Mechanistic aspects of the dithiocarbamate-induced mobilization of cadmium.

The examination of some of the species involved in the in vivo processes in which dithiocarbamates mobilize cadmium from its intracellular deposits indicates that several competing reactions occur. Rates of hydrolytic decomposition of a series of dithiocarbamates capable of mobilizing cadmium in vivo have been determined, and the solubility behavior and nuclear magnetic resonance (NMR) spectra of their cadmium complexes have been examined. Some of the dithiocarbamates most effective in this mobilization process are shown to undergo slow conversion to oxazolidine-2-thiones in the presence of cadmium. All of the cadmium complexes involved in the mobilization process are shown to undergo rapid ligand exchange. While dissociative mechanisms based on the turnover of metallothionein are inconsistent with the experimental data, at least two associative mechanisms are possible. These involve attack on the metallothionein by the dithiocarbamate itself or by a compound derived from it by known metabolic processes.

Optimal dithiocarbamate structure for immunomodulator action.

While the commercially available sodium diethyldithiocarbamate (DEDTC) has been used by several groups in the treatment of AIDS patients, chemical evidence suggests that other dithiocarbamates which are more stable at pH 7.4 might prove to be quite superior for this purpose. Of these other compounds, sodium pyrrolidinedithiocarbamate (PDTC) and sodium di-n-propyldithiocarbamate (DPDTC) which have much longer half lives at pH 7.4, are expected to exhibit similar lipophilicity to DEDTC but superior stability towards hydrolysis. They can be expected to be superior to DEDTC, especially for oral administration.

Non-Watson-Crick structures in oligodeoxynucleotides: self-association of d(TpCpGpA) stabilized at acidic pH.

The 1H NMR spectrum of the tetradeoxynucleotide d(TpCpGpA) was examined as a function of temperature, pH, and concentration. At pH 7 and above the solution conformation for this oligodeoxynucleotide appears to be a mixture of random coil and Watson-Crick duplex. At 25 degrees C, a pH titration of d(TpCpGpA) shows that distinct conformational changes occur as the pH is lowered below 7.0. These conformational changes are reversible upon readjusting the pH to neutrality, indicating the presence of a pH-dependent set of conformational equilibria. At 25 degrees C, the various conformational states in the mixture are in rapid exchange on the NMR time scale. Examination of the titration curve shows the presence of distinct conformational states at pH greater than 7, and between pH 4 and pH 5. At pH less than 4, a third conformational state is present. When the pH titration is repeated at 5 degrees C, the conformational equilibria are in slow exchange on the NMR time scale; distinct signals from each conformational state are observable. The stable conformational state present between pH 4 and pH 5 represents an ordered conformation of d(TpCpGpA) which dissociates to a less ordered structure upon raising the temperature. This ordered conformation does not result from an intramolecular rearrangement, as is shown by by spectra obtained by varying oligodeoxynucleotide concentration at constant pH. The ordered conformation differs from the Watson-Crick helix, as is shown from nuclear Overhauser enhancement experiments, as well as chemical shift data. An ordered conformation for d(TpCpGpA) was previously reported [Reid, D. G., Salisbury, S. A., Brown, T., & Williams, D. H. (1985) Biochemistry 24, 4325-4332].(ABSTRACT TRUNCATED AT 250 WORDS)

Meso-2,3-dimercaptosuccinic acid and sodium N-benzyl-N-dithiocarboxy-D-glucamine as antagonists for cadmium intoxication.

Orally administered meso-2,3-dimercaptosuccinic acid (DMSA) is an effective antagonist for acute oral cadmium chloride (1 mmol/kg) intoxication in mice when administered up to 8 h after cadmium ingestion. Administration of sodium N-benzyl-N-dithiocarboxy-D-glucamine (NaB) i.p. along with DMSA p.o. resulted in kidney and liver cadmium levels only marginally smaller than those obtained with DMSA alone. Both chelation treatment regimens permitted survival of 80% or more of the animals, in comparison to a survival rate of 40-50% in untreated animals. Intraperitoneally administered NaB by itself is a very effective antagonist for cadmium chloride administered intraperitoneally in either acute or chronic cadmium intoxication. A dose-response study was made of the mobilization of cadmium from the liver and kidney of cadmium-loaded mice by NaB; this showed that NaB is one of the most effective cadmium mobilizing agents developed to date. We have also confirmed the earlier report of Kojima and his co-workers of the ability of NaB to remove cadmium from animals which have been treated with cadmium over an extended period of time. NaB causes a very large increase in the biliary excretion of cadmium. Nuclear magnetic resonance (NMR) spectra of 113Cd in bile from treated animals and model solutions indicates that such cadmium is undergoing rapid ligand exchange.