Dose-dependent cytotoxicity of chlorinated hydrocarbons in isolated rat hepatocytes.
The aim was to determine if isolated suspended hepatocytes could differentiate between the effects of four chlorinated hydrocarbons that are hepatotoxic in vivo and four that are not. Membrane integrity was assessed by measuring alanine aminotransferase (ALT) release after 30- to 180-min incubations in vitro. From the results, the chlorinated hydrocarbons fell into three groups: tetrachloroethylene and 1,1,2,2-tetrachloroethane were the most potent cytotoxicants; CCl4, 1,1,2-trichloroethane, and trichloroethylene exhibited intermediate cytotoxicity; and low cytotoxicity was observed with CHCl3, 1,1,1-trichloroethane, and 1,1-dichloroethylene. Cytotoxicity ranking correlated poorly with the reported in vivo hepatotoxicity of these agents. The effect of adding SKF-525A on the cytotoxicity of tetrachloroethylene and CCl4 was also assessed. In addition, hepatocytes from rats pretreated with 2,5-hexanedione were used to determine if they were more susceptible to the effects of CHCl3, CCl4, or tetrachloroethylene. SKF-525A decreased the cytotoxicity of both CCl4 and tetrachloroethylene, whereas pretreatment with 2,5-hexanedione enhanced their effect. The effects of both SKF-525A and 2,5-hexanedione on CCl4 in vitro are consistent with in vivo findings. However, tetrachloroethylene is not hepatotoxic in vivo, suggesting that SKF-525A might act by stabilizing plasma membranes rendering the hepatocyte more resistant to lysis. Overall, the results cast doubts on the use of ALT release from isolated hepatocytes as an appropriate in vitro model for assessing hepatotoxic properties of chlorinated hydrocarbons.
Dahlström-King
L
L
Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Québec, Canada.
Couture
J
J
Lamoureux
C
C
Vaillancourt
T
T
Plaa
G L
GL
D000410:Alanine Transaminase / Q000097:blood / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002725:Chloroform / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006588:Hexanones / Q000494:pharmacology; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013750:Tetrachloroethylene / Q000633:toxicity; D013997:Time Factors
D006588:Hexanones; D006843:Hydrocarbons, Chlorinated; D002725:Chloroform; D011335:Proadifen; C011269:2,5-hexanedione; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase; D013750:Tetrachloroethylene