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Archives of Toxicology (v.68, #3)
Species differences in the biotransformation of ethyl chloride by N. Fedtke; H. Certa; R. Ebert; H. -J. Weigand (pp. 158-166).
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 the P450-dependent ECL metabolism in the animals are described. A concurrent report describes the in vitro and in vivo features of the GSH-dependent ECL metabolism (Fedtke et al. 1994). ECL is oxidatively dechlorinated in an NADPH-and O2-dependent reaction, resulting in the formation of acetaldehyde (AC). The oxidative ECL metabolism rates in microsomal incubations were measured. The results indicated induction of the oxidative ECL metabolism by ECL itself in mice and female rats. The hydroxylation ofp-nitrophenol, which was used as an indicator of P450IIE1 activity, was also induced in microsomal incubations from ECL-exposed mice and female rats, but, corresponding to the ECL metabolism, not in male rats. In contrast, catalytic activities related to P450IA and IIB subfamilies were not induced by ECL treatment. Additional experiments with the P450IIE1-specific inhibitor 3-amino-1,2,4-triazole and induction experiments with acetone, phenobarbital and methylcholanthrene confirmed that the isoenzyme mainly involved in the dechlorination reaction is cytochrome P450IIE1. AC was not detected in serum of ECL exposed animals and only slightly enhanced amounts were detected in urine samples from ECL exposed mice, reflecting the high capacities of the AC metabolizing pathways in vivo. The data are discussed with regard to the results of a 2-year bioassay with F-344 rats and B6C3F1 mice exposed to 15 000 ppm ECL (NTP 1989a). In conclusion, the oxidative metabolism is not considered to be a key factor for the induction of the species specific uterine carcinomas in the B6C3F1 mouse observed in this bioassay.
Keywords: Ethyl chloride; Acetaldehyde; F-344 rat; B6C3F1 mouse; Cytochrome P450-dependent monooxygenase
Comparison of CYP1A1 induction and genotoxicity in vitro as indicators of potentially harmful effects of environmental samples by Päivi Kopponen; Riitta Törrönen; Jorma Mäki-Paakkanen; Atte von Wright; Sirpa Kärenlampi (pp. 167-173).
Cytochrome P450IA1 (CYP1A1) induction of Hepa-1 mouse and H4IIE rat hepatoma cell lines was compared using selected environmental samples. The results were in agreement for both cell lines: no induction was observed for the fly ash extract from peat combustion, an intermediate induction was found for the fly ash extract from biosludge combustion, and a strong induction was detected for natural peat extract. However, Hepa-1 responded to the samples more sensitively than did H4IIE: the half maximal induction (ED50) values for Hepa-1 were smaller than those for H4IIE. In a bacterial DNA repair assay without metabolic activation and in a mammalian sister chromatid exchange test in the presence of metabolic activation the samples were virtually non-genotoxic. Thus the CYP1A1-inducing potency and genotoxicity of the samples were not correlated. In light of these results, the CYP1A1 induction test might be a useful addition to conventional genotoxicity tests, which may fail to detect potentially harmful compounds/mixtures.
Keywords: CYP1A1 induction; Hepa-1 cell line; H4IIE cell line; Genotoxicity; Environmental monitoring
Milk transfer and tissue uptake of mercury in suckling offspring after exposure of lactating maternal guinea pigs to inorganic or methylmercury by Minoru Yoshida; Chiho Watanabe; Hiroshi Satoh; Tsuyoshi Kishimoto; Yukio Yamamura (pp. 174-178).
Maternal guinea pigs were injected with mercuric chloride (HgCl2; 1 mg Hg/kg body weight) or methylmercury (MeHg; 1 mg Hg/kg) 12 h after parturition, and exposure of the offspring to mercury (Hg) via breast milk were studied on days 3, 5 and 10 postpartum. Milk Hg concentrations were lower than maternal plasma Hg concentrations regardless of the form of Hg given to the dams. Milk Hg was higher in HgCl2-treated dams than in MeHg-treated dams. In MeHg-treated dams, MeHg was separately determined. While the ratio of MeHg to T-Hg decreased in the dams’ plasma, it did not in the milk. There was a strong correlation between milk and plasma T-Hg concentrations in HgCl2 treated dams. In the milk of MeHg-treated dams, the plasma MeHg concentrations correlated better than did the plasma T-Hg concentrations. In the offspring, regardless of the chemical forms of Hg given to the dams, the highest Hg concentrations were found in the kidney, followed by the liver and the brain. Brain Hg concentrations were, however, significantly higher in the offspring of MeHg-treated dams than in those of HgCl2-treated dams. In addition, Hg levels in the major organs of the offspring of HgCl2-treated dams peaked on day 5 postpartum, while those of MeHg-treated dams did not show a significant decrease up to day 10 postpartum. These facts indicate that the two chemical forms of Hg were transferred to the offspring via the breast milk and were distributed differently, depending on the chemical form, to the offspring’s tissues.
Keywords: Inorganic mercury; Methylmercury; Guinea pig; Breast milk; Neonatal exposure; Mercury distribution
Mercuric chloride induces the production of leukotriene B4 by rabbit alveolar macrophages by Naomi Kudo; Keizo Waku (pp. 179-186).
The effects of HgCl2 on the production of leukotriene B4 (LTB4) by rabbit alveolar macrophages were investigated. Alveolar macrophages synthesized only a small amount of LTB4 when incubated in Hanks’ balanced salt solution (HBSS) in the absence of stimuli or chemical reagents (0.2±0.1 ng/106 cells). The amount of LTB4 synthesized was greatly enhanced when macrophages were incubated with 5×10−6 M HgCl2 (5.3±0.2 ng/106 cells). Increases in levels of free arachidonic acid (20∶4), a precursor of eicosanoids, were also observed on treatment of [3H]20∶4-labeled cells with HgCl2 in a concentration-dependent manner. We confirmed that [3H]20∶4 was mainly liberated from the alkenyl subclass of ethanolamine glycerophospholipids (EGP). Degradation of alkenyl-EGP was also observed when HgCl2 and [3H]20∶4-labeled lipids were incubated in HBSS, resulting in an increase in the level of [3H]20∶4-labeled lysoEGP. When a microsomal fraction prepared from macrophages was added to the same mixture, [3H]20∶4 was liberated from [3H]20∶4-containing lysoEGP. These results suggest that the alkenyl linkage of EGP was degraded in the presence of HgCl2 with resultant formation of lysoEGP which was subsequently hydrolyzed by lysophospholipase. As a consequence, the level of free 20∶4 in and the rate of production of LTB4 by alveolar macrophages were elevated.
Keywords: Alveolar macrophages; Mercuric chloride; Leukotriene B4 ; Arachidonic acid
Effect of paraquat on the malondialdehyde level in rat liver microsomes (in vitro) by Masafumi Tomita; Toshiko Okuyama (pp. 187-192).
Toxicosis due to paraquat, a redox cycling xenobiotic, is still a subject of much debate. In the present study on lipid peroxidation, paraquat had a biphasic effect on the malondialdehyde (MDA) level in rat liver microsomes; stimulation at the initial stage (within 10 min) and depression at the later stage. Although paraquat increased the initial rate of NADPH oxidation dose-dependently, the rate was not necessarily parallel with the increase in the MDA level. The MDA level increased linearly up to 0.1 mM paraquat added, but then it attained a plateau. The stimulation obtained by paraquat within 10 min was absolutely dependent on exogenous Fe2+ ion and NADPH, and the stimulation was entirely SOD sensitive, while the irondriven increase in MDA was 20% sensitive. Thus, there were different mechanisms between iron-driven lipid peroxidation and paraquat-modified peroxidation. Catalase increased the level, but mannnitol, a scavenger of OH, had no effect. EPR spectra showed that superoxide was formed dose-dependently up to 0.1 mM paraquat and that it attained a plateau at the same as MDA level described above. From these results, we concluded that paraquat stimulates lipid peroxidation through a mechanism dependent on the superoxide complex involving Fe2+ ion.
Keywords: Paraquat; Superoxide; Malondialdehyde; Lipid peroxidation; Liver microsomes
Sensory irritation and pulmonary irritation of n-methyl ketones: receptor activation mechanisms and relationships with threshold limit values by Lea Frimann Hansen; Gunnar Damgård Nielsen (pp. 193-202).
Activation of the trigeminal nerve endings in eyes and nose, termed sensory irritation, was determined from the reflexively induced decrease in respiratory rate in mice for methyl propyl ketone, methyl butyl ketone, methyl amyl ketone and methyl hexyl ketone. The relationship between exposure concentration and the decrease in respiratory rate followed Michaelis-Menten equations. Two estimates of each agonist-receptor dissociation constant were obtained, one from the Michaelis-Menten equation and one from the threshold (RD-0) of the log concentration-effect curve. The values were equal and thus one receptor type could account for the activation process. The hydrophobic properties of the receptor biophase were found to approach that of the internal part of the bilayer membrane. It therefore follows that the receptor-air partition coefficients increase with the size of the ketones, thus accounting for the observed increase in potency. Estimates of Threshold Limit Values (TLV) were obtained and compared with established values. Close agreements were found for methyl propyl ketone and methyl amyl ketone, but not for methyl butyl ketone, where the neurotoxic effect constituted a more sensitive endpoint that sensory irritation.
Keywords: Methyl propyl ketone; Methyl butyl ketone; Methyl amyl ketone; Methyl hexyl ketone; Sensory irritation; Mice; Nose; Nervus trigeminus
Embryotoxic effects of thalidomide derivatives in the non-human primateCallithrix jacchus by Stephan Klug; Annegret Felies; Helga Stürje; Ana Christina Nogueira; Reinhard Neubert; Ernst Frankus (pp. 203-205).
The teratogenic potency of the thalidomide (Thd) derivative phthalimidophthalimide (Phtpht) was assessed in the common marmoset (Callithrix jacchus), by oral administration of the relatively high daily dose of 50 mg Phtpht/kg body wt, during the susceptible period (days 48–61 of pregnancy). Since in this species daily doses of only 100 μg/kg body wt of the Thd derivative EM12 already induce typical gross structural abnormalities in nearly 100% of the fetuses, investigations with a small number of these New World monkeys allow a rough estimation of the teratogenic potency of Thd-type substances. Macroscopic inspection and skeletal evaluation of ten fetuses gave no indication of dysmorphogenesis following treatment with Phtpht. We conclude that Phtpht has little, if any, Thd-type teratogenic potency in this non-human primate.
Keywords: Phthalimidophthalimide; Thalidomide; Teratogenicity; Callithrix jacchus ; Marmosets
Decreased incorporation of14C-leucine in different liver nuclear protein fractions at early stages of carbon tetrachloride poisoning in the rat by M. Galelli; M. I. Díaz Gómez; J. A. Castro (pp. 206-209).
Administration of CCl4 to 12–14 h starved Sprague Dawley male rats (220–240 g) at a dose of 5 ml of a 20% (v/v) olive oil solution/kg i.p. decreased the incorporation of14C-leucine into microsomal and nuclear proteins at 1 or 2 h after the hepatotoxin. Decreased amino acid incorporation capacity in nuclear but not in microsomal proteins returned to control values at 4 h after poisoning. Cycloheximide given i.p. at a dose of 1 mg/kg in saline either alone or before CCl4 also decreased to a similar or greater extent the incorporation of14C-leucine into both, microsomal and nuclear proteins at 1 h. The CCl4-induced decrease in amino acid incorporation was observable and significant even 1 h after CCl4 and involved histone and different non-histone nuclear protein fractions. Results suggest that decreased protein synthesis at the endoplasmic reticulum occurring in the very early stages of CCl4 poisoning might provoke temporary deficiencies in protein supplies to nuclei with as yet unknown consequences. However, some of the proteins involved have major regulatory properties in DNA expression.
Keywords: Carbon tetrachloride and nuclei; Carbon tetrachloride and protein synthesis; Carbon tetrachloride and nuclear proteins; Nuclei and protein synthesis; Cycloheximide and nuclear proteins
Ethylmorphine concentrations in human samples in an overdose case by P. Kintz; C. Jamey; P. Mangin (pp. 210-211).
Capillary gas chromatography coupled to mass spectrometry was employed to quantify ethylmorphine in biological fluids and tissues in a death attributed to oral ethylmorphine ingestion. The femoral blood concentration of the drug was 488 ng/ml. Hair analysis revealed the individual’s drug abuse pattern, particularly the switching from heroin to ethylmorphine.