Mechanism of toxicity of 2,2,2-trifluoroethanol in rats.
2,2,2-Trifluoroethanol (TFE) is the toxic metabolite of the anesthetic agent fluroxene. TFE treatment (0.21 g/kg, ip) of male Wistar rats significantly reduced peripheral white blood cell count, bone marrow nucleated cellularity, and dry weight of the small intestine. These toxic effects of TFE were first observed at 8 to 16 hr after treatment, persisted for 96 hr, and were accompanied by severe diarrhea and edema of the small intestine. A non-lethal dose of TFE increased the sensitivity of rats to bacterial endotoxin lethality by approximately 1000-fold. Antibiotic and antiendotoxin pretreatment reduced the lethality of TFE from 80 to 20% of the rats, but did not prevent the other toxic effects of TFE. In vitro experiments with serum from TFE-pretreated rats (0.13 g/kg) supported the growth of an average of 65% fewer cultured bone marrow cell colonies compared to the number of colonies produced when serum from control rats was used. This suggests that TFE-induced bone marrow depression and leukopenia are related to a decrease in colony stimulating factor activity. Taken together these results explain the rapid development of lethal bacterial infections in TFE-treated rats. TFE-mediated damage to the small intestine combined with prolonged leukopenia decreases the resistance of the rat to endogenous pathogens leading to systemic bacterial infection. In addition, the increased sensitivity to endotoxin induced by TFE leads to lethal endotoxemia.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects; D003115:Colony-Stimulating Factors / Q000097:blood; D004731:Endotoxins; D000431:Ethanol / Q000031:analogs & derivatives*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects; D007792:Lactulose / Q000494:pharmacology; D007958:Leukocyte Count; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014270:Trifluoroethanol / Q000633:toxicity*
D000900:Anti-Bacterial Agents; D003115:Colony-Stimulating Factors; D004731:Endotoxins; D000431:Ethanol; D007792:Lactulose; D014270:Trifluoroethanol