2,2,2-Trifluoroethanol intestinal and bone marrow toxicity: the role of its metabolism to 2,2,2-trifluoroacetaldehyde and trifluoroacetic acid.
2,2,2-Trifluoroethanol (TFE) produces bone marrow and small intestine toxicity resulting in leukopenia, loss of intestinal dry weight, and consequent lethal septicemia in male Wistar rats. Its metabolic pathway, based on serum and small intestine time courses of substrate and metabolites, was determined to be TFE in equilibrium 2,2,2-trifluoroacetaldehyde (TFAld)----trifluoroacetic acid (TFAA). Administered TFE and TFAld were not toxic per se, since their toxicity and metabolism were inhibited by pyrazole. TFE and TFAld were equipotent at equimolar doses thus precluding the oxidative reaction, TFE to TFAld, from being the toxic step. Since equimolar TFAA exhibited no toxic effects, an oxidative intermediate on the pathway from TFAld to TFAA, most likely F3C-C+(OH)2, must thus be the toxic moiety. The intermediate TFAld is stable in serum, as determined by a novel assay developed for its analysis in biological systems, and can be transported to the target tissues, bone marrow, and small intestine, after formation probably in the liver. On the basis of the more rapid metabolism of TFE to higher levels of TFAld in the small intestine and bone marrow than in the serum, the closer correspondence of bone marrow and small intestine metabolite ratios than serum ratios at high and low doses of TFE to the corresponding ratios of toxicity, and the decreased toxicity of TFAld when administered ig versus ip, the formation of the toxic metabolic intermediate of TFE probably occurs in the target tissues.
Fraser
J M
JM
Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201.
Kaminsky
L S
LS
D000079:Acetaldehyde / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D002728:Chlorohydrins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005023:Ethylene Chlorohydrin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D005463:Fluoroacetates / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects*; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014269:Trifluoroacetic Acid / Q000378:metabolism* / Q000633:toxicity
D002728:Chlorohydrins; D005463:Fluoroacetates; D011720:Pyrazoles; C055298:trifluoroacetaldehyde; D005023:Ethylene Chlorohydrin; C005849:2,2,2-trichloroethanol; D014269:Trifluoroacetic Acid; D000079:Acetaldehyde