Metabolism of dichloromethane (methylene chloride) to formaldehyde in human erythrocytes: influence of polymorphism of glutathione transferase Theta (GST T1-1)
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Human hemolysate was incubated in vitro with different concentrations of dichloromethane (methylene chloride). The resulting enzymatically mediated production of formaldehyde was determined by two independent analytical methods (Nash-reaction/colorimetry or HPLC). The formation of formaldehyde from dichloromethane is influenced by the polymorphism of glutathione-S-transferase (GST) Theta, in the same way as the metabolism of methyl bromide, methyl chloride, methyl iodide and ethylene oxide. Three quarters of the population (“conjugators”) possess, whereas one quarter (“non-conjugators”) lack this enzyme activity in human erythrocytes. The metabolism of dichloromethane in hemolysate in vitro can be described by Michaelis-Menten kinetics; for an individual with high GST T1-1 enzyme activity, the maximum velocity of formaldehyde production was calculated to be approximately 180 pmol/min per mg Hb, the kM being approximately 60 mM dichloromethane. Carcinogenicity of dichloromethane in long-term inhalation exposure of rodents has been attributed to metabolism of the compound via the GST-dependent pathway. Extrapolation of the results to humans for risk assessment should consider the newly discovered polymorphic enzyme activity of GST Theta. Furthermore, the possible existence of a “high-risk” population among humans should be considered in epidemiological research.
Key wordsDichloromethane Methylene chloride Formaldehyde Human erythrocytes Enzyme polymorphism Glutathione-S-transferase Theta Risk assessment
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