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Archives of Toxicology (v.70, #1)
Metabolism of 2-thiobenzothiazoles in the rat by Masamichi Fukuoka; Michio Satoh; Akira Tanaka (pp. 1-9).
Metabolic fates of 2-benzothiazyl sulfenamides, N-oxydiethylene-2-benzothiazyl sulfenamide and N-cyclohexyl-2-benzothiazyl sulfenamide in rats were studied using tracer technique. These compounds given orally to rats were excreted rapidly in the urine and feces. Five urinary metabolites, 2-mercaptobenzothiazole (MBT), its three conjugates, mercapturate, glucuronide and sulfate, and 2,2′-dibenzothiazyl disulfide (BTDS) were confirmed. Furthermore, BTDS was found as a fecal metabolite. The sulfenamides were partly transformed in the stomach to BTDS, which was predominantly excreted into the feces. In the liver, the sulfenamides were mainly transformed to MBT and its conjugates. The S-glucuronide and S-sulfate conjugates were predominantly excreted into the bile. Mechanisms were discussed concerning the metabolite formation of sulfenamide derivatives in vivo and in vitro.
Keywords: Vulcanization accelerator; 2-Benzothiazyl sulfenamides; Metabolism; N-Oxydiethylene-2-benzothiazyl sulfenamide; Urinary metabolites; 2-Mercaptobenzothiazole; Mercapturate; Glucuronide; Sulfate; Disulfide formation; Rat stomach
N-Nitroso-N-(3-keto-1,2-butanediol)-3′-nitrotyramine by C. -J. Wang; H. -P. Huang; T. -H. Tseng; Y. -L. Lin; S. -J. Shiow (pp. 10-15).
N-Nitroso-N-(3-keto-1,2-butanediol)-3′-nitrotyramine (NO-NTA) is a product of a model browning system in the presence of sodium nitrite. In this study, the chemical structure is confirmed by spectral studies, including UV, mass spectrometry, nuclear magnetic resonance and infrared spectroscopy. NO-NTA is strongly genotoxic to the rat hepatocyte and is moderately cytotoxic to mouse C3H10T1/2 cells. Results obtained in this study indicate that NO-NTA inflicted DNA damage through the formation of a DNA adduct. In addition, C3H10T1/2 cells were treated with NO-NTA and, following addition of 12-O-tetradecanoylphorbol-13-acetate (TPA) as promotor, the increase of transformed foci indicated that NO-NTA could possibly be an inhibitor of TPA tumor promotion. A transformed cell line from NO-NTA initiated and TPA promoted foci increased saturation density and growth ability in soft agar reactive to the control line. These results suggest that the formation of a genotoxic agent of nitroso-derivatives may take place in a nitrite-containing food system during processing and cooking.
Keywords: N-nitroso-N-(3-keto-1,2-butanediol)-3′-nitrotyramine; Unschedule DNA synthesis; Genotoxicity; Initiating agent
Methantheline improves the reactivation by HI 6 of human erythrocyte acetylcholinesterase inhibited by soman in vitro by M. Hallek; L. Szinicz (pp. 16-19).
The effect of methantheline, a quaternary ammonium compound, on the reactivation by HI 6 of soman-inhibted human erythrocyte acetylcholinesterase (AChE) was investigated in vitro using purified human erythrocyte AChE or washed human erythrocytes. Methantheline itself was found to be a mixed competitive/non-competitive inhibitor of AChE (Kii 360±70 μmol/l; Ki 240±10 μmol/l). In all experiments the enzyme was first inhibited by soman for 30 min under conditions preventing ageing (pH 10,0°C) and then ageing was allowed by changing the pH to 7.3 and the temperature to 37°C. Methantheline addition (0.36 or 3.6 mmol/l) at the start of ageing increased the portion of AChE which could be reactivated by HI 6 (0.32 mmol/l) added 5 min later, from 24.6±1.0% (mean±SEM) of the original activity to 42.1±1.8% or 45±2.9%, respectively. With HI 6 alone, the portion of AChE activity which could be reactivated 25 min after the start of ageing decreased rapidly with the delay of the oxime addition (100% of the original activity at immediate addition), the half-life being approximately 2.5 min. With methantheline alone (0.36 mmol/l) the AChE activity was lower after immediate addition (37% of the original value), but the loss of activity due to the increasing delay of methantheline addition exhibited a similar half-life as with HI 6. Finally, when methantheline (0.36 mmol/l) was added at the start of ageing and HI 6 at various intervals thereafter the half-life of AChE activity loss due to the delay of HI 6 addition at least doubled, compared to incubations without methantheline.
Keywords: Methantheline; Acetylcholinesterase; Soman; Reactivation; HI 6
Treatment of organophosphate poisoning in pigs: antidote administration by a new binary autoinjector by A. Göransson-Nyberg; G. Cassel; T. Jeneskog; L. Karlsson; R. Larsson; M. Lundström; S. -Å. Persson (pp. 20-27).
The therapeutic effectiveness of a new binary autoinjector containing 500 mg HI-6 and 2 mg atropine sulphate was tested in anesthetized pigs poisoned by a lethal dose of soman i.v. (9 μg/kg per 20 min). Pharmacokinetics and pharmacodynamics of HI-6 were studied concomitantly on administration of HI-6 alone, together with atropine sulphate, or together with atropine sulphate during soman intoxication. Cardiopulmonary parameters were monitored and serum concentrations of oxime and acetylcholinesterase (AChE) were measured in blood samples taken at intervals over a 6-h period postinjection. Five minutes after the start of soman infusion, mean AChE activity was decreased to 27±4.3% of baseline and signs of poisoning appeared. The antidotes, HI-6 and atropine sulphate, were then administered i.m. One minute after this injection there was a transient significant increase in AChE activity of 76±8.2% of baseline (p<0.01). It then again decreased and remained suppressed throughout the experiment. Mean respiratory rate was significantly decreased (p<0.01) to 20±3.2% of baseline after 20 min of soman infusion and remained low during the rest of the experiment. The poisoning signs were counteracted 15–20 min after antidote therapy and all pigs survived soman intoxication without ventilatory assistance. Administration of either atropine or atropine and soman had no significant effect on the pharmacokinetics of HI-6 in anesthetized pigs.
Keywords: Acetylcholinesterase; organophosphate poisoning; HI-6; Atropine sulphate; Soman; Pharmacokinetics; Pharmacodynamics; Pig
Fulvic and humic acids decrease the absorption of cadmium in the rat intestine by Anders Wicklund Glynn (pp. 28-33).
Dissolved organic carbon (DOC) in drinking water is mainly composed of fulvic and humic acids, which may form complexes with metal ions. The influence of DOC on the intestinal absorption of Cd in the rat was investigated using an “isolated intestinal segment” technique in anaesthetised rats. The lumens of segments were exposed for 60 min to different concentrations of CdCl2 and DOC in intact animals. The fractional absorption (FA) was not dose dependent in the dosage interval 0.01–0.03 μg Cd/kg. However, at 15 and 150 μg Cd/kg both FA and intracellular Cd distribution in the segments were dose dependent, which is in line with results from other studies performed on similar experimental models. In the presence of 1 and 10 mg DOC/1, FA of Cd was just half as high as FA in animals that received Cd alone (0.01 μg/kg). Moreover, a higher percentage of Cd was associated with the metallothionein fraction in the intestinal segment of the DOC-dosed rats. An in vitro speciation experiment showed that only 0.2–7.9% of the Cd in the incubation solution was complexed to DOC. In deionized water, however, more than 99% of the Cd was complexed to DOC. This result indicates that the incubation solution contained substances that negatively affect complexation of Cd to DOC. Mechanisms other than complexation of Cd to DOC in the intestinal lumen may there-fore be involved in the inhibitory effect of DOC on the absorption of Cd.
Keywords: Metal speciation; Drinking water; Dissolved organic carbon; Cd; Metallothionein
Prediction of uptake of methyl mercury by rat erythrocytes using a two-compartment model by Guang Wu (pp. 34-42).
The uptake of methyl mercury (MeHg) by isolated rat erythrocytes was studied at 37°C using MeHg-cysteine (MeHgCySH), MeHg-glutathione (MeHgGSH), MeHg-mercaptalbumin (MeHgMASH) and the mixture of MeHgCySH with MeHgGSH, MeHgCySH with MeHgMASH, MeHgGSH with MeHgMASH at different MeHg concentrations. The measured MeHg concentrations were analyzed according to the Akaike’s information criterion in order to determine the suitable compartment model. After determining a two-compartment model, a model-independent two-compartment model was developed from the kinetics of uptake of MeHg at a concentration of 1 mmol MeHg/l packed erythrocytes using MeHgCySH CySH, MeHgGSH and MeHgMASH, respectively. The developed two-compartment model was validated by predicting the kinetics of uptake of MeHg by rat erythrocytes at different MeHg concentrations and different mixtures of MeHg-complexes. Then, the predicted values were compared with the measured values. The results suggested: 1) MeHg uptake appeared suitable to be described by a two-compartment model, while using MeHgGSH, MeHgMASH, MeHgCySH at lower concentrations and the mixtures of MeHg-complexes; 2) MeHgCySH uptake was slowest among three kinds of MeHg-complexes, although a postulated cysteine-facilitated MeHgCySH transport system might exist in erythrocyte membrane; 3) the mixture of MeHg-complexes might facilitate MeHgCySH uptake; 4) there might be a second MeHg intracellular compartment in rat erythrocytes.
Keywords: Compartment model; Erythrocytes; Intracellular compartmentation; Methyl mercury; Rat; Uptake
Inhalation toxicity of diborane in rats assessed by bronchoalveolar lavage examination by Tetsuo Nomiyama (pp. 43-50).
Changes in bronchoalveolar lavage fluid (BALF) and blood were examined to assess the toxic effects of diborane (B2H6, CAS: 19287-45-7) on the lung. Male Wistar rats were exposed to diborane at 20 ppm (intended concentration) for 4 h (phase I study) to evaluate time-course changes up to 14 days, and at 10 or 1 ppm (intended concentrations) to assess the dose-effect relationship after 3 days (phase II study). BALF parameters [leukocyte counts, α1-antitrypsin (α1-AT), superoxide dismutase (SOD), total protein, phospholipids etc.] were examined and biochemical and histopathological studies were also carried out. In the phase I study, neutrophils (%) in BALF increased on the day of exposure and then decreased gradually for 3 days. Rapid and marked increases in α1-AT and SOD activity in BALF were detected on the day of exposure, and phospholipids had sharply increased on day 3. After 14 days, these parameters in the exposed rats had returned to their background level and α1-AT decreased significantly. In the phase II study, total protein, α1-AT activity and phospholipids in BALF showed dose-dependent increases, and serum α1-AT activity increased significantly. Alveolar capillary and alveolar cell damage were confirmed in rats exposed to 20 ppm, 10 ppm or 1 ppm diborane for 4 h by evaluating the parameters examined. The protection system appeared to start operating immediately after exposure, and the recovery mechanism seemed to start operating 1 day after exposure and cease by day 14. The no-observed-effect level could not be observed.
Keywords: Diborane; Semiconductor; Bronchoalveolar lavage fluid; α1-Antitrypsin; Surfactant
Olfactory toxicity of methyl iodide in the rat by C. J. Reed; B. A. Gaskell; K. K. Banger; E. A. Lock (pp. 51-56).
The monohalomethanes (methyl iodide, methyl bromide and methyl chloride) are widely used industrial methylating agents with pronounced acute and chronic toxicity in both experimental animals and man. Recently inhalation exposure of rats to methyl bromide has been shown to result in severe olfactory toxicity. This study examined the effects on the rat nasal cavity of inhalation of methyl iodide (100 ppm for 0.5–6 h), and demonstrated that methyl iodide is a more potent olfactory toxin than methyl bromide. Within the nasal cavity the olfactory epithelium was the principle target tissue, and it was only at high doses (600 ppm.h) that limited damage to transitional epithelium occurred. The squamous and respiratory epithelia were consistently unaffected. Within olfactory epithelium the sustentacular cells were the primary cellular target and damage to sensory cells appeared to be a secondary event. Methyl iodide induced olfactory damage was reversible, and 2 weeks after exposure almost complete repair had taken place.
Keywords: Methyl iodide; Nasal cavity; Olfactory toxicity
Genotoxicity of wood dust in a human embryonic lung cell line by Z. -C. Zhou; K. H. Norpoth; E. Nelson (pp. 57-60).
Wood dust exposure has been found to be an occupational hazard, being linked to an enhanced incidence of various neoplasias. Here we performed an experiment to evaluate the ability of solvent extracts of natural woods to induce chromosome aberrations in respiratory cells in culture. Human embryonic lung cells, MRC-5, grown in Dolbecco’s medium were exposed to various concentrations of the dust extracts of pesticide-free (untreated) beech, oak and pine woods. Three concentrations per extract with and without metabolic activation (S9) and 100 metaphase cells per dose were examined for possible structural aberrations. Although no dose-dependent activity could be found with any extract in the presence of S9, most aberrations observed were of the chromatid type caused by oak wood. Dose-dependent chromosomal breaks caused by oak and chromatid breaks caused by both beech and oak were observed in the absence of S9. These data might support the early hypothesis that hard wood dust per se contains some in vivo genotoxic and thus possibly carcinogenic components.
Keywords: Woodworkers; Furniture industry; Cancer; Mutagenicity; Chromosome aberration
Tissue specific basal expression of soluble murine epoxide hydrolase and effects of clofibrate on the mRNA levels in extrahepatic tissues and liver by C. Johansson; A. Stark; M. Sandberg; B. Ek; L. Rask; J. Meijer (pp. 61-63).
The soluble epoxide hydrolase mRNA level in liver was increased eight-fold upon administration of the hypolipidemic drug and peroxisome proliferator clofibrate for 7 days to mice. The soluble epoxide hydrolase mRNA was back at control levels within 1–2 days after clofibrate withdrawal. The highest expression was in liver, intestine and kidney. Lower levels were found in heart and muscle and very low levels were found in testes, lung, brain and spleen. The mRNA levels were increased in liver, kidney and heart by clofibrate.
Keywords: Epoxide hydrolase mRNA; Mouse; Peroxisome; Clofibrate; Hypolipidemic drug
In vitro biotransformation of 2-methylpropene (isobutene) in rat lung tissue in comparison with liver tissue by M. Cornet; A. Callaerts; A. Vercruysse; V. Rogiers (pp. 64-67).
The epoxidation of the gaseous alkene 2-methylpropene or isobutene was studied in vitro in rat lung tissue in comparison with rat liver. Pulmonary tissue appears to be less exposed to the toxic epoxide metabolite than is the case for hepatic tissue. The results are correlated with the low capacity of the mixed function oxidase system, expressed by means of the cytochrome P-450 content and the 7-ethoxycoumarin O-deethylase activity, to form reactive intermediates. The activities of the principal epoxide detoxifying enzymes glutathione S-transferase and epoxide hydrolase represent only 5–10% of the values measured in rat liver.
Keywords: 2-Methylpropene (isobutene); 2-Methyl-1,2-epoxypropane; Rats; Epoxidation; Lung tissue