Damage to hepatic cellular membranes by chlorinated olefins with emphasis on synergism and antagonism.
The fundamental reactivity or stability of the chloroethylene molecules affects their hepatotoxic potential. Extent and symmetry of the chlorine substitution, which alters electron delocalization, charge polarization, and solubility, affect biologic response. The most nonsymmetrically depolarized chloroethylene, 1,1-dichloroethylene (1,1-DCE) is the most hepatotoxic and causes a unique pattern of hepatocellular injury involving mitochondria, plasma membranes, and chromatin. The injury caused by the other chloroethylenes examined appears to profoundly affect the structural integrity of the endoplasmic reticulum with toxic potential in the order: trichloroethylene (TRI) greater than vinyl chloride (VCM) greater than perchloroethylene (PER). Pretreatments which increased cytochrome P-450 contents, thus presumably augmenting metabolic activation to a reactive intermediate such as an epoxide, enhanced or were synergistic to the hepatotoxic potential of TRI, VCM and PER but were protective or antagonistic to 1,1-DCE hepatotoxicity. Biologic response to 1,1-DCE may be expressed by a different metabolic pathway. Glutathione appears to be involved in the biologic response to all nonsymmetric chloroethylenes and toact as an antagonist against injury. Marked differences in the patterns of injury and the biologic responses suggest that more than one mechanism is involved in the production of injury by chloroethylenes.
D000475:Alkenes / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D004000:Dichloroethylenes / Q000633:toxicity; D004336:Drug Antagonism; D004357:Drug Synergism; D004781:Environmental Exposure; D005978:Glutathione / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D013750:Tetrachloroethylene / Q000633:toxicity; D014241:Trichloroethylene / Q000633:toxicity; D014752:Vinyl Chloride / Q000633:toxicity
D000475:Alkenes; D004000:Dichloroethylenes; D006843:Hydrocarbons, Chlorinated; D014241:Trichloroethylene; D005978:Glutathione; D013750:Tetrachloroethylene; D014752:Vinyl Chloride