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PubMed2006

Effect of arachidonic acid reacylation on leukotriene biosynthesis in human neutrophils stimulated with granulocyte-macrophage colony-stimulating factor and formyl-methionyl-leucyl-phenylalanine.

Priming of human neutrophils with granulocyte-macrophage colony-stimulating factor (GM-CSF) followed by treatment with formyl-methionyl-leucyl-phenylalanine (fMLP) stimulates cells in a physiologically relevant manner with modest 5-lipoxygenase activation and formation of leukotrienes. However, pretreatment of neutrophils with thimerosal, an organomercury thiosalicylic acid derivative, led to a dramatic increase (>50-fold) in the production of leukotriene B(4) and 5-hydroxyeicosatetraenoic acid, significantly higher than that observed after stimulation with calcium ionophore A23187. Little or no effect was observed with thimerosal alone or in combination with either GM-CSF or fMLP. Elevation of [Ca(2+)](i) induced by thimerosal in neutrophils stimulated with GM-CSF/fMLP was similar but more sustained compared with samples where thimerosal was absent. However, [Ca(2+)](i) was significantly lower compared with calcium ionophore-treated cells, suggesting that a sustained calcium rise was necessary but not sufficient to explain the effects of this compound on the GM-CSF/fMLP-stimulated neutrophil. Thimerosal was found to directly inhibit neutrophil lysophospholipid:acyl-CoA acyltransferase activity at the doses that stimulate leukotriene production, and analysis of lysates from neutrophil preparations stimulated in the presence of thimerosal showed a marked increase in free arachidonic acid, supporting the inhibition of the reincorporation of this fatty acid into the membrane phospholipids as a mechanism of action for this compound. The dramatic increase in production of leukotrienes by neutrophils when a physiological stimulus such as GM-CSF/fMLP is employed in the presence of thimerosal suggests a critical regulatory role of arachidonate reacylation that limits leukotriene biosynthesis in concert with 5-lipoxygenase and cytosolic phospholipase A(2)alpha activation.

Arachidonate 5-Lipoxygenase↗
PubMed1996

Patch test reactions in children, adults and the elderly. A comparative study in patients with suspected allergic contact dermatitis.

The age- and sex-related distribution of positive patch test reactions was investigated in 234 children (0-7 years, n = 72 and 8-14 years, n = 162), 1200 adults (20 to 50 years) and 295 elderly patients (> or = 70 years) with suspected allergic contact dermatitis using a European standard series. In girls from 0 to 7 years, the most frequent contact allergens were thimerosal (37.5%) and nickel (27.5%), in girls from 8 to 14 years, nickel (28.7%) and thimerosal (26.6%), in women, thimerosal (25.3%) and nickel (25.2%), and in elderly women, nickel (12.6%) and balsam of Peru (9.7%). The most frequent contact allergens in boys from 0 to 7 years were ethylmercuric chloride (28.1%) and thimerosal (25.0%), in boys from 8 to 14 years, thimerosal (30.9%) and ethylmercuric chloride (14.7%), in men, thimerosal (21.1%) and ethylmercuric chloride (13.7%) and in elderly men, nickel (11.2%) and balsam of Peru (6.7%). Females showed more positive reactions than males. Whilst 0 to 7 year-old girls and boys showed relatively more frequent reactions, the elderly of both sexes were clearly less affected. Nickel is the most frequent contact allergen in females of 8 years and more. In men, thimerosal is most frequent and reactions to balsam of Peru show a peak incidence in the elderly. Results indicate that patch testing should be considered in children and elderly patients with appropriate indications.

Adolescent↗
PubMed1982

Safety considerations in handling exoantigen extracts from pathogenic fungi.

Currently, exoantigen test procedures for identifying mycelial form cultures of pathogenic molds require that the fungi being extracted be treated with thimerosal to render them safe for handling. Recent studies have demonstrated that thimerosal may not be fungicidal. In view of these reports, we investigated the effects of thimerosal and formaldehyde on a variety of exoantigen preparations. Mature mycelial form fungal cultures, including cultures of Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum and morphologically similar fungi, were grown on Sabouraud dextrose agar slants and treated with 0.02, 0.04, and 0.08% thimerosal for 24 and 48 h and with 0.2 and 0.5% formaldehyde for 24 and 48 h. We found that 0.5% formaldehyde killed all of the fungi studied, whereas 0.2% formaldehyde permitted the growth of only one fungus; 0.02, 0.04, and 0.08% thimerosal were fungistatic. Furthermore, 0.2 and 0.5% formaldehyde and 0.08% thimerosal affected certain antigens adversely. For those investigators who prefer to use 0.02% thimerosal and to work with sterile extracts, we recommend that the procedure be modified, and we advocate sterilization of extracts by passage through membrane filters.

Antigens, Fungal↗
PubMed1999

Redox modulation of intracellular free calcium concentration in thyroid FRTL-5 cells: evidence for an enhanced extrusion of calcium.

Redox modulation is involved in the regulation of the intracellular free calcium concentration ([Ca2+]i) in several cell types. In thyroid cells, including thyroid FRTL-5 cells, changes in [Ca2+]i regulate important functions. In the present study we investigated the effects of the oxidizing compounds thimerosal and t-butyl hydroperoxide on [Ca2+]i in thyroid FRTL-5 cells. Thimerosal mobilized sequestered calcium, and evoked modest store-dependent calcium entry. Both compounds potently attenuated the increase in [Ca2+]i when store-operated calcium entry was evoked with thapsigargin. The entry of barium was not attenuated. Experiments performed with high extracellular pH, in sodium-free buffer and in the presence of vanadate suggested that thimerosal decreased [Ca2+]i by activating a calcium extrusion mechanism, probably a plasma membrane Ca2+-ATPase. All the observed effects were abrogated by the reducing agent beta-mercaptoethanol. The mechanism of action was apparently mediated via activation of protein kinase C, as thimerosal potently stimulated binding of [3H]phorbol 12, 13-dibutyrate, and was without effect on store-operated calcium entry in cells treated with staurosporine or in cells with down-regulated protein kinase C. Thimerosal did not depolarize the membrane potential, as evaluated using patch-clamp in the whole-cell mode. In immunoprecipitates obtained with an antibody against plasma membrane Ca2+-ATPase, we observed several phosphorylated bands in cells stimulated with thimerosal. In conclusion, we have shown that thimerosal attenuates an increase in [Ca2+]i, probably by activating a plasma membrane Ca2+-ATPase.

Animals↗
PubMed2000

Effects of different activation treatments on fertilization of horse oocytes by intracytoplasmic sperm injection.

The effects of four reagents on the activation and subsequent fertilization of equine oocytes, and the development of these after intracytoplasmic sperm injection, were investigated. Cumulus-oocyte complexes collected from equine ovaries obtained from an abattoir were matured in vitro for 40-44 h in TCM199 medium before being injected, when in metaphase II, with an immobilized stallion spermatozoon. The cumulus-oocyte complexes were then subjected to one of five activation treatments: (a) 10 micromol ionomycin l(-1) for 10 min; (b) 7% (v/v) ethanol for 10 min; (c) 100 micromol thimerosal l(-1) for 10 min; (d) 250 micromol inositol 1,4, 5-triphosphate l(-1) injection; and (e) no treatment (control). After 18-20 h further culture, the cumulus-oocyte complexes were assessed for activation by observing whether they had progressed through second anaphase-telophase and had formed a female pronucleus. The proportions of oocytes activated after each treatment were: 16/27 (59%) for ionomycin; 14/25 (56%) for ethanol; 22/28 (79%) for thimerosal; 15/27 (56%) for inositol 1,4,5-triphosphate; and 0/20 (0%) for the untreated controls. Thus, significantly more oocytes (P < 0.05) were activated by treatment with thimerosal than by the other four treatments. The proportions of oocytes that cleaved to the two-cell stage at 24-30 h after sperm injection in the groups treated with ionomycin, ethanol and thimerosal were 7/20 (35%), 5/19 (26%) and 11/23 (48%), respectively. No cleavage was observed in any of the control oocytes or those treated with inositol 1,4, 5-triphosphate. Furthermore, evidence of normal fertilization was observed in 2/7 (29%), 2/5 (40%) and 7/11 (64%) of the oocytes treated with ionomycin, ethanol and thimerosal, respectively. These results demonstrated that: (a) it is possible to activate equine oocytes with the chemical stimulants, ionomycin, ethanol, thimerosal and inositol 1,4,5-triphosphate; (b) thimerosal is more effective than the other three reagents in facilitating both meiotic activation and normal fertilization of equine oocytes; and (c) chemical activation may also stimulate parthenogenetic cleavage of oocytes without concurrent changes in the head of the spermatozoon.

Animals↗
PubMed1986

Inhibitors of acyl-coenzyme A:lysolecithin acyltransferase activate the production of endothelium-derived vascular relaxing factor.

Considerable acyl-CoA:lysolecithin acyltransferase (LAT) activity could be demonstrated in homogenates of cultured bovine endothelial cells. This LAT activity was inhibited by thimerosal and p-hydroxymercuribenzoate in a concentration-dependent manner. Preconstricted strips of rabbit aorta were relaxed by acetylcholine or the LAT inhibitors in a concentration-dependent fashion if the endothelium was intact (maximal effect of both LAT inhibitors at 10(-5) M). In rabbit aortic strips thimerosal also induced a concentration-dependent stimulation of the formation of 6-keto-prostaglandin F1 alpha, the major cyclooxygenase metabolite of this tissue. This effect of thimerosal was more pronounced in endothelium-intact than in endothelium-denuded preparations. Inhibition of prostaglandin synthesis with indomethacin (10(-5) M) did not impair the relaxation. Thimerosal and acetylcholine-induced relaxations were abolished when the endothelium was removed or when endothelium-intact preparations were pretreated with nordihydroguaiaretic acid (3 X 10(-5) M), gossypol (5 X 10(-6) M) or dithiothreitol (3 X 10(-4) M). In contrast, mepacrine (3 X 10(-5) M), that abolished the acetylcholine response, had no effect on the thimerosal relaxation. In other experiments bovine endothelial cells were grown to confluence on microcarrier beads and packed into columns. Adding thimerosal (5 X 10(-6) M) or bradykinin (10(-10) to 10(-8) M) to the medium superfusing the columns induced the release of an unstable nonprostanoid factor (or factors) that relaxed endothelium-denuded rabbit femoral artery segments. Bradykinin induced a transient effect whereas there was a strong and long-lasting release of the factor after administration of thimerosal.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed1984

Effects of analogs of salicylate on p-aminohippurate uptake into basal-lateral membranous vesicles.

In basal-lateral membranes of the renal cortex, thiol substituted analogs of salicylate inhibited the uptake of p-aminohippurate (PAH). The mercury-containing analogs, thimerosal and mercaptide V (formed from 2 mol of thiosalicylate and 1 mol of Hg++), were highly inhibitory. Compared with probenecid, thimerosal and mercaptide V yielded dose-response curves of steeper slope and higher maximal effect. The dose-response curves of thimerosal and mercaptide V were similar in shape, although mercaptide V was more potent. The inhibition by thimerosal, mercaptide V and mersalyl acid, an anionic sulfhydryl reagent which also inhibits uptake of PAH ( Tse et al., J. Pharmacol. Exp. Ther. 226: 19-26, 1983), was found to be competitive with Ki values of 0.39 +/- 0.05, 0.12 +/- 0.06 and 0.05 +/- 0.02 mM, respectively. The inhibitory effects of thimerosal and mercaptide V were only partially reversible. Thimerosal and mercaptide V reacted 35 and 62%, respectively, with membrane sulfhydryl groups which may explain the nonreversibility of the inhibitor. The nonreversibility is probably not due to irreversible destruction of the vesicles, as the "glucose space" of the vesicles was not affected by these two compounds. That derivatives of salicylates capable of reacting with sulfhydryl groups were more inhibitory than thiosalicylate is consistent with a hypothesis that the PAH transporter contains a sulfhydryl group(s) essential for uptake. Based on the degree of inhibition, the degree of reversibility, the degree of membrane sulfhydryl group oxidation and the computer-generated three dimensional models of thimerosal, mercaptide V and mersalyl acid, a model of the PAH transporter is proposed.

Aminohippuric Acids↗
PubMed2003

Characterization of cytotoxic and genotoxic effects of different compounds in CHO K5 cells with the comet assay (single-cell gel electrophoresis assay).

Different variants of the comet assay were used to study the genotoxic and cytotoxic properties of the following eight compounds: chloral hydrate, colchicine, hydroquinone, DL-menthol, mitomycin C, sodium iodoacetate, thimerosal and valinomycin. Colchicine, mitomycin C, sodium iodoacetate and thimerosal induced genotoxic effects. The other compounds were found to be inactive. The compounds were tested in the standard comet assay as well as in the all cell comet assay (recovery of floating cells after treatment), designed in our laboratory for adherently-growing cells. This latter procedure proved to be more adequate for the assessment of the cytotoxicity for some of the compounds tested (hydroquinone, DL-menthol, thimerosal, valinomycin). Colchicine was positive in the standard comet assay (3h treatment) and in the all cell comet assay (24h treatment). Sodium iodoacetate and thimerosal were positive in the standard and/or the all cell comet assay. Chloral hydrate, hydroquinone, sodium iodoacetate, mitomycin C and thimerosal were also tested in the modified comet assay using lysed cells. Mitomycin C and thimerosal showed effects in this assay, whereas sodium iodoacetate was inactive. This indicates that it does not induce direct DNA damage. Compounds that are known or suspected to form DNA-DNA cross-links or DNA-protein cross-links (chloral hydrate, hydroquinone, mitomycin C and thimerosal) were checked for their ability to reduce ethyl methanesulfonate (EMS)-induced DNA damage. This mode of action could be demonstrated for mitomycin C only.

Animals↗
PubMed1999

Calcium release and subsequent development induced by modification of sulfhydryl groups in porcine oocytes.

The mechanism of Ca2+ release induced by modification of sulfhydryl groups and the subsequent activation of porcine oocytes were investigated. Thimerosal, a sulfhydryl-oxidizing compound, induced Ca2+ oscillation in matured oocytes. In thimerosal-preincubated oocytes, the amount of Ca2+ released after microinjection of inositol 1,4,5-trisphosphate (InsP3) or ryanodine increased strikingly, indicating that thimerosal potentiated both InsP3- and ryanodine-sensitive Ca2+ release pathways. Thimerosal also enhanced the sensitivity of oocytes to microinjected Ca2+ so that in pretreated oocytes a Ca2+ injection triggered a larger transient. Heparin at concentrations that normally block the InsP3-induced Ca2+ release were without effect; higher doses significantly increased the time leading up to the first spike. The thimerosal-induced Ca2+ release could not be blocked by procaine, and it did not require the formation of InsP3 since preinjection with neomycin did not prevent the oscillation. Immunocytochemistry revealed that thimerosal treatment destroyed the meiotic spindle, preventing further development, an effect that could be reversed by dithiothreitol. The combined thimerosal/dithiothreitol treatment triggered second polar body extrusion in 50% of the oocytes, and as a result of this activation scheme approximately 15% of the in vitro- and approximately 60% of the in vivo-matured oocytes developed to blastocyst during a 7-day culture in vitro.

Animals↗
PubMed2004

Direct dialysis quantification: investigation of the impact of dialysate preservation techniques on solute assays.

AIMS: Urease-producing microorganisms may lower urea nitrogen (UN) during dialysate-side dosing. We investigated the impact of 3 proven preservatives (acetic acid, ceftazidime, thimerosal) on UN concentration, and the concentrations of creatinine (CR) and beta2-microglobulin (beta2M). METHODS: The UN, CR and beta2M concentrations were assayed in 3 separate aliquots from 20 spent dialysate samples (ceftazidime, 125 mg/l, or 1% thimerosal, 1 ml/l, vs. control). The beta2M concentration was assayed in 10 further spent dialysate collections (concentrated glacial acetic acid, 5 ml/l, vs. control). Solute concentrations were compared with the concordance correlation coefficient (rc). RESULTS: Ceftazidime and thimerosal had little effect on the concentrations of UN and CR (rc >0.97). For the beta2M concentration, agreement remained good (rc >0.96) for ceftazidime and thimerosal (although the former tended to lower concentrations) but acetic acid was less optimal (rc = 0.893). CONCLUSIONS: Ceftazidime and thimerosal may be used as dialysate preservatives without affecting the UN or CR concentrations. Thimerosal is to be preferred when studying beta2M. Acetic acid produces unacceptable inaccuracy when measuring beta2M.

Acetic Acid↗
PubMed2001

Hepatitis B vaccination practices in hospital newborn nurseries before and after changes in vaccination recommendations.

BACKGROUND: Routine use of hepatitis B vaccine for low-risk newborns was suspended on July 7, 1999, because of concern about the potential risk of thimerosal, a mercury-containing vaccine preservative. Reinstatement of the birth dose was recommended when a thimerosal-free vaccine became available. OBJECTIVE: To explore changes in hepatitis B vaccination practices for newborns related to the revised recommendations for low-risk infants (in this study, the terms newborn and infant are used interchangeably). DESIGN: A telephone survey of a random sample of 1000 US hospitals. PARTICIPANTS: Nurse managers, nursery directors, and staff nurses of the newborn nurseries. MAIN OUTCOME MEASURES: Nursery vaccination practices before and after July 7, 1999, and the availability and use of thimerosal-free vaccine. RESULTS: Interviews were conducted with 773 (87%) of 886 eligible hospitals. Before July 7, 1999, 78% of the hospitals reported vaccination practices that were consistent with recommendations at that time, although only 47% vaccinated all low-risk infants at birth. After July 7, 1999, almost all hospitals discontinued vaccination of low-risk infants, in accordance with the recommendation change; however, there was a 6-fold increase in the number of hospitals that were not vaccinating all high-risk infants. After the introduction of thimerosal-free vaccine, only 39% of the hospitals reported vaccinating all low-risk infants. CONCLUSIONS: Most hospital nurseries altered their newborn hepatitis B vaccination practices consistent with changes in national recommendations. However, unintended consequences included the failure of some hospitals to continue vaccinating all high-risk infants and the delay in reintroducing vaccination for low-risk newborns after the introduction of a thimerosal-free vaccine. Assessments of the appropriateness of this country's response to the threat of thimerosal in vaccines should consider these findings.

Data Collection↗
PubMed1994

Purified reconstituted inositol 1,4,5-trisphosphate receptors. Thiol reagents act directly on receptor protein.

Thimerosal, a sulfhydryl oxidizing reagent, has been shown to induce Ca2+ mobilization in several cell types and to increase the sensitivity of intracellular Ca2+ stores to inositol 1,4,5-trisphosphate (IP3). Using purified IP3 receptor (IP3R) protein reconstituted in vesicles, we demonstrate pronounced stimulation by thimerosal of its Ca2+ channel activity. Effects of thimerosal are dependent on the redox state of the receptor, implying an action of thimerosal on a critical sulfhydryl group(s) of IP3R. Thimerosal enhances the affinity of IP3R for IP3 binding. The manner in which thimerosal modulates IP3R responsiveness to IP3 provides evidence for receptor heterogeneity with implications for mechanisms of quantal Ca2+ release. These results clarify regulation of IP3R activity by redox modulation.

Amino Acid Sequence↗
PubMed1997

Interaction between thiol-modifying agents and P1075, a K(ATP) channel opener, in rat isolated aorta.

In vascular smooth muscle, openers of ATP-dependent potassium channels (K(ATP) channels), such as P1075 (N-cyano-N'-(1,1-dimethylpropyl)-N"-3-pyridylguanidine), produce relaxation. In this study we have investigated the effects of thiol-modifying agents on the binding of P1075 and on the 86Rb+ efflux stimulating and vasorelaxant effects of the opener in rat aortic rings. The increase in 86Rb+ efflux induced by P1075 was taken as a qualitative measure of K+ channel opening. The hydrophilic SH-group-oxidizing substance, thimerosal (1 to 100 microM), abolished specific binding of [3H]-P1075 with an IC50 value of 7.6+/-1.2 microM; at 30 microM, the half time for inhibition was 38 min. Two other thioloxidizing agents, PMB (4-hydroxy-mercuribenzoic acid) and DTBNP (2,2'-dithio-bis(5-nitropyridine)), inhibited binding up to 86% and 44%, respectively. The disulphide bond reducing substance, DTT (1,4-dithiothreitol, 0.1 to 1 mM), reduced [3H]-P1075 binding by up to 20% and partially reversed the inhibitory effect of thimerosal. In 86Rb+ efflux experiments, thimerosal (3 to 100 microM) concentration-dependently increased basal efflux but inhibited P1075-stimulated tracer efflux with an IC50 value of 7+/-1 microM. The inhibitory effect occurred with a half-time of approximately 8 min and was essentially reversed by DTT. In rings precontracted with noradrenaline, thimerosal inhibited the vasorelaxant effect in a noncompetitive manner, shifting the concentration-relaxation curves to the right and reducing maximum relaxation. The data show that oxidation of thiol groups interferes with the binding of the K(ATP) channel opener, P1075; concomitantly, the 86Rb+ efflux stimulating and the vasorelaxant effects are inhibited. Reduction of disulphide bonds by DTT has only minor effects on the action of P1075. Collectively, the results suggest that intact thiol groups are essential for the functioning of the K(ATP) channel in rat aorta. The different kinetics governing the inhibition of opener binding and of opener-stimulated 86Rb+ efflux suggest that the SH-groups involved in the two processes differ in their accessibility to thimerosal and/or in their reactivity.

Animals↗
PubMed1997

Effects of thiol-modifying agents on a K(Ca2+) channel of intermediate conductance in bovine aortic endothelial cells.

Ca2+-activated K+ channels (K(Ca2+)) constitute key regulators of the endothelial cell electrophysiological response to InsP3-mobilizing agonists. Inside-out and outside-out patch clamp experiments were thus undertaken to determine if the gating properties of a voltage-insensitive K(Ca2+) channel of intermediate conductance present in bovine aortic endothelial (BAE) cells could be modified by specific sulfhydryl (SH) oxidative and/or reducing reagents. The results obtained first indicate that cytosolic application of hydrophilic oxidative reagents such as 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB) (0.2 to 5 mM) or [(O-carboxyphenyl)thio]ethyl mercury sodium salt (thimerosal) (0.5 to 5 mM) reduces gradually the K(Ca2+) channel activity with no modification of the channel unitary conductance. The inhibitory action of DTNB (1 to 5 mM) or thimerosal (1 to 5 mM) was not reserved following withdrawal of the oxidative agents, but channel activity could partly be restored by the addition of the SH group reducing agents dithiothreitol (DTT) (5 mM) or reduced glutathione (GSH) (5 mM) in 53% and 50% of the inside-out experiments performed with DTNB and thimerosal respectively. Similar results were obtained using H2O2 at concentrations ranging from 500 microM to 10 mm as oxidative reagent. In contrast, the lipid soluble oxidative agent 4,4'-dithiodipyridine (4-PDS) (1 mM) appeared in inside-out experiments less potent than DTNB and thimerosal at inhibiting the K(Ca2+) channel activity, suggesting that the critical SH groups involved in channel gating are localized at the inner face of the cell membrane. This conclusion was further substantiated by a series of outside-out patch clamp experiments which showed that DTNB (5 mM) and thimerosal (5 mM) were unable to inhibit the K(Ca2+) channel activity when applied to the external surface of the excised membrane. Finally, no significant changes of the gating properties of the K(Ca2+) channel were observed in inside-out experiments where the SH group reducing agents DTT and GSH were applied immediately following membrane excision. However, the application of either GSH or DTT was found to partly restore channel activity in experiments where the K(Ca2+) channels showed significant rundown.

Animals↗
PubMed1999

Evidence that the nitrergic neurotransmitter and endothelium-derived relaxing factor might be S-nitrosothiols in the mouse corpus cavernosum.

The effects of thimerosal, a sulfhydryl oxidizing agent on nitrergic, endothelium-dependent and -independent relaxations were investigated to examine the possibility that the nitrergic neurotransmitter and endothelium-derived relaxing factor (EDRF) could be S-nitrosothiol or free nitric oxide (NO) in the isolated mouse corpus cavernosum. Thimerosal (5 x 10(-6)-2 x 10(-5) M) inhibited or almost abolished electrical field stimulation--(EFS, 30V, 0.5 ms, 15 sec, 1, 2, 4, 8, 16 Hz), acetylcholine--(ACh, 5 x 10(-8)-1.25 x 10(-6) M), glyceryl trinitrate--(GTN, 3 x 10(-7)-3 x 10(-6) M), and S-nitrosoglutathione--(GSNO, 5 x 10(-6)-1.25 x 10(-4) M) induced relaxations. Thiomerosal inhibition seems to be specific to L-arginine NO pathways since it had no effect on acidified sodium nitrite--(10(-4)-5 x 10(-4) M), photoactivated sodium nitrite--(2 x 10(-4) M), isoprenaline--(10(-6) M), or papaverine--(10(-4) M) elicited relaxations. Moreover, the inhibitory effect of thimerosal on the nitrergic, ACh- or GTN-induced relaxations were partly reversed by sulfhydryl-containing compounds, L-cysteine (10(-3) M), dithiothreitol (10(-3) M), or glutathione (10(-3) M). However L-methionine (10(-3) M), which contains a methyl group on the sulphur atom, failed to restore the thimerosal inhibition. Thimerosal did not change the contraction produced by 10(-4) M NG-nitro-L-arginine methyl ester. These findings indicate that the nitrergic neurotransmitter as well as EDRF may not be free NO but NO-transferring molecules, probably S-nitrosothiols, in the mouse corpus cavernosum.

Animals↗
PubMed1992

Influence of free thiol group(s) on autoantibody-defined epitope of proliferating cell nuclear antigen.

Proliferating cell nuclear Ag (PCNA) is an intranuclear protein involved in DNA replication directed by DNA polymerase delta and is the target Ag of autoantibodies in some patients with SLE. There is evidence that the epitope on PCNA recognized by human autoantibodies is conformation-dependent and is not a continuous peptide sequence. Thimerosal, a mercury-containing sulfhydryl blocking compound, markedly reduced or abolished the reactivity of this autoantibody-defined PCNA epitope. The thimerosal effect was observed in various Ag-detecting systems including indirect immunofluorescence, immunodiffusion, immunoprecipitation, and flow cytometry. The mechanism of the thimerosal effect appeared to be mediated through free but not readily accessible sulfhydryl group or groups. The sulfhydryl-modification by thimerosal could be reversed by competition with thiol-containing compounds. Experimentally induced mAb to PCNA generated by immunization with purified PCNA have been shown to recognize epitopes that are continuous peptide sequences and these epitopes were not affected by thimerosal. It has been shown that the human autoantibody-defined epitope is related to the function of PCNA because autoantibodies are able to inhibit DNA polymerase delta directed DNA replication, whereas experimentally induced antibodies are not. These studies show that certain sulfhydryl groups in PCNA have a role in determining the antigenicity of the epitope recognized by autoantibody and raise the possibility that certain sulfhydryl groups might also be associated with its function.

Autoantibodies↗
PubMedDate not supplied

[An evaluation of the allergizing properties of merthiolate as a component of adsorbed DTP vaccine].

The study of the allergenic properties of thimerosal contained in adsorbed DPT vaccine was carried out. Two variants of this vaccine, with and without thimerosal, as well as thimerosal alone (diluted 1:10,000, which corresponds to the content of this preservative in the vaccine), were used in experiments. The phenomenon of anaphylactic shock, passive dermal anaphylaxis and skin tests were used as test-systems. The injection of each of the two variants of the vaccine induced the state of sensitization in guinea pigs. At the same time no differences in the intensity of manifestations of immediate and delayed hypersensitivity induced by preparations with and without thimerosal were registered. The solution of thimerosal alone exhibited no sensitizing properties.

Adsorption↗
PubMed1993

Thiol reagents increase the affinity of the inositol 1,4,5-trisphosphate receptor.

Thiol reagents have been shown to increase cytosolic Ca2+ in several cell types. In non-muscle cells, these agents induce Ca2+ spikes by increasing the sensitivity of the intracellular Ca2+ stores to D-myo-inositol-1,4,5-trisphosphate (InsP3). We have investigated the effects of thimerosal and oxidized glutathione on the binding properties of the InsP3 receptor in permeabilized hepatocytes and liver and cerebellar membranes. Thimerosal, at the maximal concentration of 100 microM, decreased the KD for the InsP3 binding to permeabilized hepatocytes and cerebellar membranes from 16 to 3 nM and from 25 to 8 nM, respectively, without affecting the maximal binding capacities. On liver membranes, both thimerosal and high Ca2+ concentrations increased the affinity for InsP3 binding. The Ca2+ and the thimerosal effects were differentiated by kinetic experiments. In low Ca2+ media, two kinetic components were identified and thimerosal decreased the rate of dissociation from both these components without affecting the rate of association. In the high Ca2+ medium, a single kinetic component was found with a very slow rate of dissociation. These data suggest that the InsP3 receptor exists in different states. The high-affinity inactive state induced by high Ca2+ concentrations displays slow rates of association and dissociation. The binding properties of the receptor in its active state can be regulated by thiol reagents which increase the affinity by decreasing the dissociation rate constants. At a resting concentration of 100-200 nM, Ca2+ has two effects: it increases the affinity of the active state of the receptor as thiol reagents do and transforms part of the receptors into the inactive high-affinity state.

Animals↗