RESUMEN
Interindividual variation in the in vitro conjugation of methyl chloride with glutathione by erythrocyte glutathione transferase was investigated in 208 healthy males and females from the southern and central parts of Sweden. It was found that 11.1% of the individuals lacked this activity, whereas 46.2% had intermediate activity and 42.8% had high activity. This distribution of three phenotypes is compatible with the presence of one functional allele with a gene frequency of 0.659 and one defect allele with a gene frequency of 0.341. The proportion of non-conjugators in this Swedish material was considerably smaller than that previously found in Germany (Peter et al., Arch Toxicol 1989: 63, 351-355). The polymorphic distribution of another glutathione transferase, GST mu, was determined in the same individuals with a PCR method. No connection between the genotype for GST mu (GSTM1) and the glutatione conjugation with methyl chloride in erythrocytes was found.
Asunto(s)
Glutatión Transferasa/sangre , Glutatión Transferasa/genética , Isoenzimas/sangre , Isoenzimas/genética , Cloruro de Metilo/sangre , Polimorfismo Genético , Adulto , Anciano , Alelos , Eritrocitos/enzimología , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , SueciaRESUMEN
NMRI female mice were exposed to 100, 250 and 500 ppm vinyl chloride (VC). Cell nuclei were prepared from the liver, and single-strand breaks (SSB) were determined by the DNA unwinding technique. Haemoglobin (Hb) was isolated from the blood, and the degree of alkylation was determined as a measure of in-vivo dose by means of a gas chromatography-mass spectrometry (GC-MS) technique. A maximum level of SSB in liver DNA and of adduct levels of Hb was reached at 500 ppm, indicating that saturation of metabolic activation of VC had been achieved. The results demonstrate that VC induces SSB in liver DNA of mice in a dose-dependent manner and that about 80% of the damage is repaired within 20 h.
Asunto(s)
Daño del ADN , ADN de Cadena Simple/efectos de los fármacos , Hígado/efectos de los fármacos , Cloruro de Vinilo/toxicidad , Compuestos de Vinilo/toxicidad , Administración por Inhalación , Animales , Femenino , RatonesRESUMEN
In vivo lipid peroxidation was studied in phenobarbital pretreated rats exposed for chloroform. Lipid peroxidation was monitored as ethane exhalation or malondialdehyde (MDA) excretion in urine. A single oral dose of chloroform (0.7 ml/kg b.wt.) showed a marked increase in ethane exhalation in animals starved for 48 hours prior to chloroform treatment. This increase became evident after a lag-period of about 100 min. Pretreatment with diethylmaleate (1 ml/kg b.wt.) 1 hour prior to chloroform treatment gave a similar result. MDA excretion in urine from non-starved animals, exposed to chloroform, markedly increased after 4 hours and after 24 hours 115 nmol/kg had been excreted. In animals starved for 48 hours prior to chloroform treatment about 270 nmol/kg excreted within 24 hours. Small molecular weight thiols were measured in liver, kidneys and lungs. Chloroform decreased the thiol content of the liver by 43.2% within 100 min. while the concentration in the kidneys and the lungs were less affected. It is suggested that chloroform may act as a potent inducer of lipid peroxidation in vivo. The synergistic effects of the pretreatments and the lag phase indicate that glutathione depletion in the liver was an essential factor in this response.
Asunto(s)
Cloroformo/toxicidad , Etano/metabolismo , Peróxidos Lipídicos/metabolismo , Malonatos/orina , Malondialdehído/orina , Administración Oral , Animales , Pruebas Respiratorias , Masculino , Maleatos/farmacología , Ratas , Ratas Endogámicas , Inanición/metabolismo , Compuestos de Sulfhidrilo/análisisRESUMEN
Four dihalomethanes; dichloromethane, bromochloromethane, dibromomethane and diiodomethane, have been studied with respect to their reactivities towards nucleophilic compounds of different strengths in water solution and with respect to their toxicities and mutagenic effectiveness in bacterial test systems. The correlation between biological activity (toxicity and mutagenic effectiveness in Salmonella TA100) and reactivity towards strong nucleophiles indicates that reactions with nucleophilic groups of high reactivity in the biological material, possibly SH or amino groups in proteins, are involved in their mechanism of action.
Asunto(s)
Hidrocarburos Bromados/toxicidad , Hidrocarburos Clorados/toxicidad , Hidrocarburos Halogenados/toxicidad , Hidrocarburos Yodados/toxicidad , Cloruro de Metileno/toxicidad , Mutágenos/toxicidad , Mutación , Fenómenos Químicos , Química , Cinética , Pruebas de Mutagenicidad , Salmonella typhimurium , Relación Estructura-ActividadRESUMEN
After 10 weeks of treadmill training, female Sprague-Dawley rats had developed a bradycardia at exercise on submaximal work loads. This bradycardia was also present after autonomic denervation and in isolated perfused heart preparations. The heart weight/body weight ratio was increased in these trained animals compared to untrained littermates. Sympathectomized, trained rats developed the same degree of cardiac hypertrophy, but their heart rate after denervation and in the isolated heart was the same as in sympathectomized, untrained rats. It is concluded that the bradycardia of trained and thereafter denervated animals seen in this and a previous investigation represents an adaptation within the heart itself, since it was present in the isolated heart. These results thus provide further evidence for a non-neural component in training-induced bradycardia. Since the trained sympathectomized rats had a cardiac hypertrophy but no reduction of intrinsic heart rate, it seems likely that the myocardial mass is of minor importance for the level of intrinsic heart rate.
Asunto(s)
Frecuencia Cardíaca , Esfuerzo Físico , Adaptación Fisiológica , Fibras Adrenérgicas/efectos de los fármacos , Animales , Cardiomegalia , Femenino , Corazón/inervación , Hidroxidopaminas/farmacología , Ratas , Ratas Endogámicas , Simpatectomía QuímicaRESUMEN
Sprague-Dawley rats, normal and chemically sympathectomized with 6-hydroxy-dopamine, were trained by treadmill running. The normal rats, unlike the sympathectomized animals, showed reduction of the exercise heart rate after the training period. Compared to a sedentary control group the sympathectomized rats showed no difference in intrinsic heart rate after pithing and denervation and no increase in heart weight. The increase of the heart weight/body weight ratio after training was smaller in the sympathectomized group than in the normal one. The results show that a functioning adrenergic nervous system is necessary for an efficient adaptation to physical training. Administration of noradrenaline to pithed trained and untrained rats showed that betaadrenergic receptor sensitivity was not altered by physical training. The intrinsic heart rate of normal trained rats was lower than that of normal control rats.
Asunto(s)
Frecuencia Cardíaca , Esfuerzo Físico , Sistema Nervioso Simpático/fisiología , Adaptación Fisiológica , Animales , Femenino , Hidroxidopaminas/farmacología , Norepinefrina/farmacología , Ratas , Receptores Adrenérgicos beta/fisiología , SimpatectomíaRESUMEN
The distribution of methylchloroform and n-octane, respectively, in the blood, liver, kidney, and brain of mice was studied at different inspired air concentrations and after different exposure times. The air concentration varied between 10 and 10,000 ppm; and the exposure time, between 0.5 and 24 h. The resulting solvent concentrations in kidney and brain were about the same, but the liver concentrations were usually somewhat higher for both solvents. There was a linear dependence between inspired air concentration and tissue concentrations at fixed exposure times. A correlation between blood and organ concentrations was observed in animals exposed at different inhalation air concentrations but not in animals exposed only at one fixed concentration. The ratios between the concentrations of the solvents in the organs and blood were higher for n-octane than for methylchloroform. The ratios increased as the exposure concentration increased for all organs studied in the case of n-octane but only for the liver in the case of methylchloroform. When the exposure dose, i.e., inspired air concentration X time, was generated in different ways, a high concentration during a short exposure resulted in a ten times higher organ concentration than a low concentration during a long exposure. The liver, kidney, and brain concentrations generally did not differ more than twice between methylchloroform and n-octane after exposure of the same concentration and duration. The blood concentration, however, was much less in n-octane exposed animals than in methylchloroform exposed ones. A pharmacokinetic model with both uptake and elimination of the first order fitted the empirical data better for methylchloroform than a model with zero order uptake and first order elimination. Postexposure concentrations of methylchloroform were linear in a semilog graph. A one-compartment pharmacokinetic model was in accordance with the experimental data for methylchloroform. For n-octane, however, at least a two-compartment model must be assumed.