Glutathione transferase T1 phenotype affects the toxicokinetics of inhaled methyl chloride in human volunteers.
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.
Löf
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Program for Toxicology and Risk Assessment, National Institute for Working Life, Stockholm, Sweden. agneta.lof@niwl.se
Johanson
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Rannug
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Warholm
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D000280:Administration, Inhalation; D000328:Adult; D001944:Breath Tests; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008737:Methyl Chloride / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic
D008737:Methyl Chloride; D005982:Glutathione Transferase