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At least 19 recordsLinked to original sources
PubMed1978

Mechanisms for the biomethylation of metals and metalloids.

The case of methylmercury pollution has demonstrated the profound importance of understanding biologically mediated transformation reactions that yield organometallic compounds with a high potential for bioaccumulation and toxicity. Toxic elements that form organometallic compounds, especially the metal-alkyls (e.g., methylmercury), deserve special concern. Most metal-alkyls are poisonous to the central nervous systems of higher organisms, and these compounds do accumulate in cells. Metal-alkyls that are stable in water, and that have been reported to be synthesized biologically, can be formed from the following toxic elements: Hg, Sn, As, Se, Te, Pd, Au, Tl and Pb. In this report we present details of the mechanisms for biological methylation of certain metals and metalloids with special emphasis on those elements that are widely dispersed in the biosphere. In addition we present preliminary results on the use of flourescence quenching techniques to determine cellular diffusion rates and partition coefficients for methylmercuric chloride.

Alkylmercury Compounds↗
PubMed1979

Lymphocytotoxicity and immunosuppression by organotin compounds. Suppression of graft-versus-host reactivity, blast transformation, and E-rosette formation by di-n-butyltindichloride and di-n-octyltindichloride.

Di-n-butyltindichloride (DBTC) and di-n-octyltindichloride (DOTC) represent a new group of organometallic compounds with antilymphocytic properties. In rats they induce lymphocyte depletion in thymus and thymus-dependent areas of spleen and peripheral lymph nodes without signs of myelotoxicity or a generalized toxicity. The number and viability of cells isolated from thymus and peripheral lymphoid organs was severely decreased, whereas the number and viability of bone marrow cells was not reduced. Immunosuppressive properties of DBTC and DOTC are indicated, in this study, by a severe decrease of the graft-versus-host response and the response to the T-cell mitogens phytohemagglutinin and concanavalin A. The T-cell selectivity of these compounds is discussed. In vitro DBTC and DTOC are extremely cytotoxic. Blast transformation of human as well as rat thymocytes was already inhibited at concentrations as low as 0.02 micrograms DBTC (or 0.1 micrograms DOTC) ml medium. Also the E-rosette formation was inhibited at very low drug levels. The similarity of effects upon rat and human lymphocytes suggests that DBTC and DOTC acts in the same manner in rat and man and offers the possibility of a therapeutic use of these compounds.

Animals↗
PubMed1978

Toxicology of triethyllead, methylmercury and cadmium, determined in chick embryo brain cell cultures.

The toxicology of water soluble chemical compounds may be investigated in tissue culture systems. The toxicology of triethyllead chloride, methylmercury chloride and cadmium acetate was studied in chick embryo brain cell cutlures. Tetraethyllead is added to petrol as an anti-knock agent. When tetraethyllead is absorbed by the organism, it is converted to triethyllead which cause the symptoms of tetraethyllead poisoning. Chick embryo brain cell cultures derived from cerebrum of 11-day-old chick embryos developed both neurons and glial cells. The neurons formed nerve processes and synapsis in the cultures. The effect of triethyllead chloride was investigated by addition of triethyllead chloride to the nutrient medium. The median tissue culture lethal dose, TCLD50 = 1.9 mg/l, was determined as the concentration of triethyllead chloride at which the confluent layer of glial cells was destroyed in 50% of the cultures. The neurons lost their processes at even lower concentration, TCED50 = 0.57 mg/l. Electron microscopy revealed cells with swollen Golgi apparatus and dilated endoplasmic reticulum in chick embryo brain cell cultures which were treated with triethyllead chloride, 1.0 mg/l. Studies with radioactive labelled precursors revealed that triethyllead chloride inhibited the synthesis of DNA, sulfatides and cerebrosides without hydroxyfatty acids.

Animals↗
PubMed1978

Synthetic analogs of antitumor drugs under development in Japan.

Synthetic studies on new antitumor drugs in Japan are mainly oriented toward analogs of known active structures. In the nitrosourea area ACNU, a pyrimidine analog of CCNU, is currently under clinical investigation and has myelosuppression as a side effect Nitrosoureas with a sugar moiety are of great interest and two compounds called GANU and MCNU are now ready for phase I study in Japan. Among new alkylating agents are included a series of bis-methanesulfonate of aminoglycols, an analog of cyclophosphamide called 4-hydroperoxy-cyclophosphamide, and aziridine derivatives which include the now commercially available carbazilquinone. In the antimetabolite field cyclocytidine is an analog of arabinosyl cytosine which has been extensively studied. A newer analog called N4-behenoyl-cytosine arabinoside is now being studied experimentally. In the fluorinated pyrimidine area Ftorafur has been extensively studied and a new compound FD-1 is of interest.

Alkylating Agents↗
PubMed1979

Bis(L-cysteinato)gold(I): chemical characterization and identification in renal cortical cytoplasm.

L-Cysteinatogold(I) was prepared by the reaction of L-cysteine with KAuBr4 in acidic media and its solubility determined from pH 4 to 10. The solubility at pH 7.4 and 37 degrees C is 1 microM. In the presence of excess cysteine, the solubility increases because of formation of bis(L-cysteinato)gold(I). The equilibrium-constant for formation of the bis complex is 2.1 +/- 0.4 X 10(-3), which at pH 7.4 CORRESPONDs to an apparant formation constant of 4.4 X10(4). The formation of the bis adduct was confirmed by chromatographic separation of the products of the reaction between [35S]-L-cysteine and Na2AuTM. This complex elutes with Kav = 1.15 which allows it to be distinguished from other gold thiolates that might form in vivo. The bis(cysteinato)gold(I) complex is shown to be present in kidney cytosol isolated from rats given Na2AuTM in vivo. When additional cysteine is added to the cytosol in vitro, the peak at 1.15 is increased, but if glutathione is added, the low molecular weight gold elutes at Kav = 1.00, which is taken as evidence for the existence of bis(cysteinato)gold(I) in the cytosol preparation. The amount of gold present as bis(cysteinato)gold(I) after 4 different dose schedules has been measured and found to increase with the total cytosol gold concentration. L-Cysteinatogold(I) does not dissolve in the presence of bovine serum albumin to form an adduct.

Animals↗
PubMed1975

Induction of maturation (meiosis) in Xenopus laevis oocytes by three organomercurials.

Three organomercurials, p-hydroxymercuribenzoate, p-hydroxymercuriphenylsulfonate, and mersalyl, induce maturation (meiosis) in a large percentage (20-100 percent) of Xenopus laevis oocytes. Maturation takes place even when the follicle cells which surround the oocytes have been withdrawn. Organomercurial- and progesterone-induced maturations have many features in common: they do not occur when the inducer is injected into the oocytes, they require the presence of Ca++ in the medium, they are inhibited by cycloheximide but not by actinomycin D. In both cases, the maturation producing factor and the pseudomaturation inducing factor are produced. Organomercurial-treated oocytes react normally to activating stimuli; their protein synthesis increases, but uptake of amino acids is strongly inhibited. Progesterone and p-hydroxymercuriphenyl-sulfonate act synergically in inducing maturation. The main difference between the two agents is that p-hydroxymercuriphenylsulfonate must act for several hours, whereas, short contact with progesterone is sufficient to induce maturation.

Animals↗
PubMed1975

Adenylate cyclase from rat-liver plasma membrane: inhibition by mersalyl and other mercurial derivatives.

The adenylate cyclase activity from a rat liver plasma membrane preparation was inhibited by low concentrations (1-10 muM) of the mercurial diuretic mersalyl. Complete inhibition was obtained with 0.1 mM mersalyl. Similar effects were observed whether the adenylate cyclase preparation was assayed in the presence of 10 muM GTP, 0.1 muM glucagon, 10 mM NaF or without any addition. The effect of mersalyl was not due to inhibition of the regenerating system present in the incubation medium, since the effect of mersalyl was preserved and even enhanced in its absence. The inhibition brought about by mersalyl was due to both a decrease of the maximal velocity of the reaction and of the affinity of the enzyme for the substrate. It was immediate, and irreversible spontaneously, but it was reversed by the simultaneous additions of 2-mercaptoethanol, in a dose-dependent fashion. Other -SH reagents were found to have an effect equal to, or lower than, that of mersalyl. Mersalyl had no effect upon Mg2+-ATPase, although it inhibited the (Na+-K+) activated ATPase. Since mersalyl is known to be a 'non-penetrant' reagent, it is postulated that a catalytically important, mercurial-sensitive, part of adenylate cyclase is at the surface of the plasma membrane. This view is supported by the following facts: (a) mersalyl acted with a similar dose-response curve upon an intact as well as a detergent-dispersed cyclase preparation while no effect was observed upon a solubilized Mg2+-ATPase preparation; (b) a covalent p-chloromercuribenzoate-Sephadex preparation (but not its supernatant) inhibited the cyclase from intact membranes. It is proposed that mercurial derivatives, by their relative specificity of action (no effect on Mg2+-ATPase), can serve as useful probes in the elucidation of the multicomponent structure of the cyclase system.

Adenosine Triphosphatases↗
PubMed1976

Study of the interaction of 4-bromomercuriocinnamic acid with alpha-chymotrypsin by 79 Br and 81Br pulsed nuclear-magnetic resonance.

Br- has been used as a nuclear magnetic resonance (NMR) probe to study the reversible association of alpha-chymotrypsin and an Hg-labelled substrate (4-bromomercuriocinnamic acid, BrHgCin) which rapidly exchanges Br-. T1 was measured for 79Br and 81Br, using a pulse spectrometer. Values of the parameters that determine T1, Obs in aqueous solutions of KBr (pH=5.5) containing alpha-chymotrypsin and BrHgCin are reported. It is found that the rate of Br exchange is diffusion-limited and faster than the rate of reorientation of the BrHgCin-alpha-chymotrypsin complex. The rate constant for the formation of the covalent BrHgCin-alpha-chymotrypsin complex determined by this technique agrees well with previously published data. The rapid rate of Br exchange with the complex, however, is incompatible with the side chain of BrHgCin being entirely buried in a nonpolar pocket on the enzyme but compatible with the side chain being exposed to the solution. The contribution to the NMR signal from the non-covalent complex is negligible.

Binding Sites↗