The significance of multiple detoxification pathways for reactive metabolites in the toxicity of 1,1-dichloroethylene

Abstract

Chlorinated ethylenes are metabolized to reactive epoxidic intermediates. Epoxides are detoxified in vivo by reaction with glutathione (GSH) or by enzymatic hydration which can be inhibited by various competitive epoxidic substrates. In an attempt to quantitatively describe the contribution of these two pathways to detoxification of metabolites of 1,1-dichloroethylene (1,1-DCE), we studied the ability of pretreatment with various epoxides or with the sulfhydryl depleting agent, diethylmaleate (DEM), to (1) increase the acute oral and inhalation toxicity of 1,1-DCE, (2) deplete hepatic-GSH levels, and (3) diminish the rate of metabolism of 1,1-DCE in vivo in fasted, male rats. Seven epoxides were used: trichloropropane oxide (TCPO), styrene oxide (SO), cyclohexene oxide (CHO), 2,3-epoxypropan-1-ol (2,3-EP), epichlorhydrin (EPI), epoxypropane (EP), and butadiene monoxide (BMO). BMO, SO, 2,3-EP, CHO, and DEM caused virtually total depletion of hepatic-GSH for over 2 hr. The rank order for the ability of these chemicals to decrease the 2 hr LC50 of 1,1-DCE was: 2,3-EP > DEM > EPI > SO > BMO > CHO. As measured by gas uptake procedures, CHO, BMO, SO, and DEM inhibited the rate of 1,1-DCE metabolism. The product (rate of metabolism at the LC50) × (duration of the LC50 exposure) is the inhalation LQ50; it is that quantity of metabolite on a per weight basis formed in a 2-hr exposure which killed half the exposed animals. The rank order of these chemicals in terms of their ability to decrease the LQ50 was DEM > CHO > 2,3-EP > SO > BMO > EPI. When the extent of inhibition of 1,1-DCE metabolism was taken into account, the exacerbation of 1,1-DCE toxicity by these competitive epoxide substrates was found to be related to their ability to decrease hepatic GSH. Specific, epoxide-hydrating pathways appear to be of minimal significance in the metabolism of reactive intermediates of 1,1-DCE.