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- W1980033440 abstract "Dihalomethanes are metabolized by two major pathways: an oxidative, cytochrome P-450-mediated pathway that has been previously thought to yield only CO, and a glutathione (GSH)-dependent one that yields CO2. Both give 2 mol of halide ion. We studied the kinetic properties of the two pathways in vivo by exposing male rats to various inhaled concentrations of CH2Cl2, CH2F2, CH2FCl, CH2BrCl, and CH2Br2 and determining end-exposure carboxyhemoglobin (HbCO) and plasma bromide (where appropriate). Closed atmosphere gas uptake studies were employed for CH2F2, CH2FCl, CH2Cl2, and CH2BrCl metabolism. A physiologically based kinetic model was used to determine kinetic constants based on gas uptake or plasma bromide data and these constants were used to predict HbCO concentrations. Oxidation was high affinity, low capacity. The maximum metabolic rates for this pathway with CH2Br2, CH2BrCl, and CH2Cl2 were, respectively, 72, 54, and 47 μmol metabolized/kg/hr. CH2FCl did not undergo significant oxidative metabolism and appears more like CH3Cl than a dihalomethane in its metabolic reactivity. The GSH pathway was low affinity, but high capacity and could be described as a single first-order process at all accessible exposure concentrations. The rate constant for this first-order GSH-dependent pathway was related as CH2BrCl > CH2Cl2 ⋍ CH2FCl > CH2Br2 > CH2F2. Presumably bromide is a preferred leaving group but steric hindrance in the initial reaction with GSH is important with CH2Br2. We also studied the effects of pyrazole (which inhibits microsomal oxidation) and 2,3-epoxypropanol (which depletes GSH) on dihalomethane metabolism. Pyrazole abolished CO production from CH2Br2, CH2BrCl, and CH2Cl2. GSH depletion did not change the yield of halide ion from the high-affinity pathway; it did increase the steady-state HbCO concentrations with CH2Cl2 and CH2ClBr, but not with CH2Br2. The putative formyl chloride (FC) intermediate from CH2Cl2 or CH2BrCl appears to have a longer life than the formyl bromide from CH2Br2 and a significant portion of the FC (⋍20–30%) may react with other cellular nucleophiles instead of spontaneously decomposing to CO. This portion of the oxidative pathway probably yields CO2." @default.
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- W1980033440 date "1978-01-01" @default.
- W1980033440 modified "2023-09-26" @default.
- W1980033440 title "High amplitude in the dihalomethanes" @default.
- W1980033440 doi "https://doi.org/10.1016/0047-2670(78)80103-8" @default.
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