Susceptibility to the cytogenetic effects of dichloromethane is related to the glutathione S-transferase theta phenotype.
The carcinogenicity of dichloromethane (DCM) has been demonstrated by mutagenicity studies using bacteria and yeasts and using animal bioassays. Epidemiological studies indicate that exposure to DCM increases the incidences of liver and pancreas cancers. In the present study, we determine whether DCM generates DNA damage in human peripheral blood mononuclear cells (PBMCs) and whether that process depends on glutathione S-transferase theta (GSTT)-1 activity. GSTT1 is one of the enzymes that biotransforms DCM. To this end, PBMC cultures from healthy men were treated with DCM (15-500 ppm) for 72 h. Cell cultures were harvested and processed according to classical cytogenetic techniques. The frequency of sister chromatid exchanges (SCEs), the mitotic index (MI), the cell proliferation kinetic (CPK) value, and the level of GSTT1 activity were determined. DCM exposure decreased the MI in a dose-dependent manner in all individuals tested (20). The CPK value decreased from 125 ppm DCM, and the SCEs frequency increased from 60 ppm DCM. A significantly different response was observed when the group of individuals with low GSTT1 enzymatic activity (4 individuals), the group with medium GSTT1 activity (10 individuals), and the group of individuals with high GSTT1 enzymatic activity (6 individuals) were compared (0.077 ± 0.0124, 0.325 ± 0.0269, and 7.365 ± 1.3474 nmol HCOH/min/mg protein, respectively). These differences were reflected in the amount of change for all of the evaluated cytogenetic parameters (p<0.05, ANOVA) and indicated a clear susceptibility to DCM genotoxic effects related to GSTT1 activity because the cytogenetic effects were directly related to the GSTT1-specific activity. DCM was highly cytotoxic in PBMCs, even at doses within the safety range. Due to this toxicity, a review of the maximal limits for occupational exposure to DCM is advised.
Olvera-Bello
Alejandra E
AE
Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México D.F., Mexico.
Estrada-Muñiz
Elizabet
E
Elizondo
Guillermo
G
Vega
Libia
L
D000328:Adult; D002273:Carcinogens / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D008752:Methylene Chloride / Q000493:pharmacokinetics / Q000633:toxicity*; D010641:Phenotype; D012854:Sister Chromatid Exchange / Q000187:drug effects
D002273:Carcinogens; D008752:Methylene Chloride; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase