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PubMed1990

Involvement of calcium in the thimerosal-stimulated formation of leukotriene by fMLP in human polymorphonuclear leukocytes.

Only small amounts of leukotrienes could be detected by reverse-phase HPLC analysis after stimulation of human polymorphonuclear leukocytes (PMN) by the receptor agonist N-formyl-methionyl-leucyl-phenylalanine (fMLP). Preincubation of the cells with the organomercury compound thimerosal prior to fMLP-addition, however, resulted in the formation of significant amounts of 5-lipoxygenase derived metabolites. This effect was dose-dependent with respect both to fMLP and thimerosal. Thimerosal alone did neither lead to the formation of HPLC-detectable leukotrienes nor to the release of arachidonic acid in [1-14C]arachidonic acid prelabelled cells. The formation of leukotrienes by fMLP/thimerosal required extracellular Ca2+. Measurements of intracellular Ca2(+)-levels revealed that (i) thimerosal alone is able to release Ca2+ from internal stores and (ii) thimerosal causes a persistent accumulation of Ca2+ within the cells after stimulation by fMLP. We conclude that by the synergistic action of fMLP and thimerosal the Ca2(+)-levels exceed the threshold for phospholipase A2 activation resulting in the liberation of arachidonic acid and subsequently in the formation of 5-lipoxygenase products. Our results suggest that thimerosal may provide a model for leukotriene formation under pathophysiological conditions when SH-group oxidation leads to increased intracellular Ca2(+)-levels.

Arachidonate 5-Lipoxygenase↗
PubMed2004

Solid-phase extraction-gas chromatography-mass spectrometry using a fullerene sorbent for the determination of inorganic mercury(II), methylmercury(I) and ethylmercury(I) in surface waters at sub-ng/ml levels.

A novel, straightforward solid-phase extraction system for the determination of inorganic mercury and organomercury compounds in water is proposed. The analytes, in a buffer medium at pH 4.5, are sorbed as diethyldithiocarbamate complexes on a C60 fullerene column an subsequently eluted and derivatized with sodium tetra-n-propylborate in ethyl acetate. Following elution, 1 microl of extract is injected into a gas chromatograph-mass spectrometer system. The proposed gas chromatography-mass spectrometry speciation method exhibits a linear range of 4-1 ng/ml, and a detection limit of 1.5 ng/l (sample volume, 50 ml). Its repeatibility, as relative standard deviation (RSD) (from 11 standards containing 50 ng/l for each analyte), is ca. 7%. No interferences from metals ions, such as Zn2+, Fe3+, Sb3+, As3+, Pb2+, Ni2+, Cu2+, Sn2+, Co2+, Mn2+ and Cd2+ were encountered at concentrations 1000 times higher than those of the mercury compounds. The method was used for the speciation of inorganic mercury, methylmercury and ethylmercury in various types of water including sea and waste water.

Ethylmercury Compounds↗
PubMed1986

A review of metal accumulation and toxicity in wild mammals. I. Mercury.

Release of Hg compounds into the environment from point sources has largely been curtailed due to the known impacts of Hg on biological systems. Mercury continues to be released into the environment, however, from nonpoint sources such as combustion of fossil fuels and smelting operations. While the accumulation and toxicity of Hg in aquatic biota, domestic animals, and humans is well documented, relatively little is understood about these processes in wild terrestrial mammals. The purpose of this paper is to review the available literature on Hg levels and toxicity in wild mammals (excluding marine mammals). It is clear that Hg levels are biomagnified within terrestrial food chains, where carnivores greater than omnivores greater than herbivores. Among carnivorous species, Hg levels are generally highest in fish-eating animals. There is usually a high degree of correlation of Hg levels between different animal tissues. The age and sex of an animal appear to influence observed Hg levels, but field data are conflicting for both factors. Tissue Hg levels are affected by location, with significant differences attributable to both local contamination and natural background variability. Experimental studies have shown many mammal species to sensitive to Hg intoxication, but documented incidents of Hg poisoning in wild mammals are rare. Such rarity may be more a function of our inability to observe and demonstrate Hg poisoning in wild populations, rather than an absence of the disease.

Absorption↗
PubMed2000

Ecological effects, transport, and fate of mercury: a general review.

Mercury at low concentrations represents a major hazard to microorganisms. Inorganic mercury has been reported to produce harmful effects at 5 microg/l in a culture medium. Organomercury compounds can exert the same effect at concentrations 10 times lower than this. The organic forms of mercury are generally more toxic to aquatic organisms and birds than the inorganic forms. Aquatic plants are affected by mercury in water at concentrations of 1 mg/l for inorganic mercury and at much lower concentrations of organic mercury. Aquatic invertebrates widely vary in their susceptibility to mercury. In general, organisms in the larval stage are most sensitive. Methyl mercury in fish is caused by bacterial methylation of inorganic mercury, either in the environment or in bacteria associated with fish gills or gut. In aquatic matrices, mercury toxicity is affected by temperature, salinity, dissolved oxygen and water hardness. A wide variety of physiological, reproductive and biochemical abnormalities have been reported in fish exposed to sublethal concentrations of mercury. Birds fed inorganic mercury show a reduction in food intake and consequent poor growth. Other (more subtle) effects in avian receptors have been reported (i.e., increased enzyme production, decreased cardiovascular function, blood parameter changes, immune response, kidney function and structure, and behavioral changes). The form of retained mercury in birds is more variable and depends on species, target organ and geographical site. With few exceptions, terrestrial plants (woody plants in particular) are generally insensitive to the harmful effects of mercury compounds.

Amphibians↗
PubMed1999

Activation and inhibition of purified skeletal muscle calcium release channel by NO donors in single channel current recordings.

The actions of the nitric oxide (NO) donors 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3 methyl-1-triazine (NOC-7), S-nitrosoacetylcysteine (CySNO) and S-nitrosoglutathione (GSNO) on the purified calcium release channel (ryanodine receptor) of rabbit skeletal muscle were determined by single channel current recordings. In addition, the activation of the NO donor modulated calcium release channel by the sulfhydryl oxidizing organic mercurial compound 4-(chloromercuri)phenylsulfonic acid (4-CMPS) was investigated. NOC-7 (0.1 and 0.3 mM) and CySNO (0.4 and 0.8 mM) increased the open probability (P(o)) of the calcium release channel at activating calcium concentrations (20-100 microM Ca(2+)) by 60-100%, with no effect on the current amplitude; this activation was abolished by the specific sulfhydryl reducing agent DTT. High concentrations of CySNO (1.6-2 mM) decreased P(o). Activation by GSNO (1 mM) was observed in two thirds of the experiments, but 2 mM and 4 mM GSNO markedly reduced P(o) at activating Ca(2+) (20-100 microM). In contrast to 4-CMPS, NOC-7 or GSNO had no effect at subactivating free Ca(2+) (0.6 microM). 4-CMPS further increased the open probability of NOC-7- or CySNO-stimulated channels and reversed transiently the reduced open probability of CySNO or GSNO inhibited channels at activating free Ca(2+). High concentrations of GSNO did not prevent channel activation of 4-CMPS at subactivating free Ca(2+). The NOC-7-, CySNO- or GSNO-modified channels were completely blocked by ruthenium red. It is suggested that nitrosylation/oxidation of sulfhydryls by NO donors and oxidation of sulfhydryls by 4-CMPS affect different cysteine residues essential in the gating of the calcium release channel.

Acetylcysteine↗
PubMed1976

Conversion of Thebaine to Codeine.

An improved conversion of thebaine to codeine has been developed. Oxymercuration of thebaine with mercuric acetate in refluxing methanol, followed by hydrolysis of the intermediate 7-acetomercurineopinone dimethyl ketal with 3 N acetic acid, or, alternatively, reduction of the organomercury compound with sodium borohydride and mild acid hydrolysis of the resulting neopinone dimethyl ketal, gives neopinone in 95-100% yields. Either acid- or alkali-catalyzed isomerization to codeinone leads to the equilibrium mixture consisting of codeinone-neopinone, 3:1. Complete conversion to codeinone in 85-90% yield results from treatment of neopinone with anhydrous hydrogen chloride or hydrogen bromide in ether-methylene chloride, followed by elimination of hydrogen halide from the intermediate 8-halodihydrocodeinone. The known borohydride reduction of codeinone then gives codeine in 85% overall yield from thebaine.

Codeine↗
PubMed1988

The precursor of a metalloendopeptidase from human rheumatoid synovial fibroblasts. Purification and mechanisms of activation by endopeptidases and 4-aminophenylmercuric acetate.

Two active forms (Mr 45,000 and 28,000) of a metalloendopeptidase that digest proteoglycans and other extracellular matrix components of connective tissues have previously been purified from rheumatoid synovial cells and characterized [Okada, Nagase & Harris (1986) J. Biol. Chem. 261, 14245-14255]. To study the mechanisms of activation the precursor of this metalloendopeptidase has now been purified. The final products are homogeneous on SDS/polyacrylamide-gel electrophoresis and identified as a set of zymogens of Mr 57,000 and 59,000, in which the latter form is probably the product of post-translational glycosylation of the Mr 57,000 zymogen, as it binds to concanavalin A. The zymogen can be activated by trypsin, chymotrypsin, plasma kallikrein, plasmin and thermolysin, but not by thrombin. Although the activated metalloendopeptidase is further degraded by trypsin, plasma kallikrein and thermolysin during a prolonged incubation, it is relatively stable against plasmin and chymotrypsin. Activation with 4-aminophenylmercuric acetate is dependent on its concentration. It requires the reaction with the zymogen, possibly through thiol groups, and the continued presence of the agent. During this treatment the zymogen undergoes a sequential processing; first it becomes active without changing its apparent molecular mass, and then it is processed to low-Mr species of Mr 46,000, 45,000 (HMM) and 28,000 (LMM). The rate of conversion of the precursor into an initial intermediate of Mr 46,000 follows first-order kinetics (t1/2 2.0 h with 1.5 mM-4-amino-phenylmercuric acetate at 37 degrees C) and is independent of the initial concentration of the zymogen or the presence of up to a 676-fold molar excess of substrate, whereas the generation of HMM and LMM species is affected by these parameters. These results indicate that activation of the prometalloendopeptidase by an organomercurial compound is initiated by the molecular perturbation of the zymogen that results in conversion into the 46,000-Mr intermediate by an intramolecular action; the subsequent processing of this intermediate in HMM and LMM species is a bimolecular reaction. In vivo it is probable that the precursor of this metalloendopeptidase is activated either by direct limited proteolysis by tissue or plasma endopeptidases, or, alternatively, by factors that cause certain conformational changes in the zymogen molecule.

Arthritis, Rheumatoid↗
PubMed1989

Tissue cooperation in a proteolytic cascade activating human interstitial collagenase.

We present a cascade of proteolytic events catalyzed by the proteases secreted by cultured keratinocytes and fibroblasts that results in the activation of interstitial procollagenase. Cultured human skin fibroblasts constitutively secrete interstitial collagenase and stromelysin as proenzymes. In contrast, interstitial collagenase found in serum-free skin organ culture conditioned medium is activated. Cocultivation of the major cellular components of skin organ culture, dermal fibroblasts and epidermal keratinocytes, induces activation of interstitial procollagenase and prostromelysin in the presence of plasminogen. This activation occurs through a urokinase-dependent pathway where added keratinocytes secrete the plasminogen activator urokinase, which converts plasminogen into plasmin. Plasmin is capable of activating purified procollagenase and prostromelysin. Plasmin-dependent activation of procollagenase generates an enzyme species, by amino-terminal processing, identical to those generated by limited proteolysis with trypsin or treatment with organomercurial compounds. Catalytic amounts of activated stromelysin can in turn convert plasmin- or trypsin-activated collagenase into a fully active enzyme by removal of approximately 15 amino acid residues from the carboxyl end of the enzyme. This results in a 5- to 8-fold increase in collagenase specific activity that is due to its proteolytic cleavage and not to the presence of the activator stromelysin. Stromelysin alone in both pro- and activated forms is not capable of efficient activation of human fibroblast interstitial procollagenase.

Cells, Cultured↗
PubMed1990

Multiple modes of activation of latent human fibroblast collagenase: evidence for the role of a Cys73 active-site zinc complex in latency and a "cysteine switch" mechanism for activation.

Latent human fibroblast collagenase (HFC) can be activated by a variety of seemingly disparate means. In addition to the well-characterized activation by trypsin and organomercurial compounds, the enzyme can be activated to various extents by surfactants such as sodium dodecyl sulfate, by chaotropic ions such as SCN-, by disulfide compounds such as oxidized glutathione, by sulfhydryl alkylating agents such as N-ethylmaleimide, and by oxidants such as NaOCl. The underlying basis for these activations is the modification, exposure, or proteolytic release of the Cys73 residue from its habitat in the latent enzyme where it is thought to be complexed to the active-site zinc atom. This residue is not accessible for reaction with small molar excesses of dithionitrobenzoate in native, latent HFC. However, on addition of EDTA, this residue becomes fully exposed and is quantitatively labeled. All modes of activation of latent HFC are believed to involve the dissociation of Cys73 from the active-site zinc atom and its replacement by water, with the concomitant exposure of the active site. This is thought to be the primary event that precedes the well-known autolytic cleavages that are observed following the appearance of collagenase activity. The dissociation of Cys73 from the zinc atom in the latent enzyme "switches" the role of the zinc from a noncatalytic to a catalytic one. This "cysteine switch" mechanism of regulation may be applicable to the entire collagenase gene family.

Amino Acid Sequence↗
PubMed1995

Mechanism of activation of human neutrophil gelatinase B. Discriminating between the role of Ca2+ in activation and catalysis.

Gelatinase B is a Zn(2+)- and Ca(2+)-dependent endopeptidase that is secreted from cells as an inactive proenzyme. The enzyme can be activated in vitro by organomercurial compounds and by trypsin. The role of Ca2+ in autoproteolytic processing initiated by 4-aminophenylmercuric acetate and trypsin and in catalytic activity of the activated enzyme was investigated by zymography and by kinetic analysis. Treatment of unglycosylated 57.5-kDa pro-gelatinase B with 4-aminophenylmercuric acetate (1 mM) in the absence of Ca2+ generated a 49-kDa inactive intermediate (E'), whereas a 41.5-kDa active species (E") was generated in the presence of Ca2+ (5 mM). Upon addition of Ca2+ to the reaction mixture of Ca(2+)-depleted E' or E" at 37 degrees C, E' showed a lag period in generation of the product as a function of time, but E" presented an immediate activity. The appearance of enzymatic activity of E' correlated with the generation of the E" species. NH2-terminal sequence analyses showed that E' and E" had the same NH2 termini, i.e. Met-75, suggesting that Ca(2+)-dependent removal of COOH terminus of E' is required for activation of the enzyme. Treatment of pro-gelatinase B with trypsin in the absence of Ca2+, led to degradation of the enzyme. In the presence of Ca2+, trypsin processed the pro-enzyme to a 40-kDa active species. In contrast to E", this active species did not require Ca2+ for activity. The Ca2+ dependence of E" activity was also abolished by treatment of the enzyme with trypsin. NH2-terminal sequence analysis indicated that amino acid residues 75-87 had been removed from the NH2 terminus of E" by trypsin, suggesting that these residues are responsible for the Ca(2+)-dependent activity of the enzyme. Removal of Ca2+ and catalytic Zn2+ inhibited the activities of both E" and trypsin-treated E". In the absence of Ca2+, either Zn2+, Co2+, Mn2+, or Cd2+ was able to restore the activity of trypsin-treated E". None of the divalent cations tested however, was able to stimulate the activity of E" in the absence of Ca2+. These experiments further suggest that binding of Ca2+ to E" or removal of the NH2-terminal residues of the enzyme by trypsin induces a conformational change in the protein and makes the active site of the enzyme accessible to various metal ions rendering the enzyme active.

Amino Acid Sequence↗
PubMed1996

Mechanism of Ca2+-dependent activity of human neutrophil gelatinase B.

Progelatinase B can be activated in vitro by organomercurial compounds and by proteolytic enzymes such as trypsin, chymotrypsin, and stromelysin. Activation of the proenzyme by either 4-aminophenylmercuric acetate or chymotrypsin yielded proteins that absolutely required Ca2+ for activity, regardless of the pH of the reaction mixture. The trypsin- and stromelysin-activated gelatinases, on the other hand, did not require Ca2+ for activity at pH 7.5, but the activity of the trypsin-activated enzyme became Ca2+ dependent as the pH increased. The pH study revealed that an amino acid residue with an apparent pKa of 8.8 was involved in this process. The NH2-terminal analyses showed that trypsin- and stromelysin-activated enzymes had the same NH2 termini (Phe88), but 4-aminophenylmercuric acetate- and chymotrypsin-activated enzymes had Met75 and Gln89 or Glu92 as the NH2-terminal amino acid, respectively. These data, in conjunction with the x-ray crystal structure of collagenase, suggest that a salt linkage involving Phe88 is responsible for the Ca2+-independent activity of trypsin- and stromelysin-activated gelatinase. Replacing Asp432 in progelatinase with either Glu, Asn, Gly, or Lys resulted in the proteins that, upon activation by trypsin, required Ca2+ for activity. These substitutions did not significantly affect Km for the synthetic substrate but decreased the kcat and increased the half-maximal Ca2+ concentration required for enzyme activity (KCa) by severalfold. The effects on kcat and KCa depended on both charge and size of the side chains of the substituted amino acids. The decrease in kcat correlated well with the increase in KCa of the mutants. The orders of decrease in kcat and increase in KCa were wild type >/= D432E > D432N > D432G > D432K and wild type </= D432E < D432N < D432G < D432K, respectively. These data suggest that in trypsin- or stromelysin-activated enzyme, the NH2-terminal Phe88 forms a salt linkage with Asp432, rendering the enzyme Ca2+ independent. Ca2+ affects catalytic activity of the 4-aminophenylmercuric acetate- and chymotrypsin-activated enzymes by substituting for the salt linkage and interacting with Asp432. This interaction generates a similar, if not identical, conformational change to that generated by the salt linkage in the protein, leading to catalysis.

Amino Acid Sequence↗
PubMed2000

The isolation, characterization, and molecular cloning of a 75-kDa gelatinase B-like enzyme, a member of the matrix metalloproteinase (MMP) family. An avian enzyme that is MMP-9-like in its cell expression pattern but diverges from mammalian gelatinase B in sequence and biochemical properties.

We have isolated a novel 75-kDa gelatinase from a chicken macrophage cell line, HD11. Biochemical and immunological characterization of the purified enzyme demonstrated that it is distinct from the chicken 72-kDa gelatinase A (MMP-2). The enzyme is capable of specific gelatin binding and rapid gelatin cleavage. Incubation with an organomercurial compound (p-aminophenylmercuric acetate) induces proteolytic processing and activation of this enzyme, and the resultant gelatinolytic activity is sensitive to both zinc chelators and tissue inhibitors of metalloproteinases. A full-length cDNA for the enzyme has been cloned, and sequence analysis demonstrated that the enzyme possesses the characteristic multidomain structure of an MMP gelatinase including a cysteine switch prodomain, three fibronectin type II repeats, a catalytic zinc binding region, and a hemopexin-like domain. The 75-kDa gelatinase is produced by phorbol ester-treated chicken bone marrow cells, monocytes, and polymorphonuclear leukocytes, cell types that charac- teristically produce the 92-kDa mammalian gelatinase B (MMP-9). The absence of a 90-110-kDa gelatinase in these cell types indicates that the 75-kDa gelatinase is likely the avian counterpart of gelatinase B. However, the protein is only 59% identical to human gelatinase B, whereas all previously cloned chicken MMP homologues are 75-90% identical to their human counterparts. In addition, the new 75-kDa chicken gelatinase lacks the type V collagen domain that is found in all mammalian gelatinase Bs. Furthermore, the secreted enzyme appears structurally distinct from known gelatinase Bs and the activated enzyme can cleave fibronectin, which is not a substrate for mammalian gelatinase B. Thus the results of this study indicate that a second MMP gelatinase exists in chickens, and although it is MMP-9/gelatinase B-like in its overall domain structure and expression pattern, it appears to be biochemically divergent from mammalian gelatinase B.

Amino Acid Sequence↗
PubMed1976

Purification and properties of an enzyme catalyzing the splitting of carbon-mercury linkages from mercury-resistant Pseudomonas K-62 strain. I. Splitting enzyme 1.

An enzyme (S-1) which catalyzes the splitting of carbon-mercury linkages of organomercury compounds was purified about 24-fold from the cell-free extract of mercury-resistant Pseudomonas K-62 strain by treatment with streptomycin, precipitation with ammonium sulfate, and successive chromatography on Sephadex G-150, DEAE-Sephadex, and DEAE-cellulose. A purified preparation of the enzyme showed a single band on polyacrylamide gel electrophoresis, and was colorless. The molecular weight of the enzyme was estimated to be 19,000, and Km was 5.3 X 10(-5) M for p-chloromercuribenzoic acid (PCMB). The temperature and pH optimum for the reaction were 50degrees and 7.0, respectively. The enzyme was capable of catalyzing the decomposition of methylmercuric chloride (MMC), ethylmercuric chloride (EMC), phenylmercuric acetate (PMA), and PCMB in the presence of a sulfhydryl compound to form a mercuric ion plus methane, ethane, benzene, or benzoic acid, respectively. The mercuric ion thus formed was reduced to metallic mercury by metallic mercury-releasing enzyme (MMR-enzyme).

Chloromercuribenzoates↗
PubMed1991

The complex between a tissue inhibitor of metalloproteinases (TIMP-2) and 72-kDa progelatinase is a metalloproteinase inhibitor.

Human rheumatoid synovial cells in culture secrete both 72-kDa progelatinase and a complex consisting of 72-kDa progelatinase and a 24-kDa inhibitor of metalloproteinases, TIMP-2. In addition, the culture medium contains TIMP-1, the classical inhibitor of metalloproteinases, with a molecular mass of 30 kDa. TIMP-1 does not form a complex with free 72-kDa progelatinase. Free progelatinase and progelatinase complexed with TIMP-2 can be activated with the organomercury compound p-aminophenylmercury acetate. The activated complex shows less than 10% the enzyme activity of activated free gelatinase. The progelatinase-TIMP-2 complex could be shown to be an inhibitor for other metalloproteinases, such as gelatinase and collagenase secreted by human rheumatoid synovia fibroblasts, as well as for the corresponding enzymes from human neutrophils.

Arthritis, Rheumatoid↗
PubMed1999

Thimerosal positivities: patch testing to methylmercury chloride in subjects sensitive to ethylmercury chloride.

The aim of this paper was to evaluate whether methylmercury chloride (MeHgCl) aq., when patch tested in a group of thimerosal-positive subjects reacting to ethylmercury chloride (EtHgCl), might be a reliable model for the better understanding of interactions between alkylmercury compounds and the skin. 19 out of 21 consecutive patients who previously had given positive patch-test reactions to both ethylmercury chloride 0.0165% eth.(EtHgCl, 0.615 mM) and MeHgCl 0.031% aq.(1.23 mM), and negative reactions to thiosalicylic acid 0.05% (3.24 mM) aq./eth. 50/50, were repatch tested to 8 microl of MeHgCl 0.031% aq. and to 8 microl of aq. solutions containing MeHgCl mixed with cysteine, glutathione, ZnSO4, MgSO4, MnSO4, ZnCl2, MgCl2 and MnCl2, respectively. The results showed that cysteine, glutathione and Zn(II) salts were able to abolish the positive reactions, demonstrating the rôle played by both thiol groups and Zn(II) itself. Patch tests concomitantly carried out in 16 out of 19 patients to 8 microl of aqueous MeHgCl and to 8 microl of aqueous solutions containing MeHgCl and MeHgCl mixed to fragment 56-61 of metallothionein I (MT I), MT I and MT II-Zn, respectively, revealed that all the MTs tested were able to reduce or to inhibit the reactions, demonstrating the effect of the thiol groups. Due to the close chemical similarities to EtHgCl and to its water solubility, MeHgCl seems to be a suitable model for evaluating the reactivity of alkylmercury compounds in the skin. We speculate that both EtHg- and MeHg-derivatives are xenobiotics with similar reactivity. However, the lack of clinical relevance of the reactions to both alkyl compounds lead us to conclude that, since environmental exposure does not seem to play a pivotal rôle, they probably have mostly to do with compounds included in in the standard series, and are elicited by reduced function of physiological SH chelators.

Adult↗