2,2,2-Trifluoroethanol-Induced Enteropathy in Rats: Chemically or Bacterially Mediated Effects

Abstract

The lethal effects of the fluorinated ether anesthetic, fluroxene, in rats are a consequence of its metabolism, which is catalyzed by cytochrome P-450 to the toxic metabolite 2,2,2-trifluoroethanol (TFE). The anesthetic or TFE (0.21 g/kg) caused decreased white blood cell counts, necrosis of bone marrow and lymphocytes, and decreased small intestine dry weight and was associated with septicemia. To elucidate the mechanism of TFE toxicity in rats we undertook histopathologic, ultrastructural and bacteriologic studies. TFE produced severe edema of intestinal lamina propria and submucosae, dilatation of crypts, loss of surface epithelium, vacuolation and necrosis of intestinal epithelial cells, and infiltration of polymorphonuclear leukocytes into the edematous lamina propria. Intestinal epithelial villi lost their cellular tissue integrity. Coccobacillary organisms were numerous in the ulcerated intestine. Hemolytic E. coli were isolated from intestinal tissue at a two-log increase in concentration relative to controls. Hemograms from TFE-treated rats exhibited marked leukopenia and morphologic differences. The platelets lost their discoid shape, extended pseudopods, and centralizing granules. Hemoglobin precipitation as Heinz bodies and crystalloid structures was observed in TFE-treated rats. Together the data suggest that TFE-induced enteropathy was most probably due to E. coli precipitated from TFE-mediated alterations in the population of small intestinal microbes.

The antibiotics erythromycin, active against gram-positive bacteria, and streptomycin, active against gramnegative bacteria, and the antiendotoxin, polymyxin B, were administered to rats prior to TFE in an effort to differentiate between these mechanisms by altering the intestinal bacteria populations. The results indicate that the TFE-induced small intestinal lesions are initiated by the direct focal necrotic effect of TFE or its metabolites on the small intestinal epithelium. The focal coagulation necrosis produced by TFE predisposes the animals to lethal enteritis and systemic bacteremia.

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