Biomedical subjects

F X Reichl

Publications and source records attributed to F X Reichl.

At least 19 recordsLinked to original sources

PubMed2005

In vitro embryotoxicity assessment with dental restorative materials.

OBJECTIVES: Resin (co)monomers may be released from restorative dental materials and can diffuse into the tooth pulp or the gingiva, and can reach the saliva and the circulating blood. Genotoxic potential of some dental composite components has been clearly documented. The genotoxic effects of xenobiotics can represent a possible step in tumor initiation and/or embryotoxicity/teratogenesis. A modified fluorescent mouse embryonic stem cell test (R.E.Tox) was used to test the embryotoxic potential of following dental restorative materials: Bisphenol A glycidylmethacrylate (BisGMA), urethanedimethacrylate (UDMA), hydroxyethylmethacrylate (HEMA), and triethyleneglycoldimethacrylate (TEGDMA), as well as some of their metabolic intermediates 2,3-epoxy-2-methyl-propionicacid-methylester (EMPME), methacrylic acid (MA), and 2,3-epoxy-2-methylpropionic acid (EMPA). METHODS: Mouse embryonic stem (ES) cells stably transfected with a vector containing the gene for the green fluorescent protein under control of the cardiac alpha-myosin heavy chain promoter were differentiated in the presence of various concentrations of the test compounds for 12 days. Fluorescence was measured using the TECAN Safire and values were expressed as percent of control values. To distinguish between cytotoxic and embryotoxic effects, all compounds were tested in a standard MTT assay. RESULTS: HEMA, TEGDMA and EMPME did not influence the differentiation process of ES cells towards cardiac myocytes. No cytotoxic effects were observed at any of the concentration levels tested. Exposure to BisGMA resulted in a 50% decrease in cell survival and a very strong inhibition of cell differentiation at 10(-5)M (p<0.01). Embryotoxic effects were also present at 10(-6) and 10(-7)M (p<0.05). EMPA induced a decrease in ES cell differentiation at 10(-5)M (p<0.01) without cytotoxic effects. No embryotoxic effects were induced at lower concentrations. Exposure to UDMA resulted in a slight decrease of cell differentiation at 10(-5)M (p<0.05). Exposure of cells to MA resulted in an increase of cardiac differentiation up to 150% (p<0.05) at 10(-5)M without cytotoxic effects. CONCLUSIONS: BisGMA induced a significant high embryotoxic/teratogenic effect over a large range of concentration. Therefore attention should be focused on this dental monomer, which should be investigated further by in vivo experiments.

Animals↗

PubMed2004

Antioxidative vitamins decrease cytotoxicity of HEMA and TEGDMA in cultured cell lines.

OBJECTIVES AND METHODS: In a previous study it was postulated that toxicity of 2-hydroxyethylmethacrylate (HEMA) and triethleneglycoldimethacrylate (TEGDMA) is based on oxidative metabolites. In this study the influence of antioxidative vitamins (including uric acid) on the toxicity of HEMA or TEGDMA was tested. Toxicity of HEMA and TEGDMA was determined in rat alveolar epithelial L2, human malignant A549, and human fibroblast-like 11Lu cells by inhibition of methionine incorporation (as a marker of protein synthesis inhibition) and by determination of glutathione depletion, as well as by measurement of GSSG increase. RESULTS: Toxicity of the composite components HEMA and TEGDMA was demonstrated by GSH depletion as the most sensitive method. Five hundred micromoles per litre Vitamin C or 250 micromol/l Vitamin E were mostly able to decrease toxicity of HEMA and TEGDMA in the cell lines tested. In addition, 250 micromol/l Vitamin A was only effective in L2 cells impairing HEMA toxicity and 250 micromol/l uric acid impairing TEGDMA toxicity as assessed by decreased GSH depletion. In A549 cells only methionine incorporation inhibition but not GSH depletion was significantly affected. By contrast, in 11Lu cells methionine incorporation inhibition was not significantly changed, but GSH depletion was. CONCLUSIONS: The postulated mechanism of HEMA or TEGDMA toxicity based on radical metabolites is supported by the effectivity of the antioxidative substances tested in mitigating toxicity and by the greater susceptibility of the glutathione redox system as compared to protein synthesis inhibition in assessing toxicity.

Animals↗

PubMed2002

Cytotoxicity of ingredients of various dental materials and related compounds in L2- and A549 cells.

Various ingredients of dental materials and related compounds were tested for cytotoxicity in two alveolar epithelial cell lines (L2 and A549 cells). Release of lactate dehydrogenase (LDH) from cells was measured after incubation with the test substances for time intervals up to 48 h and expressed as percentage of total LDH content of lysed cells. Furthermore, the glutathione content of cells was determined in the nonmalignant L2 cells. Additionally, cell viability was assessed by microscopic examination. The highest cytotoxicity was observed with mercury compounds (methylmercuric chloride and mercury dichloride) in the range of 5-20 micromol/l. The composite components 2-hydroxyethylmethacrylate (HEMA) and triethleneglycoldimethacrylate (TEGDMA) showed time- and concentration-dependent effects of cytotoxicity at high concentrations (about 1-5 mmol/l). A time dependence for GSH decrease was mainly found for the composite components up to 12 h of cellular exposure. L2 cells were more sensitive to both mercury and composite compounds than A549 cells. Gold compounds (sodiumaurothiomalate and gold particles < 1.5 microm) did not produce any sign of toxic reactions. A time-dependent increased toxicity in pulmonary cell lines was found for the composite components HEMA and TEGDMA, but not for mercury and gold compounds.

Animals↗

PubMed2002

Biological clearance of HEMA in guinea pigs.

No toxicokinetic data are available about the dental composite component 2-hydroxyethylmethacrylate (HEMA) in vivo in the literature. Therefore, the excretion of HEMA in feces and urine in vivo and, using the pendular perfusion technique with segments of jejunum and colon, in the biliary and enteric excretion in situ were investigated in anesthetized guinea pigs. In the in situ experiments, guinea pigs (n = 4) received HEMA (0.02 mmol/kgbw labelled with a tracer dose 14C-HEMA 0.3 kBq/gbw) injected into the jugular vein. In the in vivo experiments, guinea pigs (n = 4) received HEMA (+ 14C-HEMA, same dose as above) via gastric tube. Urine and feces were collected for 24h. In the in situ experiments, organs from guinea pigs were removed 60 min after the beginning of the experiment, and then the 14C-radioactivity was measured. During the 60 min perfusion period the calculated amount of 14C-activity excreted into the total jejunum and colon was 6.0 +/- 1.0% and 2.7 +/- 0.7% of the dose administered, respectively (mean +/- sem). Of the 14C-HEMA dose, 5.3 +/- 0.3% was found in the bile. Significantly (p < 0.05) higher bile/blood concentration ratios were found at 10-40 min after the injection of HEMA, as compared to the ratio at 60 min. The total 14C-recovery in all organs tested was 20.0 +/- 2.6%. During 24h the amounts of 14C-activity excreted in the feces and urine were 1.1 +/- 0.1% or 17.1 +/- 1.50% of the dose administered, respectively (mean +/- sem). The total 14C-recovery in all organs tested was 11.6 +/- 0.6%. In a second series of in vivo experiments, exhaled air from the animals was captured during the 24h experimental period. 14C was exhaled to 63.6 +/- 2.11% of the administered 14C-HEMA dose (mean +/- sem; n = 4) as 14C-carbondioxide. The results indicate a rapid clearance of 14C-HEMA and/or 14C-HEMA metabolite(s) from the organism, exhalation being the major route of elimination.

Animals↗

PubMed2001

Effects of Lewisite on cell membrane integrity and energy metabolism in human keratinocytes and SCL II cells.

Lewisite is a highly toxic arsenic compound which can cause skin damage. In the present study effects of Lewisite on cell membrane integrity and energy metabolism as well as antidotal effects of DL-2,3-dimercaptopropanesulfonate (DMPS), and meso-2,3-dimercaptosuccinic acid (m-DMSA) were investigated in a keratinocyte derived cell line (SCL II) and primary human keratinocytes (HK). Cells were incubated in Lewisite (60 microM) containing medium for 5 min. During the following 6 h lactate dehydrogenase (LDH) activity in the supernatant, intracellular ATP content, tetrazolium reduction, glucose consumption and lactate formation were measured. Glucose consumption and lactate production were decreased in both cell lines after Lewisite exposure. In SCL II cells an increase of LDH activity in the supernatant, a decrease of ATP content, and an impaired ability to reduce tetrazolium was found 3 h after Lewisite exposure. In HK cultures tetrazolium reduction was significantly decreased already after 2 h, whereas LDH increase in the supernatant and ATP content decrease occurred only at 6 h after Lewisite exposure. When DMPS or m-DMSA was added directly after Lewisite exposure to SCL II cells, glucose consumption and lactate formation were restored and LDH leakage was prevented. SCL II cells might be more prone to membrane damage whereas in keratinocytes mitochondrial impairment seems to be the predominant effect of Lewisite.

Adenosine Triphosphate↗

PubMed2001

Biological clearance of TEGDMA in guinea pigs.

The excretion of the dental composite component triethylene glycol dimethacrylate (TEGDMA) in feces and urine in vivo and, using the pendular perfusion technique with segments of jejunum and colon, the biliary and enteric excretion in situ were investigated in anesthetized guinea pigs. In the in situ experiments guinea pigs (n = 4) received TEGDMA (0.02 mmol/kg body weight labelled with a tracer dose 14C-TEGDMA 0.7 kBq/g body weight) injected into the jugular vein. In the in vivo experiments guinea pigs (n = 4) received TEGDMA (+14C-TEGDMA; same dose as above) via a gastric tube. Urine and feces were collected for 24 h. In the in situ experiments organs were removed from the guinea pigs 60 min after the beginning of the experiment, and the 14C radioactivity measured. During the 60-min perfusion period the calculated amount of 14C radioactivity excreted into the total jejunum and colon was 0.9 +/- 0.2% and 1.9 +/- 0.1% of the dose administered, respectively (means +/- SEM). Of the 14C-TEGDMA dose, 3.7 +/- 0.2% was found in the bile. A significantly (P < 0.05) higher bile/blood concentration ratio was found 10 min after injection of TEGDMA as compared with the ratios at 20 to 60 min. The following 14C activities (percent of the dose) per total organ were found in guinea pigs (in situ experiment; means +/- SEM): 6.9 +/- 1.7 (muscle), 3.9 +/- 0.5 (kidney), 3.3 +/- 0.1 (skin), 1.4 +/- 0.1 (blood), and 1.2 +/- 0.1 (liver). The 14C activity in all other organs was < 0.4%. The total 14C recovery in all organs tested was 17.5 +/- 1.8%. Over 24 h the amounts of 14C activity excreted in the feces and urine were 0.5 +/- 0.1% and 14.7 +/- 1.8% of the dose administered, respectively (means +/- SEM). The following 14C activities (percent of the dose) per total organ or contents of organs were found (means +/- SEM): 1.4 +/- 0.3 (liver), 0.8 +/- 0.3 (muscle), 0.5 +/- 0.1 (skin), and 0.5 +/- 0.1 (contents of cecum). The 14C activity in all other organs was < 0.2%. The total 14C recovery in all organs tested was 3.9 +/- 0.9%. In a second series of in vivo experiments exhaled air from the animals was captured during the 24-h experimental period. Of the administered dose, 61.9 +/- 4.6% of the 14C (means +/- SEM; n = 4) was exhaled as 14C-carbon dioxide. The results indicate a rapid clearance of 14C-TEGDMA and/or 14C-TEGDMA metabolite(s) from the organism and exhalation is the major route of elimination.

Animals↗

PubMed2001

Cytotoxicity of dental composite components and mercury compounds in lung cells.

OBJECTIVE: The effect of dental composite components triethyleneglycoldimethacrylate (TEGDMA) and hydroxyethylmethacrylate (HEMA), as well as mercuric chloride (HgCl2) and methylmercury chloride (MeHgCl) was investigated on the release of lactatedehydrogenase (LDH) from alveolar epithelial lung cell lines in vitro. METHODS: The confluent cell layers from the A549 (human, malignant) and the L2 cells (rat) were incubated with various concentrations of HEMA, TEGDMA, MeHgCl and HgCl2 at 37 degrees C in 2% (v/v) CO2 atmosphere for 8h. In further experiments the L2 cells were incubated with the same compounds for 6-48 h. LDH release was measured and the values were expressed as percentage of the LDH content. The values were plotted on a concentration log-scale and the substance concentration at the maximum slope was assessed as effective concentration (EC50). RESULTS: A significant (p<0.05) increase in the LDH release was found in the L2 cells after 8-h incubation with HEMA (4 mmol/l), TEGDMA (2 mmol/l), MeHgCl (0.01 mmol/l) and HgCl2 (0.015 mmol/l), and in A549 cells with HEMA (14 mmol/l), TEGDMA (15 mmol/l), MeHgCl (0.15 mmol/l) and HgCl2 (0.05 mmol/l), compared to controls. The EC50 values from compounds in the L2 cells are shown in the following table (mean; sem in parentheses; n=3-6; #n=1): [see text]. SIGNIFICANCE: The toxic effect of HgCl2 and MeHgCl from the L2 cells was about 100-700-fold higher than of the dental composite components. A significant (p<0.05) time dependent increase of toxicity was observed with TEGDMA, HEMA and MeHgCl.

Animals↗

PubMed2001

Cytotoxicity of dental composite components and mercury compounds in pulmonary cells.

The cytotoxic potentials of the dental composite components triethyleneglycoldimethacrylate (TEGDMA) and 2-hydroxy-ethylmethacrylate (HEMA) as well as mercuric chloride (HgCl2) and methyl mercury chloride (MeHgCl) were investigated. Proliferating A549 and L2 cell monolayers were cultured in the absence or presence of composite components or mercurials. Twenty-four hours later the tetrazolium salt XTT (sodium 3'-[1-phenyl-aminocarbonyl)-3,4-tetrazolium]bis(4-methoxy-6-nitro)benzenesulphonic acid) was added. Formazan formation was quantified using a microtiter plate reader. EC50 values were obtained as half-maximum-effect concentrations from fitted curves. EC50 values were in A549 cells (mean values +/- standard deviation; n = 12; micromol/l); HEMA 8854+/-1882; TEGDMA 1821+/-529; HgCl2 41+/-7 and MeHgCl 27+/-3. EC50 values in L2 cells were: HEMA 191+/-28; TEGDMA 112+/-16; HgCl2 25+/-6 and MeHgCl 8+/-6. All tested substances induced a dose-dependent loss of viability in A549 and L2 cells after 24 h. The EC50 values of both mercurials were significantly (p < 0.05) lower compared to the values of both composite components. TEGDMA was about 5-fold (A549 cells) and about 2-fold (L2 cells) more toxic compared to HEMA. It is to be assumed that the risk of lung cell damage by dental composite components is even more unlikely.

Acrylic Resins↗

PubMed2001

Distribution and excretion of TEGDMA in guinea pigs and mice.

The monomer triethyleneglycoldimethacrylate (TEGDMA) is used as a diluent in many resin-based dental materials. It was previously shown in vitro that TEGDMA was released into the adjacent biophase from such materials during the first days after placement. In this study, the uptake, distribution, and excretion of 14C-TEGDMA applied via gastric, intradermal, and intravenous administration at dose levels well above those encountered in dental care were examined in vivo in guinea pigs and mice as a test of the hypothesis that TEGDMA reaches cytotoxic levels in mammalian tissues. 14C-TEGDMA was taken up rapidly from the stomach and small intestine after gastric administration in both species and was widely distributed in the body following administration by each route. Most 14C was excreted within one day as 14CO2. The peak equivalent TEGDMA levels in all mouse and guinea pig tissues examined were at least 1000-fold less than known toxic levels. The study therefore did not support the hypothesis.

Animals↗

PubMed1999

Effect of dental materials on gluconeogenesis in rat kidney tubules.

The effect of dental composite components triethyleneglycoldimethacrylate (TEGDMA) and hydroxyethylmethacrylate (HEMA) as well as mercuric chloride (HgCl(2)) and methylmercury chloride (MeHgCl) on gluconeogenesis was investigated in isolated rat kidney tubules. From starved rats kidney tubules were prepared and isolated by digestion with collagenase. Every 10 min up to 60 min 1-ml samples were drawn from the cell suspension for quantitating the glucose content. Glucose formation in controls was 3.3 +/- 0.2 nmol/mg. per min (mean +/- SEM, n=21). Relative rates of glucose formation were obtained by expressing individual rates as a percentage of the corresponding control. X-Y concentration curves (effective concentration, EC) of the substances were calculated by fitting a four-parametric sigmoid function to the relative rates of glucose formation at various test concentrations. At the end of the incubation period cell viability was assessed by trypan blue exclusion. Cell viability decreased within the 60 min interval from 90 to approx. 80% (controls), <25 (HEMA), <20 (TEGDMA), <10 (MeHgCl), and <10% (HgCl(2)). Values of 50% effective concentration (EC(50)) were calculated from fitted curves. EC(50) values were (mmol; mean +/- SEM; n=4): HEMA, 17.7 +/- 2.9; TEGDMA, 1.8 +/- 0.2; MeHgCl, 0.018 +/- 0.0005; and HgCl(2), 0. 0016 +/- 0.0005. The toxic effect of HgCl(2) was approximately 1000 or 10 000 higher than that of the dental composite components TEGDMA or HEMA, respectively.

Animals↗

PubMed1997

Are we ready to replace dimercaprol (BAL) as an arsenic antidote?

1 Dimercaprol (BAL), 2,3-dimercaptopropanesulphonate sodium (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are effective arsenic antidotes, but the question which one is preferable for optimal therapy of arsenic poisoning is still open to discussion. Major drawbacks of BAL include (a) its low therapeutic index, (b) its tendency to redistribute arsenic to brain and testes, for example, (c) the need for (painful) intramuscular injection and (d) its unpleasant odour. 2 The newer antidotes DMPS and DMSA feature low toxicity and high therapeutic index. They can be given orally or intravenously due to their high water solubility. While these advantages make it likely that DMPS and DMSA will replace BAL for the treatment of chronic arsenic poisoning, acute intoxication-especially with lipophilic organoarsenicals-may pose a problem for the hydrophilic antidotes, because their ionic nature can adversely affect intracellular availability. 3 This article focuses on aspects dealing with the power of BAL, DMPS, and DMSA to mobilize tissue-bound arsenic in various experimental models, such as monolayers of MDCK (= Madin-Darby canine kidney) cells from dog kidney, isolated perfused liver from guinea-pigs, and perfused jejunal segments from rat small intestine. 4 The results show that hydrophilic DMPS and DMSA may fail to rapidly and completely remove arsenic that has escaped from the extracellular space across tight epithelial barriers. However, owing to their low toxicity, which allows larger doses to be applied, and the potential modification of their pharmacokinetics by means of inert oral anion-exchange resins, DMPS and DMSA may advantageously replace BAL whenever intervention time is not critical. With severe intoxication by organic arsenicals, when the point-of-no-return is a limiting factor, BAL may still have a place as an arsenic antidote.

Animals↗

PubMed1995

Antidotal efficacy of newly synthesized dimercaptosuccinic acid (DMSA) monoesters in experimental arsenic poisoning in mice.

The efficacy of four newly synthesized monoesters of meso-2,3-dimercaptosuccinic acid (DMSA), mono-i-amyl- (Mi-ADMS), mono-n-amyl- (Mn-ADMS), mono-i-butyl- (Mi-BDMS), and mono-n-butyl-meso-2,3-dimercaptosuccinate (Mn-BDMS) in increasing survival and arsenic elimination in experimental arsenic poisoning was investigated. Male mice (strain NMRI) received arsenite sc (survival study: 130 mumol/kg, 7 mice/group; elimination study: 85 mumol/kg (LD5) together with a tracer dose of 73As(III), 6 mice/group). After 30 min mice were treated with 0.7 mmol/kg of DMSA or a monoester ip or via gastric tube (ig). Control animals received saline ip. In the survival study mice were observed for 30 days. In the elimination study, the 73-arsenic content of several organs (blood, liver, heart, lung, kidneys, spleen, testes, brain, small intestine, large intestine, muscle, and skin) was measured 0.5, 2, 4, 6, and 8 hr after the arsenic injection using a gamma counter. Survival increased correspondingly well with the increase of arsenic elimination. DMSA, Mi-ADMS, Mn-ADMS, Mi-BDMS, and Mn-BDMS markedly decreased arsenic content in most organs as soon as 1.5 hr after treatment. Only in small and large intestine were higher arsenic amounts found, indicating a shift in arsenic elimination from the renal to the fecal route, and thereby suggesting a protective effect for the kidneys. Given ip, the monoesters turned out to be similarly as effective as the parent drug DMSA. Following ig treatment, the DMSA monoesters Mi-ADMS and Mn-ADMS seemed to be superior to DMSA with regard to survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Influence of glucose on the toxicity of oxophenylarsine in MDCK cells.

Trivalent arsenicals like oxophenylarsine (PhAsO) inhibit cellular pyruvate dehydrogenase, thus leading to a drop of acetylCoA formation and a slow-down of the citric acid cycle. Glucose may protect cells from arsenic toxicity, because increased glycolysis may prevent fatal shortage of ATP. On the other hand, PhAsO has been shown to inhibit glucose uptake in Madin-Darby canine kidney (MDCK) cells. We have investigated the effect of PhAsO on viability, ATP levels and glucose uptake of MDCK cells in the presence of normal (5 mmol/l) and low (0.01 mmol/l) glucose concentrations. At normal as well as at low glucose concentrations, cell viability as assessed by formazan formation was not affected by PhAsO concentrations up to 2 mumol/l within 3 h of observation. At higher PhAsO concentrations viability was diminished earlier and more pronounced in the presence of low glucose concentrations. 10 mumol/l PhAsO induced a drastic drop of ATP within 30 min which was followed by an almost complete loss of viable cells after 180 min in the presence of low glucose concentrations, while at normal glucose levels no influence on ATP contents or on cell viability was detected within 60 min of incubation. On the other hand, glucose uptake, determined as 14C accumulation by cells incubated for 10 min with D-[6-14C]-glucose, was inhibited by PhAsO at low as well as at normal glucose concentrations in a dose dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyl Coenzyme A↗

PubMed1995

Effect of DMPS and various adsorbents on the arsenic excretion in guinea-pigs after injection with As2O3.

The present experiments were performed to test the possibility of interrupting the enterohepatic circulation of arsenic (As). Therefore the efficacy of adsorbents to bind As and/or As-DMPS adducts in vitro and their effect on the excretion of As into the feces and urine in vivo were investigated after injection of As2O3 and DMPS in guinea-pigs. The adsorbents bentonite, activated charcoal or colestyramine, respectively, were tested. Only slight binding of 73As (< 5% of the 73As dose) was observed to all adsorbents in vitro. After addition of DMPS, a good binding was found for 73As to colestyramine (50%) or activated charcoal (60%), respectively. However, the 73As-DMPS adduct was removed from the activated charcoal during washing. In the first in vivo experiment, male guinea-pigs (n = 4/group) received As2O3 [0.02 mmol As(III)/kg s.c. labelled with a tracer dose of 73As(III) (0.14 kBq/g)], 30 min later DMPS (0.1 mmol/kg i.p.) and by gastric tube (10 ml/kg body wt) either saline, bentonite (1 g/kg), activated charcoal (1 g/kg) or colestyramine (0.2 g/kg), respectively. Urine and feces were collected for 24 h. No increase in 73As excretion into the feces was observed after administration of DMPS and all adsorbents, compared to control animals. In the second in vivo experiment male guinea-pigs (n = 4/group) received the same As2O3 (+ 73As)- and DMPS dose. In addition, with a gastric tube (10 ml/kg) saline, colestyramine (0.2 g/kg), DMPS (0.1 mmol/kg), or the combination of DMPS (0.1 mmol/kg) + colestyramine (0.2 g/kg) were administered according to the scheme given in the following table. The amount of feces excreted did not differ between groups. Excretion of 73As within the feces during the first 12 h after As injection is shown in the following table (mean +/- SEM). The same amount of 73As (34% of the 73As dose) was excreted into the urine from animals in groups 4 and 5 during this time. Obviously, the combined oral administration of DMPS + colestyramine markedly enhanced fecal excretion of As mobilized by DMPS i.p. It is suggested that interruption of enterohepatic circulation of As may be a valuable adjunct in the treatment of As poisoning.

Animals↗

PubMed1994

Zinc-induced arsenite tolerance in mice.

The mechanism of tolerance to arsenic toxicity is not known. Recently it has been shown that arsenic induces metallothionein (MT), which is a sulfhydryl-rich, metal-binding protein that decreases the toxicity of a number of metals. The present studies were designed to examine the role of MT in arsenic toxicity. Zinc (Zn) pretreatment (1000 mumol/kg, sc) markedly increased hepatic MT (150-fold over controls), and also protected against the lethal effects of arsenite (130 mumol/kg, sc). However, no correlation was found between the ability of various known MT inducers (Zn, Cd, arsenite, monomethylarsenite, alpha-hederin, or oleanolic acid) to increase hepatic MT and to protect against arsenic lethality in mice. To examine the mechanism of Zn protection against arsenic toxicity, the subcellular distribution of arsenite in liver, kidney, and small intestine was determined 2 hr after arsenite injection. Zn pretreatment did not markedly alter the amount of arsenic-73 in the cytosol or the various cellular organelles (nuclei, mitochondria, microsomes) in liver kidney, or small intestine. There was also very little arsenic-73 bound to MT in the cytosol of the Zn-pretreated mice, as determined by G-75 gel-filtration chromatography. In mice pretreated with Zn (1000 mumol/kg, sc) and subsequently injected with arsenite-73 (115 mumol/kg, sc), the arsenic-73 content in blood, heart, lung, kidneys, spleen, muscle, and skin was lower than in controls, indicating increased arsenic elimination in Zn-pretreated mice. In conclusion, Zn pretreatment protects mice against arsenite toxicity, but the mechanism of tolerance does not appear to be induction of MT.

Animals↗

PubMed1994

Effect of various antidotes on the biliary and intestinal excretion of arsenic in situ and into the feces in vivo in guinea-pigs after injection of As2O3.

The effect of various antidotes on the excretion of arsenic into the feces in vivo and on the biliary and enteric excretion in situ was investigated on segments of jejunum and colon in anesthetized guinea-pigs using the pendular perfusion technique, according to Henning and Forth (1982). In the in situ experiments guinea-pigs received As2O3 (0.02 mmol As(III)/kg) and 30 min later, British-Anti-Lewisite (BAL), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA) or 2,3-bis-(acetylthio)propanesulfonamide (BAPSA) (0.1 or 0.7 mmol/kg each) into the jugular vein. In the in vivo experiments guinea-pigs received As2O3 s.c. (same dose as above) and 30 min later the same antidotes (0.1 mmol/kg i.p.). The feces were collected for 24 h and the arsenic content measured. During the 60-min perfusion period the amount of arsenic excreted into the jejunum or colon was only 3% or 0.4% of the dose administered, respectively. Of the arsenic dose, 8% was found in the bile. None of the antidotes had an effect on the arsenic excretion into the jejunum or colon. No change in biliary excretion was found in animals treated with BAL, 0.1 or 0.7 mmol/kg, respectively. DMSA, BAPSA or DMPS, 0.1 mmol/kg, increased the biliary excretion of arsenic to 14, 33, or 43% of the dose administered and after 0.7 mmol/kg to 29, 37, or 42%, respectively. Furthermore, a significant increase (P > 0.05) was found for the bile/blood concentration ratio in the following order: control < BAL < DMSA < BAPSA approximately DMPS.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Therapeutic efficacy of new dimercaptosuccinic acid (DMSA) analogues in acute arsenic trioxide poisoning in mice.

The therapeutic efficacy of six newly synthesized analogues of dimercaptosuccinic acid (DMSA) was investigated in acute arsenic trioxide poisoning in mice. Meso-2,3-di(acetylthio)succinic acid (DATSA) and meso-2,3- di(benzoylthio)succinic acid (DBTSA) are analogues of DMSA with protected thiol groups ("prodrugs"), and DMDMS, DEDMS, DnPDMS, and DiPDMS are various di-esters of DMSA with methyl, ethyl, n-propyl, and isopropyl alcohols, respectively. Thirty minutes after s.c. injection of an LD80 of arsenic trioxide (65 mumol/kg) male NMRI mice were treated with a single equimolar dose (0.7 mmol/kg) of DMSA i.p. or one of the analogues i.p. or via gastric tube (i.g.). Control animals received arsenic trioxide and saline 30 min later. The survival rate was recorded for 30 days. All of the animals treated with DMSA i.p. survived and all controls died within 2 days. Administered i.g., DATSA and DBTSA increased the survival rate to 29% and 43%, and injected i.p. to 86%. Treatment with DMDMS i.p. and i.g., and with DEDMS, DnPDMS, and DiPDMS i.g. did not reduce lethality. Given i.p., DnPDMS increased the survival rate to 72%, and DEDMS and DiPDMS to 86%, respectively. To investigate the efficacy of the DMSA analogues in reducing the tissue content of arsenic, male NMRI mice received an s.c. injection of an LD5 of arsenic trioxide containing a tracer dose of 73-As(III) (42.5 mumol/kg body wt). Thirty minutes later, saline (controls) or a single equimolar dose (0.7 mmol/kg) of DMSA i.p., or one of the analogues i.p. or i.g. was administered. The arsenic content of various organs (blood, liver, kidneys, heart, lungs, spleen, small intestine, large intestine, brain, testes, skeletal muscle, and skin) at 30 min, 2 h, 4 h, 6 h, and 8 h after the arsenic injection was measured using a gamma counter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Does intake of highly demineralized water damage the rat gastrointestinal tract?

Highly demineralized water (hd-water) is used frequently in laboratories and on an industrial scale. However, no systematic data seem available as to whether hd-water has a toxic potential beyond the physical risks of drinking water (drowning, water intoxication). This study investigated the impact of hd-water on function and morphology of the rat's gastrointestinal tract. One group of rats received hd-water together with the usual diet ad libitum for 14 d. A second group was exposed to hd-water after withdrawal of food and water for 24 h. Both experiments had control groups which were treated identically except that hd-water was replaced by tap water. Histology showed no signs of erosion, ulceration or inflammation in the esophagus, stomach or jejunum. Body weights and the uptake of food and water were not significantly different between the hd-water exposures and controls for 14 d. Tissue alkaline phosphatase activity was unaltered, and the mitotic rate in the epithelium of the esophagus and stomach were not different between controls and rats on hd-water. Exposure to hd-water caused no changes in the km or Vmax values for the uptake o of alpha-methyl-D-glucose from the upper jejunum. There findings indicate no impact of hd-water on the function or morphology of the rat gastrointestinal tract. There is no need for additional safety regulations when working with hd-water which go beyond those considered adequate to prevent drowning and water intoxication.

Animals↗