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Biomedical subjects

W Forth

Publications and source records attributed to W Forth.

At least 73 records · Page 4Linked to original sources
PubMed1990

Effect of chelating agents on biliary excretion of arsenic in perfused livers of guinea pigs pretreated with As2O3.

The effect of the dithiols British Anti-Lewisite (Bal), dimercapto-propanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA) and a new metal binding agent 2,3-bis-(acetylthio)-propanesulfonamide (BAPSA) on the biliary excretion of arsenic in perfused livers of guinea pigs pretreated with As2O3 was investigated. Guinea pigs received As2O3, 2.5 mg/kg sc twice daily for 5 consecutive days. Sixteen hours after the last dose the livers were perfused (35 ml/min) with Krebs-Henseleit buffer with glucose for 80 min. After 50 min of perfusion 0.1 mmol/L or 0.7 mmol/L BAL, DMSA, DMPS, or BAPSA were added to the perfusate and arsenic elimination in the bile and effusate was measured. The total arsenic excretion in control livers between the 50th and 80th min was 6.1% of the total arsenic liver content. After antidote addition (0.1 mmol/L) the excretion increased to 7.9% (DMSA), 9.2% (BAL), 23.9% (BAPSA), and 27.1% (DMPS), respectively. After 0.7 mmol/L of antidote the excretion of arsenic was found to be 19.3% (DMSA), 19.9% (DMSA), 24.0% (BAL), and 43.3% (BAPSA), respectively. The increase resulted mainly from increased biliary excretion. In these experiments BAPSA was significantly more effective in the overall elimination of arsenic than DMSA, DMPS, and BAL. The treatment with chelating agents may cause a substantial shift to fecal elimination by the increase in biliary excretion (BAL less than DMSA less than DMPS less than BAPSA). From the therapeutic view the shift to fecal elimination may have the advantage that the amount of the toxicant which passes the kidney is reduced and thereby also the portion which might be harmful for the organ.

Animals↗
PubMed1989

Effects on mitochondrial metabolism in livers of guinea pigs after a single or repeated injection of As2O3.

Differences in the metabolite pattern were observed in previous experiments in guinea pig livers after a single injection or prolonged (5 days) treatment with AS2O3 (Reichl et al. 1988). To elucidate the underlying mechanism the effect of As2O3 on liver metabolism was therefore investigated. Male guinea pigs received either a single dose (s.d.) of As2O3 10 mg x kg-1 s.c. or repeated doses (r.d.) of 2.5 mg x kg-1b.i.d. on 5 consecutive days. One hour after the s.d. or 1 h and 16 h after the last injection in the r.d. groups the animals were sacrificed in anaesthesia. The livers were removed by freeze clamping for the determination of various metabolites. In the s.d. group a significant decrease in hydroxybutyrate, acetylCoA, adenosinemonophosphate and in the ratio of hydroxybutyrate/acetoacetate and an increase in pyruvate, citrate, malate, and adenosinetriphosphate were observed. A significant decrease in glycogen, pyruvate, alpha-ketoglutarate, acetylCoA, and acetoacetate and a significant increase in malate and in the ratios of lactate/pyruvate and hydroxybutyrate/acetoacetate were observed in the r.d.1-h group. In the r.d.16-h group a significant decrease in glycogen, pyruvate, lactate, and adenosinemonophosphate was found, but the values tended towards control values. The data are consistent with mechanisms of As2O3 toxicity in other species as PDH inhibition with consecutive citric acid cycle and gluconeogenesis inhibition and excessive carbohydrate depletion.

Animals↗
PubMed1989

Incorporation of iron from an oral dose into the ferritin of the duodenal mucosa and the liver of normal and iron-deficient rats.

To further characterize the role of ferritin in regulating iron absorption, uptake of an oral dose of 59Fe (0.2 mg Fe/kg body wt.) into duodenal and hepatic ferritin of control and iron-deficient (ID) rats was studied. Retention and uptake of 59Fe from Fe(II)-sulfate, Fe(III)-chloride, or Fe(III)-polymaltose were measured up to 28 h after dosing. Ferritin was determined by radioimmunoassay (RIA) and 59Fe ferritin-iron by gel electrophoresis. Retention and liver content of 59Fe was higher in ID rats than in controls. The mucosa of ID rats, however, retained only one third of the amount of 59Fe retained by the mucosa of controls. The mucosal and hepatic ferritin levels were lower in ID rats than in controls. The percentage of orally administered 59Fe found in the liver ferritin was therefore higher in control than in ID rats. However, when expressed as per unit of ferritin, iron uptake was eight times higher in ID rats. In contrast, mucosa ferritin of ID rats contained one-third of 59Fe per unit of ferritin than that of controls. Assuming no change in the mechanism of iron uptake into ferritin of control and ID rats, the differential uptake of oral iron into mucosa and liver ferritin indicates either a different compartmentation of the tissue ferritin or differences in the iron transport processes, but mucosal ferritin does not withdraw iron from intestinal absorption.

Administration, Oral↗
PubMed1989

Lack of effectiveness of D-penicillamine in experimental arsenic poisoning.

Based on some anecdotal case reports D-penicillamine (DPA) has been advocated for the treatment of arsenic poisoning. Experimental evidence, however, supporting that recommendation is lacking. In the present experiments the effectiveness of DPA was compared with dimercaprol (British Antilewisite, BAL), dimercaptopropanesulfonate (DMPS), and dimercaptosuccinic acid (DMSA) using different controlled experimental settings. In one study mice received As2O3 (9-14 mg/kg sc). Treatment with DMSA after 30 min afforded almost complete protection against the lethal effects of arsenic whereas DPA was not effective. In a second study, mice and guinea pigs were injected sc with 8.4 mg/kg As2O3 (containing a tracer dose of 74As). Thirty min later 0.7 mmol/kg of DPA or one of the other antidotes was injected ip. As determined 4 and 12 h after the arsenic injection, DPA was unable to reduce the 74As content in any of the organs investigated (blood, liver, kidneys, lungs, heart, brain, testes, spleen, skeletal muscle, and skin). On the other hand, BAL, DMPS, and DMSA markedly reduced the tissue content of 74As with respect to controls. Finally, the ability of the antidotes to reverse biochemical effects of arsenic was investigated in vitro using suspensions of incubated renal tubulus cells. The marked inhibition of gluconeogenesis induced by 30 mumol/L As2O3 was almost completely reversed upon addition of 90 mumol of either BAL, DMPS, or DMSA. In this experimental model, too, DPA was ineffective. It was concluded that the use of DPA in arsenic poisoning needs to be reevaluated.

Animals↗
PubMed1989

Increase of the intestinal iron absorption in growing rats and mice after 8 days of iron-deficient feeding.

In investigations of intestinal iron absorption the combination of repetitive bleeding and iron-deficient feeding is frequently used. It induces iron deficiency which, in turn, stimulates iron absorption. When this combined procedure was compared with the effect of an 8 d iron-deficient feeding schedule in growing rats, no significant differences were found regarding the stimulating effect on intestinal iron transfer. Body iron stores, however, as represented by the hepatic ferritin and iron content are remarkably less depleted. Contrary to the effect of the combined procedure the animals growth was only marginally retarded and anaemia did not develop. This was also demonstrated in mice. The stimulation of intestinal iron absorption by iron-deficient feeding of growing animals thus seems preferable, as this procedure largely avoids the disturbing side effects observed with repetitive blood sampling.

Anemia, Hypochromic↗
PubMed1988

Metabolism of T-2 toxin in vascularly autoperfused jejunal loops of rats.

The intestinal metabolism of T-2 toxin, a major trichothecene mycotoxin, was investigated in rats using the method of the vascularly autoperfused jejunal loop in situ. Tritium-labeled T-2 toxin was injected into the tied-off intestinal segments at a dose of 5 or 500 nmol, respectively. T-2 toxin and its metabolites in the blood draining from the jejunal loops, in the intestinal lumen, and in the intestinal tissue were determined by HPLC and GLC-MS. There was an extensive metabolic degradation of T-2 toxin, the metabolite pattern being similar for the two dosage levels. During the experimental period of 50 min only some 2% of the total dose appeared in the effluent plasma as unchanged T-2 toxin. Likewise at the end of the experiments unchanged T-2 toxin in the intestinal lumen and tissue was present in minute amounts only (less than 1% of the dose). HT-2 toxin was the main metabolite. About 25% of the total radioactivity administered appeared in the effluent plasma as HT-2 toxin, 18% in the lumen and 10% in the tissue. 3'-OH-HT-2 toxin accounted for 4-7% (effluent plasma), 5% (lumen), and 2% (tissue) of the total dose. Furthermore small amounts (less than 2% of the dose) of 3'-OH-T-2 toxin, T-2 tetraol, and 4-deacetylneosolaniol were found. No glucuronide or sulfate conjugates could be detected. In the jejunal segments which had been exposed to the 5-nmol dose only minimal morphological alterations were observed. On the other hand, in jejunal segments exposed to the high dose marked tissue damage was present. Nevertheless the gut tissue retained its ability to metabolize T-2 toxin. From the present results it is concluded that T-2 toxin is subject to a marked presystemic first pass effect after oral ingestion in vivo.

Animals↗
PubMed1988

Effect of arsenic on carbohydrate metabolism after single or repeated injection in guinea pigs.

Divergent pattern in pyruvate efflux from livers perfused with As2O3 and livers of animals previously repeatedly treated with the toxicant was observed in earlier experiments (Reichl et al. 1987, 1988). Further studies of the effect of As2O3 on carbohydrate metabolism were therefore performed. Male guinea pigs received either a single dose of As2O3 10 mg.kg-1 s.c. or repeated doses of 2.5 mg.kg-1 bis in die (b.i.d.) on 5 consecutive days. One hour after the single dose or 1 h and 16 h after the last injection in the repeated treatment group the animals were sacrificed under anaesthesia. The livers were removed by a freeze-stop technique and the contents of glycogen and glycolysis intermediates were measured. In the single dose group a decrease in fructose-1,6-diphosphate and glycerol-aldehyde-3-phosphate and an increase in phosphoenol-pyruvate and pyruvate was observed. In the repeat dose, 1-h group a significant decrease in glycogen, glucose-6-phosphate, fructose-6-phosphate, glycerolaldehyde-3-phosphate, dihydroxyacetonephosphate, 2-phosphoglycerate and pyruvate was found. In the repeat dose, 16-h group the contents of glycogen, glucose-6-phosphate, pyruvate and lactate were diminished. The most prominent finding after repeated As2O3 administration was a marked depletion in total carbohydrate content. This was due mainly to depletion of glycogen.

Animals↗
PubMed1988

Effect of As2O3 on gluconeogenesis.

1) The effect of As2O3 and As2O5 on gluconeogenesis from various substrates in the liver and kidney of rats was investigated. 2) A concentration-dependent inhibition by As2O3 was found. The effect was not dependent on the amount of investigated material (hepatocytes or kidney tubules). For either hepatocytes or kidney tubules the extent of inhibition depended strongly on the substrate used. The highest degree of inhibition was observed in incubations with pyruvate. The inhibition of glucose formation was accompanied to a lesser extent by a diminution in O2 consumption and ATP content. The effect was also dependent on the substrate used. Maximum effect was found in incubations with pyruvate. 3) Oleate, 0.5 mmol/l, increased gluconeogenesis from pyruvate. The effect was not abolished by As2O3. 4) A decrease in the content of acetyl-CoA, 3-hydroxybutyrate, and reduced glutathione was found in suspensions of isolated rat kidney tubules or hepatocytes incubated with As2O3. 5) About 10 times higher concentrations of As2O5 were necessary to induce a similar extent of inhibition of gluconeogenesis, decrease in O2 consumption, and in ATP content as compared with As2O3. The extent of the As2O5 effect depended on the concentration of the toxicant and on the substrate used. Gluconeogenesis from pyruvate exhibited the highest sensitivity to As2O5. 6) All findings can be largely explained by inhibition of pyruvate dehydrogenase as the central target for arsenicals. The subsequent depletion of acetyl CoA results in impaired formation of reducing equivalents in the citric acid cycle, decrease in high energy phosphates and, acetyl CoA being a strong positive modulator of pyruvate carboxylase, in gluconeogenesis inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetoacetates↗
PubMed1988

On the origin of intestinal transferrin.

The incorporation of 35S-L-methionine (35S-Met) into TCA-precipitable protein is used to measure protein synthesis in isolated non-vascular perfused jejunal segments and in isolated liver cells under steady-state conditions in rats. 10(5) X g supernatants of homogenates from jejunal segments and from liver cells as well as the jejunal absorbate were processed immuno-electrophoretically. Incorporation of 35S-Met radioactivity into precipitin lines with sera against transferrin, IgG and plasma proteins were autoradiographed and compared semiquantitatively with each other. Calculated on a wet-weight basis this system is sensitive enough to detect transferrin synthesis down to a level of 1% of that in the liver. Still, no transferrin synthesis was found in the jejunal mucosa, while 35S-Met incorporation into TCA precipitates and into IgG continued in isolated jejunal segments for over 2 h. A good correlation was found (r = 0.88, P less than 0.01) between mucosal and plasma transferrin in normal as well as in iron deficient rats. A complete immunologic cross-reactivity could be demonstrated between different plasma transferrins and the transferrin in three different preparations of the intestinal mucosa. Immunoblots of electropherograms after isoelectric focussing showed no distinct differences between transferrin in the plasma, bile, and in the mucosal epithelium.

Animals↗
PubMed1987

Thallium(I) secretion across the isolated mucosa of rat descending colon.

Unidirectional Tl+-fluxes across the isolated mucosa of rat descending colon were measured under short circuit (SCC) or voltage clamp conditions (VCC). Under SCC a serosal-to-mucosal net flux (Jnet = -0.22 nmol X cm-2 X h-1) was observed that agrees with the voltage-independent component measured under VCC. At 7 degrees C the secretory net flux was abolished. In controls both unidirectional fluxes were unsaturable between 0.1 and 500 mumol/l thallium (I). After furosemide or withdrawal of Cl- or Na+ Jnet was abolished. Ouabain decreased serosal-to-mucosal Tl+ flux and an energy-dependent absorptive net flux of Tl+ was observed, characterized by a rather low Km (10.2 mumol/l), Vmax (3.8 nmol X cm-2 X h-1) and apparent activation energies (delta E = 10.7 kcal X mol-1) typically for enzyme catalaysed reactions or narrow channel interactions. The data suggest that in the mucosa of rat descending colon Tl+ ions share, at least in part, the same transport systems at K+.

Animals↗
PubMed1987

[Iron and the supply of iron in warm-blooded animals].

An adult man contains roughly 4-5 g of iron. Nearly 70% of this amount is present in hemoglobin and myoglobin. About 11% is accounted for by iron enzymes, e.g., heme enzymes that play a decisive role in cellular metabolism. Almost 19% of the body iron are deposed in iron stores. The distribution of iron in the body to the tissues and organs is handled by transferrin, a protein that binds iron so tightly that scarcely any free, i.e., ionized and hence toxic iron can exist. Since iron can only be excreted to an insignificant extent either in the urine or bile, the metabolism of iron is balanced almost exclusively by the absorption of this metal from food. This is especially true in the case of iron deficiency, e.g., in the young and growing organism, in pregnant females, or after iron loss.

Animals↗
PubMed1987

Role of lipid peroxidation in the toxicity of T-2 toxin.

Recent reports suggest that lipid peroxidation may be involved in the toxicity of T-2 toxin. In the present study the influence of T-2 toxin on two parameters of lipid peroxidation was examined: the formation of thiobarbituric acid reactive material in isolated hepatocytes and liver homogenates from rats and ethane exhalation in vivo. In isolated hepatocytes there was no significant increase in thiobarbituric acid reactive material, neither after addition of T-2 toxin in vitro nor when the toxin had been applied to the rats 15 hr before preparation of hepatocytes. In liver homogenates the amount of thiobarbituric acid reactive material was increased up to 50% over the controls, depending on the dose of T-2 toxin. The increased values are difficult to interpret, because the extent of the increase depends on the method used for determination of thiobarbituric acid reactive material. Measuring another parameter of lipid peroxidation, i.e. ethane exhalation, there was no difference between the T-2 toxin treated rats and the controls whereas carbon tetrachloride treated rats exhaled high amounts of ethane. These results suggest that lipid peroxidation does not play a major role in T-2 toxin toxicity.

Animals↗
PubMed1987

Metal-metal interactions among dietary toxic and essential trace metals in the rat.

Exposure to toxic and essential metals is thought to be reflected by corresponding metal concentrations in tissues. However, toxic and essential metals may influence each other in regard to their retention in the body. Therefore a basic diet containing four toxic metals (As 7, Cd 9, Ni 13, and Pb 20 ppm) and adequate amounts of essential metals was fed to rats for 2 weeks. Test groups received the basic diet with increasing concentrations of one of the toxic metals (up to 90 ppm As, 180 ppm Cd, 365 ppm Ni, and 394 ppm Pb). As, Cd, Ni, Pb, Cu, Fe, Mn, and Zn were determined by atomic emission spectroscopy in liver, kidney, intestine, brain, muscle, bone, skin, hair, and blood. A linear relationship between diet and tissue concentration is observed for As and Ni in the kidney, for Cd in the liver, and for Pb in the bone. In other tissues saturation was observed. While Cd-Fe interactions were common to most of the tissues, other interactions were detected only in specific tissues, e.g., As-Cu in the kidney, Cd-Zn in the liver, and As-Mn, Cd-Mn, or Ni-Cu in the intestine. Increases of renal Pb and intestinal Cd by dietary Ni, and a decrease in bone As by dietary Pb were the most pronounced interactions between the toxic metals. The results demonstrate that potential target organs for the evaluation of metal exposure need to be carefully analyzed for interfering metal-metal interactions.

Administration, Oral↗
PubMed1987

Absorption of di- and trivalent iron. Experimental evidence.

The present experiments were carried out on normal and iron deficient rats which were fed low iron diet and bled several times; the haemoglobin content of blood of normal rats was in the range of 12-14 g/dl, that of iron deficient rats between 6 and 8 g/dl. Iron was administered by a gastric tube and the retention of the radioactively labelled 59Fe-iron compounds was measured on the 6th day after the administration. There is no difference of the absorption of divalent and trivalent iron provided iron is administered in ionized form. This is possible when the iron solution administered is of pH less than 2.5. Since the pH values of gastric juice is in the same order of magnitude, this procedure is hardly to be called unphysiological. The decisive role of pH for the bioavailability of iron ions can be derived from an experiment with cobaltous ions that, in the range of physiological pH values, cannot be hydrolysed. Therefore, no difference of the retention of cobaltous ions was measured regardless whether the solution administered into a tied-off jejunal loop was of pH 2 or 5.5. The administration of either divalent or trivalent iron ions together with food to normal rats is followed by a slight decrease of the amount of iron retained. However, this difference of retention disappears when the ionized iron is administered to fed iron deficient rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗