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PubMed1968

The interaction of triethyltin with components of animal tissues.

1. The distribution of triethyl[(113)Sn]tin chloride in the rat, guinea pig and hamster is not uniform, the highest concentrations being in rat blood and the liver of all three species. 2. Subcellular fractionation of rat liver, brain and kidney shows that triethyltin binds to all fractions to different extents. In the liver of the rat and guinea pig the supernatant fraction contains the largest amount and the highest specific concentration; this triethyltin is bound to a non-diffusible component. 3. Rat haemoglobin is responsible for the binding of triethyltin in rat blood (2 moles of triethyltin/mole of haemoglobin). Haemoglobins from other species have much less affinity for triethyltin. 4. A variety of other proteins do not bind triethyltin.

Animals↗
PubMedDate not supplied

Effects of toxic chemicals on the respiratory activity of cultured mouse neuroblastoma cells.

Twenty common toxic chemicals were tested for their ability to inhibit respiratory activity in cultured mouse neuroblastoma C1300 cells, clone 41A3. Pentachlorophenol and hexachlorophene exhibited the properties of uncouplers of oxidative phosphorylation, whereas for KCN, pyridine, 2,5-hexandione, NaAsO2, K2Cr2O7, HgCl2, methylmercury and triethyltin more simple time-courses of inhibition were obtained. Ethanol, methanol, dimethyl sulphoxide, benzidine, nickel acetate, MnCl2, phenol, CoCl2, Na2SeO3 and CdCl2 did not cause any significant changes in respiratory activity. Among the effective compounds, those with well-known neurotoxic properties were the most potent in inhibiting respiration in 41A3 cells.

Animals↗
PubMed2005

Apoptosis of cerebellar granule cells induced by organotin compounds found in drinking water: involvement of MAP kinases.

Mono- and dialkyl organotin compounds are used primarily as heat stabilizers in polyvinyl chloride (PVC) plastics. Recently, monomethyltin (MMT), dimethyltin (DMT), monobutyltin (MBT), and dibutyltin (DBT) have been detected in water from homes and businesses served by PVC pipes. While trialkyl organotins such as trimethyltin (TMT) and triethyltin (TET) are well known neurotoxicants, the toxicity of the mono- and dialkyl organotins is not well described. The present study compared the cytotoxicity of organotins found in drinking water with the known neurotoxicant TMT in primary cultures of cerebellar granule cells, and examined the role of MAP kinase signaling in organotin-induced cell death. Twenty-four hour exposure to TMT resulted in a concentration-dependent decrease in cell viability with an EC(50) of 3 microM. Exposure to MMT, DMT, and MBT at concentrations up to 10 microM had no effect. DBT, however, was very potent, and decreased cell viability with an EC(50) of 0.3 microM. Staining of organotin-treated cerebellar granule cells with the nuclear dye Syto-13 revealed that TMT and DBT, but not MMT, DMT, or MBT, produced condensation and fragmentation of chromatin characteristic of apoptosis. TMT- and DBT-induced apoptosis was confirmed using TUNEL staining and measurement of PARP cleavage. Activation of MAP kinase pathways was examined after 6 h of exposure to the organotins which induced apoptosis. Both TMT and DBT activated ERK1/2, but only TMT activated the JNK/c-Jun and p38 pathways. Pharmacologic blockade of JNK/c-Jun and p38 activation significantly decreased apoptosis produced by TMT, but not by DBT. These results show that DBT is a potent neurotoxicant in vitro, but unlike TMT, does not induce cell death via activation of MAP kinase signaling.

Animals↗
PubMed1995

Organotin compounds induce calcium overload and apoptosis in PC12 cells.

We examined the effects of four tri-substituted organotin compounds on intracellular Ca2+ and survival in PC12 cells. Treatment with micromolar concentrations of tributyltin and triphenyltin caused a rapid increase in the cytosolic free Ca2+ concentration ([Ca2+]i). This was due to enhanced Ca2+ influx and release from intracellular stores. When the [Ca2+]i elevation was maintained for over 30 min, internucleosomal DNA cleavage typical of apoptotic cell death followed. In contrast, when the increase in [Ca2+]i was transient, cells did not show internucleosomal DNA cleavage and retained their viability. Triethyltin modified [Ca2+]i only slightly, whereas trimethyltin had no effect. The latter two agents did not modify cell viability. Our data suggest that the toxicity of organotins in PC12 cells is linked to their ability to promote intracellular Ca2+ overload, which triggers apoptosis.

Animals↗
PubMed1991

Triorganotins inhibit the mitochondrial inner membrane anion channel.

The inner membrane of liver and heart mitochondria possesses an anion uniport pathway, known as the inner membrane anion channel (IMAC). IMAC is inhibited by matrix Mg2+, matrix H+, N,N'-dicyclohexycarbodiimide, mercurials and amphiphilic amines such as propranolol. Most of these agents react with a number of different mitochondrial proteins and, therefore, more selective inhibitors have been sought. In this paper, we report the discovery of a new class of inhibitors, triorganotin compounds, which block IMAC completely. One of the most potent, tributyltin (TBT) inhibits malonate uniport via IMAC 95% at 0.9 nmol/mg. The only other mitochondrial protein reported to react with triorganotins, the F1F0ATPase, is inhibited by about 0.75 nmol/mg. The potency of inhibition of IMAC increases with hydrophobicity in the sequence trimethyltin much less than triethyltin much less than tripropyltin less than triphenyltin less than tributyltin; which suggests that the binding site is accessible from the lipid bilayer. It has long been established that triorganotins are anionophores able to catalyze Cl-/OH- exchange; however, TBT is able to inhibit Cl- and NO3- transport via IMAC at doses below those required to catalyze rapid rates of Cl-/OH- exchange. Consistent with previous reports, the data indicate that about 0.8 nmol of TBT per mg of mitochondrial protein is tightly bound and not available to mediate Cl-/OH- exchange. We have also shown that the mercurials, p-chloromercuribenzene sulfonate and mersalyl, which only partially inhibit Cl- and NO3- transport can increase the IC50 for TBT 10-fold. This effect appears to result from a reaction at a previously unidentified mercurial reactive site. The inhibitory dose is also increased by raising the pH and inhibition by TBT can be reversed by S2- and dithiols but not by monothiols.

4-Chloromercuribenzenesulfonate↗
PubMed1971

Oxidative phosphorylation. The relation between the specific binding of trimethylytin and triethyltin to mitochondria and their effects on various mitochondrial functions.

1. A binding site (site 1) is present in mitochondria with affinity for trimethyltin and triethyltin adequate for a site to which they could be attached when the processes of energy conservation are inhibited. 2. The quantitative relationships between the binding of trimethyltin and triethyltin to site 1 and their effects on various mitochondrial functions have been examined. 3. ATP synthesis linked to the oxidation of pyruvate, succinate and intramitochondrial substrate, ATP synthesis and oxygen uptake (succinate or pyruvate as substrate) stimulated by uncoupling agents are all inhibited by trimethyltin and triethyltin; when inhibition is less than 50% the ratio (percentage inhibition)/(percentage of binding site 1 complexed) is approx. 10:1. 4. ATP synthesis linked to the oxidation of reduced cytochrome c (ascorbate+NNN'N'-tetramethyl-p-phenylenediamine), ATP hydrolysis and oxygen uptake in the presence of low concentrations of trimethyltin and triethyltin approach zero activity as the proportion of binding site 1 complexed approaches 100%. 5. Possible interpretations of these findings are discussed with reference to published arrangements for coupling of electron transport to ATP synthesis and also to our present knowledge of the chemical and biological specificity of trialkyltin compounds.

Adenosine Triphosphate↗
PubMed1979

The behavioral and neuropathologic sequelae of intoxication by trimethyltin compounds in the rat.

Trimethyltin, when given by gavage to rats, has an LD50 of 12.6 mg/kg. Signs of poisoning include tremors, hyperexcitability, aggressive behavior, weight loss, and convulsions. After single (10 mg/kg) or repeated weekly doses (a maximum of four) of 4 mg/kg, rats, up to a survival time of 70 days, were perfusion-fixed for light microscopy. Trimethyltin was assayed in brain and blood in rats after similar treatments. Trimethyltin is cumulative and persistent and binds with high affinity to hemoglobin. Trimethyltin, unlike triethyltin, does not produce white matter edema in rats but does cause bilateral and symmetrical neuronal alterations involving the hippocampus (largely sparing the Sommer sector), pyriform cortex, amygdaloid nucleus, and neocortex. The earliest alteration was loss or dispersal of Nissl substance, then clumping of nuclear chromatin, followed by shrinkage and fragmentation of the nucleus within shrunken eosinophilic cytoplasm. These changes were associated with approximately 1.4 microgram trimethyltin/g wet weight in brain tissue 1 day after the second dose of 4 mg/kg or 2 days after a single dose of 10 mg/kg. Signs of poisoning gradually disappeared, and 4 rats surviving 70 days appeared normal, although their brains had severe damage with cell loss in the hippocampi and each pyriform cortex. Treatment of rats with trimethyltin, therefore, provides a chronic preparation with consistent lesions in the hippocampus of use in other behavioral and neuroanatomic studies. (Am J Pathol 97:59--82, 1979).

Animals↗
PubMed1989

Flow cytometric comparison of the effects of trialkyltins on the murine erythroleukemic cell.

Cellular effects of exposure to tributyltin (TBT), triethyltin (TET), or trimethyltin (TMT) were investigated by flow cytometry employing the murine erythroleukemic cell (MELC) as a model cellular system. Cell viability was investigated by the carboxyfluorescein diacetate (CFDA) uptake/propidium iodide (PI) exclusion method: above a critical concentration (exposure for 4 h), which was specific for each of the trialkyltin compounds, the cell becomes permeable to PI, indicating loss of viability. Cellular CF fluorescence (derived from intracellular hydrolysis of CFDA) increased as a function of alkyltin concentration below the critical concentration and decreased as viability decreased above the critical concentration. Relative membrane potential, monitored with a cyanine dye (DiOC6), correlated with viability (PI exclusion), remaining essentially unaltered below the critical concentration and decreasing above it. At/above 1 microM TBT, 5 microM TET, or 100 microM TMT, the cell cycle was blocked in the G2/M phase. The 90 degrees light scatter (a measure of refractive index), axial light loss (a measure of volume), and fluorescein isothiocyanate (FITC) fluorescence (a measure of protein content) of nuclei isolated from trialkyltin-treated MELC by detergent treatment, increased as a function of organotin dose. Fluorescence and interference microscopy revealed increased quantities of residual cytoplasmic tags adherent to the nuclei as a function of organotin dose, apparently resulting from increased cytoplasmic resistance to detergent-mediated solubilization. The effects of the trialkyltins correlated with their lipophilicity (octanol/water coefficient). These data support the hypothesis that fixation (protein denaturation, cross-linking, etc.) is an important mode of organotin cytotoxicity.

Animals↗
PubMed1982

Studies on the nature of the high-affinity trialkyltin binding site of rat liver mitochondria.

1. The proteolipid fraction isolated from rat liver mitochondria pretreated with [3H]triphenyltin chloride is enriched in triphenyltin compared with the original mitochondria. 2. Part of this [3H]triphenyltin is eluted with a protein of Mr 5000-6000 on Sephadex LH20 chromatography. 2. Mössbauer spectra of the proteolipid fraction treated with 119Sn-enriched triethyltin chloride show a doublet which corresponds closely with that assigned previously [Farrow & Dawson (1978) Eur. J. Biochem. 86. 85-95] to the absorption of triethyltin bound to the high-affinity binding site of the mitochondrial ATPase.

Animals↗