; Binding Sites; Injections, Subcutaneous; Intubation, Gastrointestinal; Kidney; Liver; Male; Metallothionein; Nitrates; Organ Specificity; Organoplatinum Compounds; Oxidation-Reduction; Platinum; Rabbits; Zinc Compounds

This paper will be the first to discuss the in vivo and in vitro properties of a Pd(II) complex, K2PdCl4, interacting with metallothioneins (MTs). In vivo experiments revealed that intraperitoneal injections of K2PdCl4 into rabbits led to the simultaneous synthesis of Pd-MT in the kidney and Zn7MT in the liver. The renal Pd-MT complex contains 3.6 +/- 0.3 Pd, 2.1 +/- 0.2 Zn, and 1.0 +/- 0.1 Cu per mole protein. It was found that pre-treatment with Zn(NO3)2 before K2PdCl4 injections significantly enhanced renal Pd-MT level. The same pre-treatment also increases hepatic Zn-MT levels. These results strongly suggest that Pd(II) ions can be bound in vivo by MT existing in the rabbit kidneys to form Pd-MT. Gel-filtration chromatographic studies after the incubation of either native Cd5Zn2MT2 or Zn7MT2 with K2PdCl4 in vitro demonstrate that Pd(II) ions promote the non-oxidative oligomerization of native MTs. Increasing the level of Pd(II) relative to MT led to a concomitant increase in the apparent yield of MT oligomers. At relatively low Pd-MT ratio, Pd(II) is found predominantly in the oligomers while the monomeric products are chiefly composed of the reactants, Cd5Zn2MT2 or Zn7MT2. Based on our experimental data, the mechanisms of the reactions between Pd(II) and MTs in vivo and in vitro are discussed.

Topics: Animals; Chlorides; Chromatography, Gel; Kidney; Liver; Male; Metallothionein; Nitrates; Palladium; Rabbits; Tissue Distribution; Zinc Compounds

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.

Topics: Animals; Antineoplastic Agents; Kidney; Liver; Male; Metallothionein; Nitrates; Organoplatinum Compounds; Oxidation-Reduction; Platinum; Platinum Compounds; Rabbits; Zinc Compounds

The properties of platinum (II) complexes to induce the biosynthesis of metallothionein (MT) were investigated in rabbits following injections of K2PtCl4, cis and trans isomers of DDP (diammine-dichloroplatinum). It was demonstrated that cis-DDP has an ability to induce MT specifically in the liver, whereas trans-DDP appears to be unable to stimulate the biosynthesis of MT in either the liver or the kidneys. In contrast, K2PtCl4 is effective to elevate the MT level in both tissues. However, all of these platinum complexes are rather poor stimulators for MT biosynthesis compared to cadmium and zinc compounds. Preinjection with Zn(NO3)2 significantly enhances the amount of Pt associated with the MT fractions compared to that resulting from injections with either cis- or trans-DDP without Zn(NO3)2 pretreatment. Metallothionein containing Pt was purified and identified from the liver and kidneys of rabbits after preinjections with Zn(NO3)2 followed by repeated injections of cis-DDP and trans-DDP, respectively. It was found for the first time that a relatively higher degree of Pt was associated with MT fractions in the case of trans-DDP treatment than that of cis-DDP injection. On this basis, the role of MT was discussed in relation to its involvement in the metabolism of cis-DDP, and the difference of the antitumor activity and toxicity between cis- and trans-DDP.

Topics: Animals; Cisplatin; Kidney; Liver; Metallothionein; Nitrates; Protein Binding; Rabbits; Stereoisomerism; Tissue Distribution; Zinc Compounds