Collapse of the blood-brain barrier in lymphostatic cerebral hemangiopathy and in triethyltin poisoning.
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Regional potassium distribution in the brain in forensic relevant types of intoxication preliminary morphometric evaluation using a histochemical method.
A histochemical-morphometric method was used to measure potassium (K+) levels in gray and white matter of rats following sublethal intoxication with 11 different neurotoxic compounds of high forensic significance. Six rats were each given a single substance applied intraperitoneally, the same dosage being given to two animals each. The animals were subsequently killed, the brains immediately frozen, and cryosections cut. K+ levels were evaluated morphometrically. A drop in K+ levels was used as the criterion for cytotoxic edema. Application of ethanol, atropine, carbromal, carbon monoxide, morphine or triethyltin led to a rise in K+ levels in the gray matter and a simultaneous decline in the white matter. By contrast, administration of amitriptyline, glycerin, potassium cyanide, parathion or phenobarbital initiated an increase in K+ levels in both gray and white matter. A cytotoxic edema could thus be reliably excluded in these intoxications. Although the study design allows no statistical analysis, these conclusions are supported by the marked differences in K+ levels in gray and white matter induced by the different toxicants.
Alcoholic Intoxication↗
The effect of organotin compounds on chloride secretion by the in vitro perfused rectal gland of Squalus acanthias.
The effects of various organotins on membrane function and electrolyte transport were studied in the marine elasmobranch, Squalus acanthias. The isolated perfused rectal gland was used as a model of electrolyte transport. This gland can be stimulated to secrete chloride by atrial natriuretic peptide, veratrine, and vasoactive intestinal polypeptide although the mechanism of action of each secretagogue is different. By analysis of the inhibitory effect of an organotin in the presence of each secretagogue, the mechanism of inhibition can be inferred. Tributyltin (TBT) produced a reversible inhibition of epithelial transport at 10(-8) to 10(-7) M which resulted from inhibition of stimulus-secretion coupling in VIP-containing neurons within the gland. The transporting epithelial cells were unaffected at these concentrations. Trimethytin (TMT) produced inhibition at 10(-7) M which was not reversible and which affected primarily the transporting epithelial cells. Triethyltin and triphenyltin were without effect. The inhibitory effect of TBT and TMT was not affected by simultaneous administration of dithiothreitol. TBT also produced inhibition of oxygen consumption, Na+,K-ATPase, and proton ATPase in dispersed rectal gland cells. These results indicate that organotins are toxic to cell membrane functions which are intimately involved in the movement of electrolytes. This is the first evidence of toxicity to membrane transport functions in a marine species which is at risk from environmental exposure.
Animals↗
The action of trialkyltin compounds on mitochondrial respiration. The effect of pH.
1. Inhibition of 2,4-dinitrophenol-stimulated respiration by trialkyltins is dependent on the presence of Cl(-) in the assay medium and is only apparent at acid pH values. It appears to be a result of the Cl(-)-OH(-) exchange mediated by trialkyltins. 2. In a KCl medium at alkaline pH values, the maximum rate of respiration produced by uncouplers is further increased by the presence of trialkyltins. 3. The inhibition of uncoupled succinate oxidation at acid pH values is not reversed by increasing the external substrate concentration, suggesting that depletion of intramitochondrial succinate is not an important factor in the inhibition. 4. It is suggested that the probable explanation for these observations is that in the presence of Cl(-) trialkyltins alter the internal pH to a more acid value and this directly affects the activity of one or more steps in succinate oxidation. 5. The oligomycin-like action of trialkyltins in a Cl(-)-free medium shows considerable pH-dependence over the pH range 6.6-7.6 in the presence of 10mm-phosphate, but very much less pH-dependence in the presence of 1mm-phosphate. 6. The binding of triethyltin to mitochondria shows a pK at pH6.3 and does not change greatly over the pH range 6.6-7.6. 7. It is suggested that the pH-dependence of the oligomycin-like action described by Coleman & Palmer (1971) is the result of the pH-dependence of the formation of a hydrophilic complex between trialkyltins and P(i).
Animals↗
Oxidative phosphorylation. The effect of anions on the inhibition by triethyltin of various mitochondrial functions, and the relationship between this inhibition and binding of triethyltin.
1. The binding of triethyltin to rat liver mitochondria is unaffected by the nature of the predominant anion in the incubation medium. 2. With chloride, bromide or iodide as the predominant anion, ATP synthesis linked to the oxidation of pyruvate or succinate and ATP hydrolysis stimulated by 2,4-dinitrophenol are much more sensitive to triethyltin than they are when nitrate or isethionate is the predominant anion. 3. When nitrate or isethionate is the predominant anion, oxygen uptake stimulated by 2,4-dinitrophenol is not inhibited by triethyltin. 4. In the presence of nitrate or isethionate anions, inhibition of ATP synthesis is directly related to the binding of triethyltin to mitochondria. 5. The relationship of the above effects to the anion-hydroxide ion exchange mediated by triethyltin and the relevance of this to published arrangements for coupling of electron transport to ATP synthesis are discussed.
Adenosine Triphosphate↗
Evidence for histidine in the triethyltin-binding site of rat haemoglobin.
One molecule of rat haemoglobin binds two molecules of triethyltin. The binding sites are located on the globin and there is co-operativity between the sites such that the intrinsic affinity constant at pH8.0 increases from 3.5x10(5)m(-1) for the binding of the first triethyltin molecule to 5.0x10(5)m(-1) for the binding of the second. Evidence is presented, from pH studies and the kinetics of inhibition due to photo-oxidation, that each binding site contains two histidine residues.
Animals↗
Effect of tri-n-butyltin on intracellular Ca2+ concentration of rat cerebellar neurons.
The effect of tri-n-butyltin on the intracellular Ca2+ concentration ([Ca2+]i) of cerebellar neurons dissociated from rats was examined using fluo-3 and a flow cytometer. Tri-n-butyltin at 100 nM or more (up to 1 microM) increased the [Ca2+]i in a dose-dependent manner. The effect of tri-n-butyltin on the [Ca2+]i was greatly reduced under external Ca(2+)-free ([Ca2+]o-free) conditions, suggesting its dependence on the presence of [Ca2+]o. Lower trialkyltins, such as triethyltin and trimethyltin at 1 microM, exerted little or no action on the [Ca2+]i. Therefore, the cytotoxic action of tri-n-butyltin may be different from those of lower trialkyltins.
Animals↗
Formation of 3-(glutathion-S-YL)-N-methyl-4-aminoazobenzene and inhibition of aminoazo dye-nucleic acid binding in vitro by reaction of glutathione with metabolically-generated N-methyl-4-aminoazobenzene-N-sulfate.
The reaction of glutathione (GSH) with metabolically-formed N-methyl-4-aminoazobenzene-N-sulfate (MAB-N-sulfate), a presumed ultimate carcinogenic metabolite of N,N-dimethyl-4-aminoazobenzene (DAB), was investigated using a hepatic sulfotransferase incubation mixture containing GSH and the proximate carcinogen, N-hydroxy-N-methyl-4-aminoazobenzene (N-HO-MAB). Under these conditions, 6--16% of the MAB-N-sulfate formed could be trapped as an aminoazo dye-GSH adduct. Upon subsequent purification, the adduct was shown to be chromatographically and spectrally identical to 3-(glutathion-S-yl)-N-methyl-4-aminoazobenzene (3-GS-MAB), a known biliary metabolite of DAB and a product of the reaction of the synthetic ultimate carcinogen, N-benzoyloxy-N-methyl-4-aminoazobenzene(N-BzO-MAB), with GSH. Neither 2'- nor 4'-GS-MAB, both products of the latter reaction, were detected in the sulfotransferase incubation mixture. GSH-S-transferases did not appear to be involved in the reaction of MAB-N-sulfate of N-BzO-MAB with GSH. The addition of triethyltin, a potent GSH-S-transferase inhibitor, had no effect on the yield of 3-GS-MAB in (N-HO-MAB sulfotransferase)-GSH incubations; and the addition of cytosol or purified GSH transferases A and B to a (N-BzO-MAB)-GSH reaction mixture did not increase the amount of 3-GS-MAB formed.
Animals↗
The interaction of triethyltin with a component of guinea-pig liver supernatant. Evidence for histidine in the binding sites.
A protein fraction was isolated from guinea-pig liver that binds triethyltin with an affinity of approx. 2x10(6)m(-1) at pH8.0. It was shown that the protein responsible for binding 70% of the triethyltin found in guinea-pig liver after injection of radioactively labelled triethyltin is at most a few per cent of the total liver protein. Evidence is presented from the kinetics of loss of binding and loss of certain amino acids on photo-oxidation with either Methylene Blue or Rose Bengal that each binding site consists of two histidine residues.
Animals↗
In vivo effects of triorganotins on calmodulin activity in rat brain.
We have recently reported that the triorganotins are effective inhibitors of calmodulin (CaM) activity in vitro. The present experiments were designed to investigate the in vivo effects of triorganotins, that is, tributyltin (TBT), triethyltin (TET), and trimethyltin (TMT) on rat brain CaM activity. Male Sprague-Dawley rats were treated orally with TET (0.5, 1.0, and 1.5 mg/kg/d), TMT (0.75, 1.50, and 2.50 mg/kg/d), and TBT (0.75, 1.50, and 2.50 mg/kg/d) for 6 d and they were sacrificed 24 h after the last dose. There was significant loss of body weight in the high-dose group of the organotin treated rats. Ca(2+)-ATPase activity was determined in rat brain synaptic membranes. TET and TMT inhibited Ca(2+)-ATPase in a dose-dependent manner but TBT exhibited its inhibitory effect only at the highest dose (2.5 mg/kg/d). The inhibition of Ca(2+)-ATPase by these triorganotin compounds was reversed to control levels by the addition of CaM (5-10 micrograms) exogenously. The CaM levels of the synaptic membranes of the organotin-treated rats were not significantly changed. The data presented in this paper demonstrate that triorganotins impair the Ca(2+)-pump activity by interacting with CaM, which is a regulatory protein of Ca(2+)-ATPase. The present in vivo data and our previously reported in vitro data together indicate that triorganotins associated neurotoxicity may be due to an altered CaM activity in brain.
Animals↗
Selective inhibition of glucose oxidation by triethyltin in rat brain in vivo.
Results are reported of a comparative study in vivo of the metabolism of [2-(14)C]-glucose and [1-(14)C]acetate in brains of rats intoxicated with triethyltin sulphate. The incorporation of (14)C from glucose into glutamate, glutamine, gamma-aminobutyrate and aspartate was greatly decreased. The incorporation of (14)C from acetate into these amino acids was unaffected. The experimental data indicated that the main action of triethyltin was to decrease the rate at which pyruvate formed from glucose is oxidized. Glycolysis was not inhibited. Changes in glucose metabolism in the brain are shown not to be directly due to hypothermia. Some of the advantages of measuring the labelling of intermediates at very short time intervals after the injection of the labelled glucose are demonstrated.
Acetates↗
Organotins disrupt components of glutamate homeostasis in rat astrocyte cultures.
A rat cortical astrocyte preparation was used to investigate the effects of organotins on glutamate regulation by astrocytes. Exposure of astrocytes to low levels of organotins produced significant changes in two key components of glutamate homeostasis: glutamine synthetase (CS) activity and the high-affinity transport of L-glutamate. Trimethyltin (TMT), triethyltin (TET), and triphenyltin (TPT) exhibited differential abilities to reduce GS activity and glutamate uptake. Cultures incubated with 1 microM TET or TPT, but not TMT, exhibited a marked decrease in GS activity. Exposure to TET or TPT also produced a significant decrease in glutamate transport activity that was not observed with TMT. These declines in activity were not attributable to cell loss as measured by MTT reduction and lactate dehydrogenase (LDH) leakage. Since the loss of GS activity and transporter activity was not seen with acute organotin exposure, it is most likely attributable to a decreased presence of fully functioning protein. While the attenuation of GS and glutamate transporter activities by organotins does not match their pattern of neurotoxicity, the results indicate the potential for subtoxic concentrations of these compounds to increase extracellular glutamate and interact with other excitotoxic episodes.
Animals↗
Neurotoxicants and central catecholamine systems.
The ubiquitous functional roles of brain catecholamines have led to the notion that in vitro neurochemical changes in these systems may predict neurotoxicity. Conversely, others have argued that the appropriate use of neurochemical methods is for testing specific hypotheses that are developed based on observed phenomena. Three studies from this laboratory are presented in support of the latter hypothesis. The first example is with inorganic lead, a major environmental pollutant. The effects of small doses of lead on CNS development have been difficult to quantify or study mechanistically. However, the serendipitous finding that lead exposure during early postnatal development increased lithium-induced polydipsia (LIP) has provided clues that have permitted testing of specific neurochemical hypotheses related to dopamine systems. Conversely, the administration of either trimethyl- or triethyltin to rats during perinatal periods causes profound neurotoxicity. However, although some changes in the neurochemistry of catecholamine systems have been found, these data have provided little insight into either the cause or sequelae of toxicity. Finally, the food color erythrosin (FD & C Red #3) was hypothesized to be a neurotoxicant because it disrupted neurotransmitter uptake in vitro. Our data suggested this was an artifact of the methodology, a position supported by clinical and behavioral studies. These data provide examples of the strengths and weaknesses in neurochemical approaches to neurotoxicity.
Animals↗
In vitro assessment of neuromuscular toxicity.
This report has presented an overview of my approach to assessing neuromuscular toxicity using primarily in vitro techniques. Our current work on triethyltin toxicity exemplifies the use of these in vitro methodologies and the data they yield. Our neurophysiological and neurochemical experiments along with reports in the literature have directed our attention to several possible mechanisms for explaining the myopathic and neuropathic manifestation of TET intoxication. These mechanisms include (a) a compromise in the bioenergetic capacity of neurons and/or myofibers via disruption in mitochondrial function and (b) the direct effect of TET on the cell membrane and/or Na+-K+-ATPase. These hypotheses are currently being explored using additional biochemical and electrophysiological techniques in the isolated vascular perfused phrenic nerve-hemidiaphragm.
Animals↗
The reduction of disulphides by rat liver mitochondria.
The capacity of rat liver mitochondria to reduce 23 non-protein disulphides to their thiols has been examined. The best reduced include the three intermolecular disulphides, bis(2-aminoethyl)disulphide (cystamine, basic), bis(2-hydroxyethyl)disulphide (HED, neutral and bis(3-carboxypropyl)disulphide (CPD, acidic). Their behaviour has been compared. In each case the thiol formed is found in highest concentration in the mitochondrial matrix. The three disulphides require an NAD-reducing substrate and respond similarly to changes in the initial disulphide concentration, pH of the medium and inhibitors. The most effective of these are N-ethylmaleimide, phenylarsenoxide (shown to be a potent swelling agent), triethyltin and 1-chloro-2,4-dinitrobenzene (CDNB). The fall in GSH induced by the latter correlates with the extent of inhibition. An uncoupler (carbonylcyanide-m-chlorophenylhydrazone, CCCP) inhibits reduction of HED and CPD but not that of cystamine. After lysis of mitochondria there is no significant reduction even in the presence of NADH or NADPH. Reduction is observed in sonicates if lipoamide is added with NADH but this reaction is insensitive to CDNB and CPD is not reduced. Also neither cystamine nor HED supports pyruvate dehydrogenation. There is also reduction if GSH and glutathione reductase are added with NADPH. All three disulphides are reduced to some extent but the rates for HED and especially CPD are inadequate to account for the rates in intact mitochondria.
Animals↗
Mitochondrial adenosine triphosphatase of the fission yeast Schizosaccharomyces pombe 972h-. Changes in inhibitor sensitivities during the cell cycle indicate similarities and differences in binding sites.
1. We used 11 different inhibitors of energy conservation as inhibitors of ATPase (adenosine triphosphatase) in extracts of Schizosaccharomyces pombe obtained from cells at different stages of the cell cycle. 2. All the inhibitors showed cell-cycle-dependent variations in their I50 values (microng of inhibitor/mg of protein giving 50% inhibition of inhibitor-sensitive ATPase at pH 8.6). 3. From the sensitivity profiles through the cell cycle it was concluded that: (a) oligomycin, venturicidin, triethyltin sulphate and dibutylchloromethyltin chloride all act at closely associated site(s); (b) NN'-dicyclohexylcarbodi-imide and leucinostatin both act at a similar site, which is, however, distinct from that at which other inhibitors of the membrane factor (Fo) act. 4. The variations in I50 values for efrapeptin closely followed changes in specific activity of ATPase, as would be expected for an inhibitor acting at catalytic sites; these fluctuations were different from those for aurovertin, Dio-9, 4-chloro-7-nitrobenzofurazan, quercetin and spegazzinine, all of which show different sensitivity profiles from one another. 5. Anomalous stepwise inhibitor-titration curves were obtained for spegazzinine, NN'-dicyclohexylcarbodiimide, dibutylchloromethyltin chloride and leucinostatin. 6. Possible explanations are proposed for the discontinuous expression of inhibitor-binding sites during the cell cycle.
Adenosine Triphosphatases↗
Tri-n-butyltin-induced change in cellular level of glutathione in rat thymocytes: a flow cytometric study.
Since some of organotins, accumulated in edible mollusks of aquatic environments, exert a variety of toxic actions on experimental animals, it causes concern for the health of humans. We examined the effects of tri-n-butyltin chloride (TBT) and other organotins (triethyltin chloride, trimethyltin chloride, triphenyltin chloride and tetrabutyltin) on cellular content of glutathione (GSH) in rat thymocytes using a flow cytometer to further characterize the toxicity of TBT. When the cells were incubated with TBT at concentrations of 3 nM or more for 15 min, the cellular content of GSH dose-dependently decreased. However, it completely or partly recovered until 180 min even in the continued presence of TBT. This recovery was temperature-sensitive, suggesting an involvement of metabolic process. The efficacy of TBT to decrease the cellular content of GSH was greater than those of other organotins. Results suggest that TBT and some organotins at environmentally relevant (nanomolar) concentrations significantly reduce the cellular content of GSH, suggesting that they increase the vulnerability to some biological and chemical insults.
Animals↗
Dibutylchloromethyltin chloride, a covalent inhibitor of the adenosine triphosphate synthase complex.
1. The synthesis of dibutylchloromethyltin chloride, a new covalent inhibitor of the mitochondrial ATP synthase [oligomycin-sensitive ATPase (adenosine triphosphatase)] complex is described, together with a method for preparing dibutylchloro[(3)H]methyltin chloride. 2. Studies with the yeast mitochondrial oligomycin-sensitive ATPase complex show that dibutylchloromethyltin chloride inhibits both the membrane-bound enzyme and also the purified Triton X-100-dispersed preparation. 3. F(1)-ATPase is not inhibited even at 500nmol of dibutylchloromethyltin chloride/mg of protein, and the general inhibitory properties are similar to those of triethyltin, oligomycin and dicyclohexylcarbodi-imide, known energy-transfer inhibitors of oxidative phosphorylation. 4. Binding studies with yeast submitochondrial particles show that dibutylchloromethyltin chloride antagonizes the binding of triethyl[(113)Sn]tin, indicating that there is an interaction between the two inhibitor-binding sites. 5. Unlike triethyltin, inhibition by dibutylchloromethyltin chloride is due to a covalent interaction which titrates a component of the inner mitochondrial membrane present at a concentration of 8-9nmol/mg of protein. 6. All of the labelled component can be extracted with chloroform/methanol (2:1, v/v), and sodium dodecyl sulphate/polyacrylamide-gel electrophoresis of the chloroform/methanol extract indicates that the labelled component has an apparent mol.wt. of 6000-8000. However, t.l.c. reveals the presence of only one labelled component which is lipophilic and non-protein and is distinct from the free inhibitor, mitochondrial phospholipids and the dicyclohexylcarbodi-imide-binding protein (subunit 9). 7. Inhibition of mitochondrial ATPase and oxidative phosphorylation is correlated with specific interaction with a non-protein lipophilic component of the mitochondrial inner membrane which is proposed to be a co-factor or intermediate of oxidative phosphorylation.
Adenosine Triphosphatases↗