2,2,2-Trifluoroethanol toxicity in aged rats.
Various anesthetics are metabolized by different forms of cytochrome P-450 yielding the same toxic metabolite, 2,2,2-trifluoroethanol (TFE). The toxicity of TFE is a consequence of its metabolism catalyzed by cytochrome P-450. Since a marked age difference exists in the composition and inducibility of the hepatic mixed function oxidase system, we have elucidated the toxicity of TFE in 36-month-old aged Wistar rats. The aged rats were injected with sublethal doses of TFE (0.10 g/kg once per week for 5 weeks), after which they were sacrificed for pathologic examination. The major TFE-related lesions observed were severe hepatocyte degenerative changes such as basophilic, eosinophilic, vacuolated hepatocytes, bile duct hyperplasia, accumulation of lipofuscin pigments, and preneoplastic nodules. Other changes seen were the hyalinization of gastric submucosal wall, generalized testicular atrophy due to the loss of seminiferous tubules, coagulation necrosis of intestinal mucosal wall, hyperpigmentation, and more advanced and severe chronic progressive glomerulonephropathy in the TFE-treated rats. More severe lipofuscin and vacuolation of white matter of thalamic area, pons, midbrain, and cerebellum reflective of enhanced aging were also seen. Ultrastructural studies of liver from TFE-treated rats revealed rather diffuse loss of glycogen, fragmentation of endoplasmic reticulum, mineralization of mitochondria, and loss of other organelles within the hepatocytes versus saline-treated aged rats. Hepatic cytochrome P-450 concentrations, measured as a possible index of endoplasmic reticulum damage, were not affected by TFE administration.
Kim
J C
JC
Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201.
Kaminsky
L S
LS
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000431:Ethanol / Q000031:analogs & derivatives*; D008099:Liver / Q000473:pathology / Q000648:ultrastructure; D008854:Microscopy, Electron; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D013270:Stomach / Q000473:pathology; D014270:Trifluoroethanol / Q000633:toxicity*
D000431:Ethanol; D014270:Trifluoroethanol; D003577:Cytochrome P-450 Enzyme System