Physiological model for tissue glutathione depletion and increased resynthesis after ethylene dichloride exposure.
Ethylene dichloride (EDC) is metabolized by two competing pathways both of which consume glutathione (GSH). EDC undergoes oxidation to form chloroacetaldehyde (CAA) which is detoxified by GSH and also reacts directly with GSH to form 2-(s-chloroethyl)-GSH. A physiological pharmacokinetic model developed for EDC was extended to describe tissue GSH turnover and its depletion after EDC exposures. This GSH model was necessary to keep track of GSH concentrations with time, as EDC metabolism is affected by GSH status. Reactions of GSH with EDC and GSH with CAA were defined as second-order. Steady-state GSH formation was modeled as zero-order and GSH loss as first-order. GSH rebound effects after its depletion were controlled by a GSH synthetase reaction, which allowed time- and GSH concentration-dependent feedback for increased GSH resynthesis. The model was developed for liver GSH in the rat and was extrapolated to include the lung. Allometric scaling was used to extrapolate the model to other animal species. Experimental observations in the rat and mouse were consistent with model predictions.
D'Souza
R W
RW
Miami Valley Laboratories, Procter & Gamble Company, Cincinnati, Ohio.
Francis
W R
WR
Andersen
M E
ME
D000818:Animals; D005025:Ethylene Dichlorides / Q000493:pharmacokinetics* / Q000494:pharmacology; D005753:Gastric Mucosa / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism*; D006843:Hydrocarbons, Chlorinated / Q000493:pharmacokinetics*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008433:Mathematics; D008954:Models, Biological; D051381:Rats; D013270:Stomach / Q000187:drug effects
D005025:Ethylene Dichlorides; D006843:Hydrocarbons, Chlorinated; C024565:ethylene dichloride; D005978:Glutathione