Metabolism of Inhaled Dihalomethanes in Vivo: Differentiation of Kinetic Constants for Two Independent Pathways,
HARRY G ARMSTRONG AEROSPACE MEDICAL RESEARCH LAB WRIGHT-PATTERSON AFB OH
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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, CH2FC1, 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 micromol metabolizedkghr. CH2FCl did not undergo significant oxidative metabolism and appears more lke 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. We also studied the effects of pyrazole which inhibits microsomal oxidation and 2,3-epoxypropanol which depletes GSH on dihalomethane metabolism.
- Anatomy and Physiology