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Archives of Toxicology (v.68, #4)
A review of the toxicology of salbutamol (albuterol) by Susan E. Libretto (pp. 213-216).
This paper reviews the published toxicology of salbutamol. Salbutamol is a relatively selective β2-Adrenoreceptor stimulant with rapid, potent bronchodilator activity and only minor inotropic or chronotropic effects. It was not found to be mutagenic. LD50 values and other acute studies indicated low toxicity. Findings published for repeat dose studies were mainly uneventful. Tachycardia and flushing of the skin were observed in dogs. There were several findings peculiar to the rat—growth of the salivary gland, enlargement of the Harderian gland, an increase in colloid in the pituitary, and mesovarian leiomyomas. Increases in heart weights associated with inflammation, hypertrophy of muscle fibres, focal myocardial necrosis and fibrosis were seen in rats. Malformation, in the form of cleft palate, was reported in mice but not in rats or rabbits. These treatment related effects reported for salbutamol are not compound-related but rather are class-related. They are an expression of pharmacological activity brought about by the excessive beta stimulant action of high dosage with the drug.
Keywords: Salbutamol; Albuterol; Toxicology review; β-Adrenergic receptors; β-Agonists
Species differences in the biotransformation of ethyl chloride by N. Fedtke; H. Certa; R. Ebert; H. J. Wiegand (pp. 217-223).
Groups of male and female F-344 rats and B6C3F1 mice were exposed to 15000 ppm ethyl chloride (monochloroethane, ECL) or to air for 5 days (6 h/day). In this report, features of GSH-dependent ECL metabolism in the animals are described. A concurrent report describes the features of the cytochrome P450-dependent oxidative ECL metabolism (Fedtke et al. 1994). ECL conjugation to GSH in hepatic cytosolic fractions was catalyzed by GSHS-transferases. The specific activities were 0.16±0.03 and 0.17±0.01 nmol ECL conjugated/(min mg protein) in air treated male and female F-344 rats, respectively. These activities were not significantly altered by the ECL treatment. Compared with rats, the GSH-transferase activities towards ECL were generally higher in male and female B6C3F1 mice (0.71±0.19 and 1.01±0.19, respectively) and were slightly decreased by ECL treatment. The ECL conjugation to GSH resulted in a marked reduction of the GSH concentration in the lung and the uterus after 5 days of exposure. In contrast, liver and kidney GSH concentrations were affected only to a minor degree. FormedS-ethyl-glutathione was converted to the mercapturic acidS-ethyl-N-acetyl-L-cysteine (SENACys), which was detected in the urine of both species. In addition, the non-acetylated intermediateS-ethyl-L-cysteine (SECys) was excreted in mouse urine but not in rat urine. The cumulative amounts of SENACys and SECys excreted after 5 days were up to fivefold higher in mice than in rats and the excretion kinetics were species specific. The results are discussed with regard to a 2 year bioassay with F-344 rats and B6C3F1 mice exposed to 15000 ppm ECL (NTP 1989). In this bioassay, a species specific carcinogenic response in the mouse uterus was observed. It is proposed that the mechanism of tumor induction is a high dose phenomenon and more likely related to the GSH conjugation than to the oxidative metabolism or to possible genotoxic effects of ECL or its metabolites.
Keywords: Ethyl chloride; GSHS-transferase; F-344 rat; B6C3F1 mouse; Species difference
Comparison of the therapeutic effects and pharmacokinetics of HI-6, HLö-7, HGG-12, HGG-42 and obidoxime following non-reactivatable acetylcholinesterase inhibition in rats by Herman P. M. van Helden; Herma J. van der Wiel; Jelly J. Zijlstra; Bert P. C. Melchers; Ruud W. Busker (pp. 224-230).
The oximes HI-6, HLö-7, HGG-12, HGG-42 and obidoxime were used in a previously developed rat model to evaluate the therapeutic effects of oximes other than acetylcholinesterase (AChE) reactivation (so-called “nonreactivating effects”). To test this, anaesthetized, atropinized and artificially ventilated rats (n=8 or 16) were poisoned with a three times LD50 dose of the potent AChE-inhibitor crotylsarin (CRS, i.v.). CRS-inhibited rat AChE reactivation by the oximes. Five minutes after poisoning the rats were treated (i.v.) with an oxime or saline and 10 min later artificial ventilation was terminated. Survival times were determined. Saline-treated animals died within 15 min. In comparison, treatment with HI-6, HLö-7, HGG-12, HGG-42 or obidoxine resulted in a significant prolongation of survival time. In the groups treated with HLö-7, HI-6 or HGG-12, 12–37% of the animals survived more than 24 h. It was investigated whether differences in pharmacokinetics of the oximes. The plasma half-lives of HI-6, HLö-7, HGG-12, HGG-42 and obidoxime amounted to 67, 63, 27, 55 and 179 min, respectively. At doses of 75 or 150 μmol/kg, all oximes could be detected in brain and medulla oblongata in similar amounts (6–10 nmol/g tissue). In vitro, all oximes were effective in restoring failure of neuromuscular transmission (NMT) caused by CRS, albeit with varying potency. All oximes bound with affinities in the micromolar range to rat brain muscarinic receptors. The present results show that (1) prolongation of survival time following lethal intoxication with an organophosphate can be achieved by non-reactivating properties of the oximes and (2) the observed differences in a) pharmacokinetics, b) potency to restore NMT and c) affinity for muscarinic receptors of the various oximes do not correlate with the observed differences in therapeutic effectiveness. There-force, it is concluded that the prolongation of survival must be due to as yet undefined effects in the brain.
Keywords: Acetylcholinesterase; Organophosphate poisoning; Non-reactivating effects; Pharmacokinetics; Survival; Oximes; HI-6; HLö-7; HGG-12; HGG-42; Obidoxime; Crotylsarin
Treatment of tabun poisoned guinea-pigs with atropine, HLö 7 or HI 6: effect on respiratory and circulatory function by Franz Worek; Thomas Kirchner; Ladislaus Szinicz (pp. 231-239).
The oxime HI 6 (in combination with atropine) is considered to be an effective antidote in soman intoxication but was shown to be less effective in tabun poisoning. In contrast to HI 6, first in vitro studies with HLö 7 demonstrated a reasonable reactivating potency at acetylcholinesterase (AChE) inhibited by soman and tabun. Therefore, the therapeutic efficacy of HLö 7, HI 6 and obidoxime (with and without atropine) was compared in tabun poisoned guinea-pigs. In addition, the therapeutic effect of atropine in guinea-pigs poisoned by various doses of tabun was investigated. Female Pirbright-white guinea-pigs were anaesthetized with urethane (1.8 g/kg) and the carotid artery, jugular vein and trachea were cannulated. After baseline measurements the animals received tabun, 60, 180 or 300 μg/kg, and 2 min later the antidotes (all i.v.): obidoxime, HLö 7, or HI 6 (30 or 100 μmol/kg, each) or atropine 10 mg/kg or a combination of atropine and one of the oximes. Respiratory and circulatory parameters were recorded for 60 min or until the death of the animal. Erythrocyte, brain and diaphragm AChE activity was determined in every animal after the experiment. Poisoning by tabun resulted in a rapid deterioration of respiratory function and respiratory arrest within 5 min. Atropine treatment was very effective in improving the respiratory function after tabun 60 μg/kg but was ineffective after tabun 300 μg/kg. However, circulatory parameters were restored almost completely in all atropine therapy groups. Therapy of tabun 300 μg/kg poisoned animals with atropine plus oxime (30 μmol/kg) improved respiration to a variable extent and restored circulation. The efficacy decreased in the order obidoxime>HLö 7> >HI 6. Use of oximes 100 μmol/kg did not further increase the therapeutic effect. Oximes alone were completely ineffective. The considerable therapeutic efficacy of atropine and oximes was not accompanied by a reactivation of diaphragm or brain AChE. Erythrocyte AChE was partially reactivated by obidoxime. Tabun primarily impaired central respiratory control but peripheral neuromuscular block developed already at low tabun doses. Atropine was very effective in restoring circulation but respiration was improved only after low doses of tabun. The results of this investigation demonstrate a considerable effect of atropine plus obidoxime or HLö 7 in improving respiration and circulation after high dose tabun. This effect was not accompanied by a noticeable AChE reactivation, indicating the involvement of some other “direct” mechanisms. HLö 7 has to be considered as a broad-spectrum antidote, being superior to obidoxime or HI 6.
Keywords: Tabun; Oximes; HLö 7; HI 6; Obidoxime; Atropine; Respiration; Guinea-pigs
Effect of acute and repeated exposure to low doses of hydrazine on hepatic microsomal enzymes and biochemical parameters in vivo by Andrew M. Jenner; John A. Timbrell (pp. 240-245).
A single dose of hydrazine (3 mg·kg−1 i.p.) caused hepatic accumulation of triglycerides and depletion of ATP in rats after 9 h. Repeated exposure of rats to hydrazine (≊2.5 mg·kg−1 per day) for 10 days resulted in depletion of hepatic reduced glutathione (GSH) and triglycerides. Repeated exposure to hydrazine also caused a significant (time dependent) induction ofp-nitrophenol hydroxylase (NPH) activity together with changes in other hepatic microsomal enzymes. These included 7-pentoxyresorufinO-deethylase (PROD) and 7-ethoxyresorufin O-de ethylase (EROD) activity, total cytochrome P450, cytochrome b5 and cytochrome P450 reductase activity. Repeated exposure to lower levels of hydrazine (≊0.250 mg·kg−1 per day) caused no significant hepatic biochemical or microsomal changes after 5 or 10 days except for an increase in NPH activity (17%) and liver ATP (15%) after 5 days.
Keywords: Hydrazine; Liver; Microsomal enzymes; CYP2E1; Rat
Effect of selenium compounds on murine B16 melanoma cells and pigmented cloned pB16 cells by Brigitte Siwek; Eliane Bahbouth; Miguel-Ángel Serra; Enrico Sabbioni; Marie-Claire de Pauw-Gillet; Roger Bassleer (pp. 246-254).
The effects of selenium compounds such as sodium selenite, sodium selenate, seleno-Dl-cystine and seleno-Dl-methionine (100 μM and 10 μM) on B16 and pigmented cloned pB16 murine melanoma cells were investigated in vitro. At the tested concentrations, B16 cells showed a greater sensitivity to the toxic effects of sodium selenite and seleno-Dl-cystine than pB16 cells, whereas no decrease of B16 and pB16 cell number was observed after incubation with sodium selenate or seleno-Dl-methionine. Glutathione (GSH) percentages were strongly decreased only by selenite and seleno-Dl-cystine; it was marked more in B16 than in pB16 cells. The pretreatment of B16 cells with a GSH depleting agent (10 μM buthionine-[S,R]-sulfoximine) did not significantly influence the cytotoxic effects of selenite and seleno-Dl-cystine. On both cell populations, GSH preincubation (50 μM) enhanced the cytotoxicity of selenite whereas the survival of seleno-Dl-cystine treated cells was increased. Glutathione peroxidase (GSH-Px) activity in B16 cells was more sensitive than in pB16 cells to the activating effect of selenite, and particularly of seleno-Dl-cystine; however, cell-free controls indicated that activation was mainly due to glutathione reductase. The rate of75Se (as sodium selenite) uptake in both cell populations was maximal within the first hour of incubation, with a preferential accumulation in the cytosol; after 24 h of incubation, the amount of75Se in cytosol and pellet was approximately the same. Gel filtration chromatography of lysed cells after incubation for 6 h with 10 μM75Se-selenite showed that the radioactivity was eluted as two peaks corresponding to low (4–9 kDa) and high (280–320 kDa) molecular weights. Possible toxicological mechanisms are discussed at molecular level. For selenite, a major involvement of GSH is proposed, with production of selenodiglutathione and selenopersulfide, which should be directly responsible of the decrease in cell number, thiol oxidation and protein synthesis inhibition. For selenocystine, an active selenol species (Cy-Se−) is also hypothesized as being responsible for thiol oxidation and mutagenic effects. For both compounds oxygen active species could also be formed; however, a relevant role of GSH-Px was not apparent. The minor sensitivity of pB16 cells to the toxic effects of selenite and seleno-Dl-cystine could be explained by the smaller depletion of GSH induced by those compounds in pB16 cells, a minor formation of selenium active species, the larger amount present of the oxyradical scavenger melanin, the secretion of some mitogenic factor by pB16 cells and/or a greater resistance to autocrine cytotoxic factors.
Keywords: Sodium selenite; Sodium selenate; Seleno-Dl-cystine; Seleno-Dl-methionine; B16 melanoma cells; Pigmented cloned B16 cells; Melanin; Glutathione
Quantitative structure activity relationship for the acute cytotoxicity of 13 (bis)aziridinyl-benzoquinones: relation to cellular ATP depletion by Bram Prins; Wim P. Dartee; Willem Verboom; David N. Reinhoudt; Andries Sj. Koster (pp. 255-260).
This study was performed to establish relationships between the structure of 2,5-bis(1-aziridinyl)-1,4-benzoquinones (BABQs) bearing different substituents at the 3- and 6-position and their acute toxic effects in rat hepatocytes. The cell viability, loss of cellular glutathione (GSH_GSSG) and loss of ATP were followed during 4 h of incubation of freshly isolated hepatocytes. The toxicity of these compounds (100 μM) was predicted better by their reactivity with GSH than by their redox cycling in rat liver microsomes. The time of 50% loss of viability (LT50) correlated very well with the time of 50% depletion of ATP (AT50). LT50 could be adequately predicted by using the electronic field parameter (Ftotal) describing the electron withdrawing or donating properties for all the substituents on the quinone-nucleus. 7-(Di)halogen-substituted BABQs that all very rapidly depleted cellular glutathione showed significant differences in AT50 as well as in LT50. This suggests that alterations in ATP levels are important for explaining the differences in cytotoxicity of these compounds.
Keywords: 2,5-Bis(1-aziridinyl)-1,4-benzoquinones; Carboquone; Diaziquone; Hepatocytes; Structure activity relationship; Toxicity in vitro; Triaziquone
Acetylsalicylic acid—inducer of cytochrome P-450 2E1? by Dieter Pankow; Britt Damme; Karsten Schrör (pp. 261-265).
Pretreatment of rats with acetylsalicylic acid or sodium salicylate stimulates the metabolism of dichloromethane to carbon monoxide as measured by the carboxyhemoglobin level in blood. Simultaneous administration of dichloromethane and acetylsalicylic acid or sodium salicylate, respectively, was accompanied by reduced carboxyhemoglobin formation. In liver microsomes of rats pretreated with acetylsalicylic acid thep-nitrophenol hydroxylase activity was increased. It is concluded that (i) cytochrome P-450 2E1 is involved in the metabolic conversion of both dichloromethane and salicylic acid, and (ii) salicylic acid may be an inducer of cytochrome P-450 2E1.
Keywords: Acetylsalicylic acid; Salicylate; Metabolism; Dichloromethane; Carboxyhemoglobin; p-Nitrophenol hydroxylase
Fasting for 24 h reveals liver microsteatosis after continuous i.v. infusion of milacemide in the rat by Jean-Louis Rakotoamboa; Marc Masson; Bernard Palate; Jacqueline Carleer; José Roba (pp. 266-271).
Milacemide (2-n-pentylaminoacetamide) hydrochloride was administered by continuous i.v. infusion for up to 7 days, at 300 and 600 mg/kg per day to male Sprague-Dawley rats. This was intended to provide high and sustained exposure to evaluate the effect of a preterminal 24-h fast on liver lipid content. Liver lipid content, as assessed by triglyceride concentration and histopathology, was not different in saline controls or rats infused with up to 600 mg/kg per day for up to 7 days, when they had access to food up to sacrifice. When the rats were fasted for 24 h before sacrifice, milacemide produced microsteatosis in the periportal and midzonal areas. The effect was significant after 2 days of infusion at 600 mg/kg per day and increased in intensity with duration of administration. After 7 days of infusion, at 600 mg/kg per day, liver triglycerides increased by more than 4-fold in rats fasted for the last 24 h. No other differences from the controls were observed at light microscopy or in liver protein content and AST activity. Liver ALT activity was decreased by 28% and plasma ALT activity by 23%. Plasma triglyceride levels were lowered by milacemide, in both fasted and fed rats. This study demonstrates that fasting for 24 h triggers the development of liver microsteatosis in rats exposed to milacemide. Fasting has been previously described to increase liver microsteatosis after administration of sodium valproate, 4-en valproate and pentenoic acid in the rat. These findings might help to identify the mechanism of the hepatic effects of milacemide. Such effects were not observed in the regular animal toxicity studies conducted by the oral route. Some patients, however, presented evidence of liver dysfunction.
Keywords: Milacemide; Liver microsteatosis; Rat; Triglycerides; Fasting
Comparison of DNA reactivity of the polyphenylethylene hormonal agents diethylstilbestrol, tamoxifen and toremifene in rat and hamster liver by F. Montandon; G. M. Williams (pp. 272-275).
The polyphenylethylene estrogenic drug diethylstilbestrol and a structural analogue tamoxifen have been found to be hepatocarcinogenic in female rats, whereas another analogue, toremifene, did not induce liver tumors. The32P post-labelling technique for detection of DNA adducts was used to investigate the DNA reactivity of these three hormonal agents in the livers of female Sprague-Dawley rats and Syrian hamsters. Adducts were quantified using a radioanalytic imaging system in comparison with the standard Cerenkov assay. With administration of the chemicals at several doses by daily gavage to rats for 10 days and to hamsters for 7 days, tamoxifen was found to produce five adducts in rat liver and six adducts in hamster liver. The amounts of adducts were dose related from 10 to 90 μmol/kg per day in rats and from 17 to 160 μmol/kg per day in hamsters. The two methods of quantification yielded comparable results. Under these conditions, neither toremifene nor diethylstilbestrol produced adducts in rats and diethylstilbestrol produced none in hamsters. We conclude that tamoxifen is highly DNA reactive in the species studied and that this is likely to be involved in its strong carcinogenicity in rat liver.
Keywords: DNA; Diethylstilbestrol; Tamoxifen; Toremifene; Liver; Rat; Hamster