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W Schütz

Publications and source records attributed to W Schütz.

At least 19 recordsLinked to original sources
PubMed1992

Functional expression of the human serotonin 5-HT1A receptor in Escherichia coli. Ligand binding properties and interaction with recombinant G protein alpha-subunits.

Signaling through serotonin 5-HT1A receptors involves multiple pathways. We have investigated the functional coupling of the human 5-HT1A receptor to different G proteins using an in vitro reconstitution system based on the expression of recombinant receptor (r5-HT1A) and G alpha-subunits (rG alpha) in Escherichia coli. The r5-HT1A receptor was expressed by insertion in a vector allowing its active expression in E. coli inner membranes. Binding of the selective agonist [3H] +/- 8-hydroxy-(2-N-dipropylamine)tetralin ([3H]8-OH-DPAT) to intact bacteria or E. coli membranes was saturable with a KD of approximately 8 nM and an average of 120 sites/bacterium. Binding properties of several serotoninergic ligands to r5-HT1A receptors were comparable with those measured in mammalian cells. Incubation of rG alpha.beta gamma with E. coli membranes resulted in high affinity agonist [3H]8-OH-DPAT binding (KD = 0.7 nM) and titration with a panel of rG alpha subtypes showed the order of potency: rGi alpha-3 greater than rGi alpha-2 greater than rGi alpha-1 much greater than rGo alpha, while rGs alpha appeared incapable of interacting with 5-HT1A receptors. Moreover, agonist-mediated enhancement of [35S]guanosine 5'-O-(3-thiotriphosphate) binding to rGi alpha confirmed the achievement of the functional interaction between receptor and G proteins. Our findings are in agreement with the in vivo ability of 5-HT1A receptors to activate Gi alpha related to adenylyl cyclase inhibition or K+ channel activation, but do not support previously reported adenylyl cyclase stimulation through interaction with Gs alpha.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Reverse intrinsic activity of antagonists on G protein-coupled receptors.

Biological effects observed with an antagonist are usually interpreted as the result of its ability to block receptor activation produced by an endogenous agonist. In this Principles article, Wolfgang Schütz and Michael Freissmuth show how considerable evidence has now been accumulated for G protein-coupled receptors that antagonists not only bind to the receptor, but also induce a conformational change that favours uncoupling of the receptor from its G protein. The spontaneous activity of the unliganded receptor (i.e. the receptor not occupied by any ligand) is a well-established phenomenon in reconstituted systems with purified components. However, its physiological relevance needs to be verified in a more physiological environment before biological effect of antagonists can be primarily ascribed to negative intrinsic activity.

Animals↗
PubMed1992

Sensitization of dopamine-stimulated adenylyl cyclase in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys and patients with idiopathic Parkinson's disease.

Dopamine-stimulated adenylyl cyclase activity was measured in striatal homogenates of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys and humans with idiopathic Parkinson's disease and compared with the activity in control tissue. No differences between parkinsonian and control tissue were found in the presence of 20 mM NaCl. However, when 120 mM NaCl was included in the assay medium, a significantly higher increase in the Vmax of dopamine-stimulated adenylyl cyclase activity was observed in the caudate of MPTP-parkinsonian rhesus monkeys and the putamen of patients with idiopathic Parkinson's disease. No such sensitization was seen in the MPTP-treated rhesus putamen or human Parkinson's disease caudate tissue. A role of D2 receptors in this sensitization could be ruled out by the concomitant use of the D2 antagonist l-sulpiride and by [3H]spiperone saturation analysis of the D2 receptor density, which was found at control level in the caudate tissue of MPTP-treated rhesus monkeys. Similarly, on the basis of saturation binding with the D1 selective ligand 125I-SCH 23982, there was no difference in caudate nucleus D1 receptor densities between control and MPTP-treated monkeys. Our results point to a region-specific functional sensitization of D1 receptors as a consequence of severe dopaminergic denervation of the striatum and suggest the possibility of a therapeutic potential of a D1 agonist with full intrinsic activity in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Expression of two human beta-adrenergic receptors in Escherichia coli: functional interaction with two forms of the stimulatory G protein.

When expressed in Escherichia coli, the human beta 1- and beta 2-adrenergic receptors retain their ligand binding specificity. Their functional integrity was investigated by analyzing receptor-guanine nucleotide-binding regulatory (G) protein coupling by using two splice variants of the alpha subunit of the stimulatory G protein Gs synthesized in E. coli (rGs alpha-S and rGs alpha-L) and the beta gamma subunits of G protein purified from bovine brain. In competition binding experiments with (-)-[125I]iodocyanopindolol and (-)-isoproterenol, rGs alpha-S.beta gamma and rGs alpha-L.beta gamma reconstituted guanine nucleotide-sensitive high-affinity agonist binding with comparable affinities, whereas rGs alpha PT, a mutant of rGs alpha-L with an altered carboxyl terminus, and a recombinant subtype of the alpha subunit of the inhibitory G protein, rGi alpha-1, were approximately 20- and approximately 200-fold less potent, respectively. A comparison of the beta 1- and beta 2-adrenergic receptor expressed in E. coli with the beta 2-receptor in S49 murine lymphoma cyc- cell membranes revealed a similar affinity of rGs alpha-S and rGs alpha-L for the recombinant and native receptors. After stable incorporation of rGs alpha-S.beta gamma into E. coli membranes, receptor-G protein coupling was also verified by determining the isoproterenol-mediated acceleration of the rate for guanine 5'-[gamma-[35S]thio]triphosphate binding. These results show that (i) receptor-G protein coupling can be reconstituted in E. coli using recombinant components and that (ii) such an approach may be more generally used to evaluate coupling preferences between defined molecular species of receptors and G-protein subunits.

Cell Membrane↗
PubMed1991

Interactions of the bovine brain A1-adenosine receptor with recombinant G protein alpha-subunits. Selectivity for rGi alpha-3.

The ability of the bovine brain A1-adenosine receptor to discriminate between different G protein subtypes was tested using G protein alpha-subunits synthesized in Escherichia coli (rG alpha-subunits). When combined with a 3-fold molar excess of beta gamma-subunit purified from bovine brain and used at high concentrations, all three subtypes of rGi alpha (rGi alpha-1, rGi alpha-2, and rGi alpha-3) and rGo alpha were capable of reconstituting guanine nucleotide-sensitive high-affinity binding of the agonist radioligand (-)-N6-3-[125I] (iodo-4-hydroxyphenylisopropyl) adenosine ([125I]HPIA) to the purified A1-adenosine receptor (Kd approximately 1.2 nM). Titration of the A1-adenosine receptor with increasing amounts of rG alpha revealed a approximately 10-fold higher affinity for rGi alpha-3 compared with rGi alpha-1, rGi alpha-2, and rGo alpha. This selectivity was also observed in the absence of beta gamma. Other alpha-subunits (rGs alpha-s, rGs alpha-L, rGs alpha PT, and rGz alpha) did not promote [125I]HPIA binding to the purified receptor. In N-ethylmaleimide-treated bovine brain membranes, rGi alpha-3 was the only rG alpha-subunit capable of reconstituting high-affinity agonist binding. Similarly, rGi alpha-3 competed potently with rGo alpha for activation by the agonist-liganded A1-adenosine receptor, whereas a approximately 50-fold molar excess of rGo alpha was required to quench the receptor-mediated release of [alpha-32P]GDP from rGi alpha-3. Hence, in spite of the extensive homology between alpha-subunits belonging to the Gi/Go group, the A1-adenosine receptor appears to discriminate between the subtypes. This specificity is likely to govern transmembrane signaling pathways in vivo.

Animals↗
PubMed1991

Interactions of purified bovine brain A1-adenosine receptors with G-proteins. Reciprocal modulation of agonist and antagonist binding.

The bovine brain A1-adenosine receptor was purified 8000-fold by affinity chromatography on xanthine-amine-congener (XAC)-Sepharose. Addition of a 120-fold molar excess of a purified bovine brain G-protein preparation (Go,i a mixture of Go and Gi, containing predominantly Go) decreases the Bmax of the binding of the antagonist radioligand [3H]XAC to the receptor. This decrease is observed not only after insertion into phospholipid vesicles but also in detergent solution, and is reversed by GTP analogues. In the presence of Go,i, about 20 and 40% of the receptors display guanine-nucleotide-sensitive high-affinity binding of the agonist radioligand (-)-N6-3-([125I]iodo-4-hydroxyphenylisopropyl)adenosine after reconstitution into lipid vesicles and in detergent solution, respectively. The ability of Go,i to enhance agonist binding and decrease antagonist binding is concentration-dependent, with a half-maximal effect occurring at approximately 10-fold molar excess of G-proteins over A1-adenosine receptors. In the presence of the receptor, the rate of guanosine 5'-[gamma-[35S]thio]triphosphate (GTP[35S]) binding to Go,i is accelerated. This rate is further enhanced if the receptor is activated by the agonist (-)(R)-N6-phenylisopropyladenosine, whereas the antagonist XAC decreases the association rate of GTP[35S] to levels observed in the absence of receptor. These results show (1) that detergent removal is not a prerequisite for the observation of coupling between the A1-adenosine receptor and Go,i, and (2) that the regulatory effect of G-proteins on antagonist binding to the A1-adenosine receptor can be reconstituted by using purified components.

Animals↗
PubMed1991

Adenosine receptors mediate a pertussis toxin-insensitive prejunctional inhibition of noradrenaline release on a papillary muscle model.

The effects of adenosine receptor agonists and antagonists on field-stimulated release of radioactivity from superfused guinea-pig papillary muscles preincubated with [3H] noradrenaline were studied. N6-cyclopentyladenosine (CPA), N6-(R-phenylisopropyl)-adenosine, and 5'-N-ethylcarboxamidoadenosine caused concentration-dependent inhibition of evoked overflow with a rank order of potency typical for interaction of the compounds with the A1-subtype of adenosine receptors. Maximum inhibition was 80%. The A1-selective antagonist 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX) induced a rightward shift of the concentration-response curve for CPA with a pA2 of 8.35. However, DPCPX per se had no effect on stimulation-evoked tritium overflow. On the other hand, in the presence of 4-nitrobenzylthioinosine (2 mumol/l) and deoxycoformycin (1 mumol/l), inhibitors of adenosine uptake and deamination, respectively, DPCPX produced a concentration-dependent increase in overflow with a pD2 of 8.1. Pretreatment of the animals with pertussis toxin caused a substantial reduction in the activity of toxin-sensitive G proteins, as indicated by a lack of [32P]ADP ribosylation in a ventricular membrane preparation. Nevertheless, the inhibitory effect of the adenosine receptor agonists on stimulus-evoked overflow remained unaffected. These results are compatible with the existence of inhibitory prejunctional adenosine receptors in guinea-pig papillary muscle, which appear to be coupled to a pertussis toxin-insensitive G protein. The role of endogenous adenosine in occupying these receptors seems minimal under basal conditions.

Animals↗
PubMed1991

Characterization of the beta-adrenoceptor blocking property of diprafenone in rats: stereoselective interaction, subtype specificity, and sensitization.

Because of their structural relationship to propranolol, propafenone and diprafenone display beta-adrenoceptor blocking activity in addition to their class Ic antiarrhythmic property. As demonstrated in membranes derived from rat ventricle (predominantly beta 1-adrenoceptors) and rat lung tissue (predominantly beta 2-adrenoceptors), the (-)-enantiomer of diprafenone was about four times more potent (Ki 6.6 nmol/L) than the (+)-enantiomer in displacing [125I]iodocyanopindolol (ICYP) binding. The Ki values for the (+)- and (-)-stereoisomer, racemic (+/-)-diprafenone, and 5-hydroxydiprafenone, the main metabolite of diprafenone in humans, were approximately 2.5 times lower in lung than in ventricular membranes, suggesting very low beta 2-selectivity for diprafenone. The regulatory effect of diprafenone on ventricular beta-adrenoceptors was studied in rats in vivo by prolonged i.p. administration of the drug. Density of beta-adrenoceptors was estimated by ICYP saturation binding after 2-day (4 or 20 mg/kg, b.i.d.) and after 7-day treatment (4 mg/kg, b.i.d.), respectively. For control purposes, different groups of animals were treated with propranolol (1.7 mg/kg, b.i.d., i.p.), isoprenaline (0.1 mg/kg/h via subcutaneously implanted osmotic minipumps), and vehicle (0.9% NaCl) only. Whereas propranolol and isoprenaline produced an increase (7-day treatment) and a decrease (2- and 7-day treatment) in beta-adrenoceptors, respectively, diprafenone did not produce any change in beta-adrenoceptor number, irrespective of the dose and duration of treatment used. Furthermore, the combined administration of diprafenone and isoprenaline did not antagonize isoprenaline-induced down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1991

Bioequivalence between two furosemide-spironolactone formulations: a pharmacokinetic and pharmacodynamic approach.

Two formulations of the drug combination furosemide (20 mg)-spironolactone (100 mg) were tested for bioequivalence in a randomized crossover trial in 12 healthy volunteers. By comparing the AUC values derived from drug serum concentrations, bioequivalence was only achieved for canrenone, the main metabolite of spironolactone, but not for furosemide. A significant difference in the tmax values indicates sustained release of furosemide from one of the formulations. By contrast, bioequivalence was achieved if pharmacodynamic criteria, such as urine volume and Na+ and Cl- excretion over a period of 12 hours, were used. Fractional measurements of urinary volume and electrolyte excretion (0 to 3 h, 3 to 6 h, 6 to 12 h) correlated with the different tmax values for both formulations. These data indicate that bioequivalence is more conclusively verified on the basis of pharmacodynamic parameters than on the basis of pharmacokinetic parameters. These considerations are applicable in particular to drugs displaying large inter-individual variations in serum levels and/or a poor correlation between serum levels and effect.

Adult↗
PubMed1991

The pharmacological basis of receptor binding.

Radiolabeled ligands can be used to characterize recognition sites of natural receptors. Verification of a receptor-specific binding of a radioligand requires a series of in vitro approaches, as saturation, competition, and kinetic (association and dissociation) experiments. Success of ligand binding depends on may factors involving the radio-pharmaceutical used as the radioligand, methods for separating bound and free ligand, proper use of the non-specific binding marker, and proper analysis of the binding data. A major theoretical constraint is the very short time available for separating bound an free radioligand, since a considerable fraction of radioligand can dissociate from the receptor binding sites during this process, in particular if the receptor affinity of the radioligand is low. Saturable, steady-state binding data can be analyzed utilizing standard binding isotherms and non-linear regression analysis as well as Scatchard plots. Competition experiments with unlabeled drugs are the most important in determining pharmacology of binding. Each method is subject to potential artifacts. Estimation of association is straightforward in order to assess the time necessary to achieve binding equilibrium.

Binding, Competitive↗
PubMed1990

[Role of G protein-mediated signal transduction in molecular pharmacodynamics].

Hormones, neurotransmitter and autacoid receptors, localized on the plasma membrane, do not interact directly with their respective downstream effector (i.e., an ion channel and/or an enzyme that synthesizes a second messenger), but control their target systems via activation of an intermediary guanine nucleotide binding protein on G protein, which serves as signal transducer. Traffic of these pathways is regulated via a GTP (on)-GDP (off) switch, which is triggered by the receptor. The combination of classical biochemistry and recombinant DNA technology has resulted in the discovery of many members of the G protein family. Receptor desensitization is a main criterion of G protein-coupled receptors with important pharmacological implications. Multiple mechanisms are responsible for the loss of sensitivity that follows against exposure. The process is initiated by uncoupling the receptor from its G protein, which is due to receptor phosphorylation by specific kinases. In the case of the beta-adrenergic receptor, two particular kinases - beta-adrenergic receptor kinase (beta ARK) and protein kinase A--are involved. Further steps of desensitization are receptor sequestration or internalization, an event as rapid and transient as receptor uncoupling, and receptor downregulation, which requires more prolonged agonist exposure. Finally, antagonists are able to induce a receptor-G protein interaction in a reverse manner to agonists. Whereas agonists stimulate both, the GDP dissociation from the G protein and the association of GTP, antagonists markedly decrease GTP association. Moreover, in the turkey erythrocyte adenylyl cyclase system antagonists decrease the GTP-stimulated adenylyl cyclase activity almost at basal levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1990

[Treatment of uncomplicated urinary tract infections. Effectiveness and tolerance of sultamicillin compared with amoxicillin/clavulanic acid].

In an open, randomized multicenter trial two aminopenicillin/betalactamase-inhibitor combinations were compared in 132 patients suffering from acute, uncomplicated urinary tract infections. In each of two groups 66 patients were included. They received 750 mg sultamicillin (STM) b.i.d. and 625 mg amoxicillin/clavulanate (AMX/CLA) t.i.d., respectively. A total of 126 patients who had positive urine cultures prior to therapy were evaluable for effectiveness. In the STM-group, 61 patients (= 95.3%) were cured as compared with 56 patients (= 90.3%) of the AMX/CLA-group. Both combinations were well tolerated; serious side effects were not observed. This study indicates that sultamicillin is as effective and safe as amoxicillin/clavulanate in the treatment of acute uncomplicated urinary tract infections, but with the advantage of b.i.d. dosage.

Adolescent↗
PubMed1990

P2-, but not P1-purinoceptors mediate formation of 1, 4, 5-inositol trisphosphate and its metabolites via a pertussis toxin-insensitive pathway in the rat renal cortex.

1. The adenosine receptor (P1-purinoceptor) agonists N6-cyclopentyladenosine and N-5'-ethyl-carboxamidoadenosine at concentrations up to 10 mumols 1(-1) affected neither basal, nor noradrenaline- and angiotensin II-stimulated formation of inositol-1-phosphate, inositol-1,4-bisphosphate, and inositol-1,4,5-trisphosphate in slices of rat renal cortex. 2. In contrast, adenine nucleotides (P2-purinoceptor agonists) markedly stimulated inositol phosphate formation. The observed rank order of potency adenosine-5'-O-(2-thiodiphosphate) (EC50 39 mumols 1(-1] greater than adenosine-5'-O-(3-thiotriphosphate) (587) greater than or equal to 5'-adenylylimidodiphosphate (App(NH)p, 899) greater than adenylyl-(beta, gamma-methylene)-diphosphate (4,181) was consistent with the interaction of the compounds with the P2Y-subtype of P2-purinoceptors. AMP and the ADP analogue (alpha, beta-methylene)-adenosine-5'-diphosphate were ineffective. ATP and ADP (less than or equal to 10 mmol 1(-1] did not produce a consistent increase, owing to their hydrolytic degradation in the incubation medium. 3. Whereas the inositol phosphate response to App(NH)p was linear only up to 5 min incubation, the time-dependent stimulation of noradrenaline declined at a slower rate. Following pre-exposure of the renal cortical slices to App(NH)p, renewed addition of App(NH)p caused no further enhancement in the accumulation of inositol phosphates, whilst noradrenaline was still capable of eliciting a response. This suggests that the apparent loss of responsiveness to App(NH)p is not due to substrate depletion or enzymatic inactivation, but most likely attributable to homologous desensitization of the purinoceptor. 4. Pretreatment of the animals with pertussis toxin caused a substantial reduction of functional Gi-protein, as indicated by the lack of [32P]-NAD incorporation in a membrane preparation of the renal cortex. Nevertheless, the increase in inositol phosphate formation induced by noradrenaline, angiotensin II, and App(NH)p was not significantly impaired. 5. We conclude that P2 gamma-purinoceptors are present in the renal cortex; these receptors stimulate formation of inositol phosphates via a pertussis toxin-insensitive pathway and undergo homologous desensitization. On the other hand, our results suggest that renal A,-adenosine receptors do not use stimulation of phosphoinositide breakdown as a transmembrane signalling system.

Adenine Nucleotides↗
PubMed1989

Differences in the GTP-regulation of membrane-bound and solubilized A1-adenosine receptors.

Using [3H]8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a 3H-labeled A1-selective adenosine antagonist with high affinity and extremely low non-specific binding, it was possible to quantitatively evaluate the effect of GTP on agonist binding. Competition experiments on [3H]DPCPX binding to guinea-pig cerebral cortical membranes in the absence of GTP showed a high- and a low-affinity state for adenosine receptor agonists (82/18% for N6-cyclopentyl-adenosine). Addition of 1 mmol/l GTP only partially converted the high-affinity state of the A1-adenosine receptor into a low-affinity state. This failure of complete conversion from high- to low-affinity state was also seen in membranes from rat testes under the same experimental conditions and, moreover, in guinea-pig brain membranes under different experimental conditions, such as in the presence of Na+ or when free Mg2+ has been reduced by EDTA. The only difference was that in the absence of Mg2+ the high-affinity state of the A1-receptor was markedly smaller than in the presence of Mg2+ (36% vs. 82%). By contrast, in the solubilized state of the receptor total conversion of all receptors into the low-affinity state was obtained upon addition of 1 mmol/l GTP. Reduction of binding of the agonist radioligand [125]iodo-N6-(4-hydroxyphenylisopropyl)-adenosine with increasing concentrations of GTP and Gpp(NH)p demonstrated that the guanine nucleotide affinity to the solubilized A1-receptor was more than 100-fold higher than to the membrane-bound receptor. Hence, the incomplete transition of the high-affinity into the low-affinity state of the membrane-bound A1-receptor upon addition of GTP may be attributable to the low affinity of the membrane-bound receptor-G-protein complex for GTP.

Adenylyl Cyclases↗
PubMed1989

A different desensitization pattern of cardiac beta-adrenoceptor subtypes by prolonged in vivo infusion of isoprenaline.

(-)Isoprenaline was continuously administered to rats at a rate of 0.4 mg/kg/h for 7 days via subcutaneously (s.c.) implanted osmotic minipumps. This treatment induced cardiac hypertrophy and a marked decrease in basal as well as catecholamine-stimulated adenylate cyclase activity in a ventricular plasma membrane fraction. The total number of beta-adrenoceptors was downregulated by one-half the amount of the receptor sites obtained in a control group. However, in the isoprenaline-treated group, the beta 2-adrenoceptors constituted a significantly smaller proportion of the total beta-adrenoceptor population (28%) than in the control group (50%). Transformation of these relative into absolute values indicates that prolonged isoprenaline treatment induced a significantly higher downregulation of beta 2- than of beta 1-adrenoceptors. The fact of a different beta-adrenoceptor desensitization pattern in response to in vivo administration of nonselective beta-adrenergic agonists therefore must be taken into consideration when desensitization is used as a method for determination of subtype selectivity of an agonist per se. However, we were unable to detect the "lost" beta-adrenoceptors in a light vesicular fraction. In our study, this fraction was not separable from plasma membranes, as substantiated by levels of plasma membrane markers as high as in the plasma membrane fraction and by a guanine nucleotide-dependent adenylate cyclase activity.

Adenylyl Cyclases↗
PubMed1989

Cysteine and crocin oxidation catalyzed by horseradish peroxidase.

The amino acid cysteine is oxidized by horseradish peroxidase, and the water-soluble carotenoid crocin is bleached by cooxidation. The monophenol p-hydroxyacetophenone stimulates oxygen uptake, cysteine oxidation and crocin bleaching, whereas its concentration does not change. Superoxide dismutase significantly enhances all these oxidative reactions. Addition of H2O2 is not required for these peroxidase-catalyzed oxidations.

Carotenoids↗
PubMed1988

Cooperative stimulation by sulfite and crocidolite asbestos fibres of enzyme catalyzed production of reactive oxygen species.

Methylthioketobutyric acid has been used as an indicator for the production of reactive oxygen species during incubation with xanthine oxidase or NADH diaphorase in the presence of an autooxidizable quinone. The production of OH-radical-type oxidants is enhanced in the presence of crocidolite but not by the asbestos types chrysotile or amosite. This activity of crocidolite in the diaphorase system is further stimulated by bisulfite. Crocidolite-dependent ethylene formation from methylthioketo-butyric acid is inhibited by both superoxide dismutase and catalase. In the presence of both crocidolite and bisulfite, however, the inhibition by superoxide dismutase is preserved, but the inhibition by catalase is lost. Since in some respect the NADH-diaphorase quinone system may reflect the situation in the activated macrophage, crocidolite activation may represent a biochemical model system describing potential asbestos toxicity.

Asbestos↗