RESUMO
The aim of the present study was to investigate how the genetic polymorphism in glutathione transferase T1 (GSTT1) affects the metabolism and disposition of methyl chloride in humans in vivo. The 24 volunteers (13 males and 11 females) who participated in the study were recruited from a group of 208 individuals previously phenotyped for GSTT1 by measuring the glutathione transferase activity with methyl chloride in lysed erythrocytes ex vivo. Eight individuals with high (+/+), eight with medium (+/0) and eight with no (0/0) GSTT1 activity were exposed to methyl chloride gas (10 p.p.m.) in an exposure chamber for 2 h. Uptake and disposition was studied by measuring the concentration of methyl chloride in inhaled air, exhaled air and blood. A two-compartment model with two elimination pathways corresponding to exhalation and metabolism was fitted to experimental data. The average net respiratory uptake of methyl chloride was 243, 158, and 44 micromol in individuals with high, intermediate and no GSTT1 activity, respectively. Metabolic clearance was high (4.6 l/min) in the +/+ group, intermediate (2.4 l/min) in the +/0 group, and close to zero in 0/0 individuals, while the exhalation clearance was similar in the three groups. No exposure related increase in urinary S-methyl cysteine was detected. However, gender and the GSTTl phenotype seemed to affect the background levels. In conclusion, GSTT1 appears to be the sole determinant of methyl chloride metabolism in humans. Thus, individuals with nonfunctional GSTT1 entirely lack the capacity to metabolize methyl chloride.
Assuntos
Glutationa Transferase/genética , Cloreto de Metila/farmacocinética , Cloreto de Metila/toxicidade , Administração por Inalação , Adulto , Testes Respiratórios , Feminino , Humanos , Masculino , Cloreto de Metila/administração & dosagem , Pessoa de Meia-Idade , Fenótipo , Polimorfismo GenéticoRESUMO
Groups of seven B6C3F1 mice per sex were exposed for 23 hr/day to 0, 250, 1250, or 5000 ppm ethyl chloride (EtCl) for 11 consecutive days to evaluate the potential toxicity of EtCl under near-continuous exposure conditions. On the day following the last exposure, a neurobehavioral observation battery was performed, samples were obtained for clinical chemistry and hematology, and necropsies were conducted. Histopathologic examination was subsequently performed. The only observed effects were increased relative liver weights and a slight increase in hepatocellular vacuolation (glycogen or fat) in 5000 ppm-exposed mice. Exposures to EtCl were well tolerated despite the unusually long exposure periods.
Assuntos
Cloreto de Etil/toxicidade , Administração por Inalação , Animais , Câmaras de Exposição Atmosférica , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cloreto de Etil/administração & dosagem , Feminino , Masculino , Cloreto de Metila/administração & dosagem , Cloreto de Metila/toxicidade , Camundongos , Camundongos Endogâmicos , Tamanho do Órgão/efeitos dos fármacosRESUMO
A physiologic mathematical model was developed to describe the time course of 14C-methylene chloride (14CH2Cl2) distribution and elimination in mice following single i.v. administrations of 10 and 50 mg/kg. A whole-body model was used to simulate 14CH2Cl2 concentrations in blood and tissues, pulmonary clearance of unchanged 14CH2Cl2, and metabolic conversion to 14CO2 and 14CO as monitored by the appearances of these metabolites in expired breath. This diffusion-limited model was identified via a sequential optimization scheme using hybrid models for each compartment. Pulmonary elimination of unchanged 14CH2Cl2 was modeled as a linear process while hepatic metabolism of 14CH2Cl2 to the compounds 14CO2 and 14CO was described by a saturable metabolic rate term. The model adequately described the dose dependence in methylene chloride distribution and metabolism when simulations were compared to experimental data.
