Kim J C, Fraser J M, Samsonoff W A, Kaminsky L S, Shin S J
Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201.
Toxicol Pathol. 1987;15(4):388-400. doi: 10.1177/019262338701500402.
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 gram-negative 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.
含氟醚麻醉剂氟烷对大鼠的致死作用是其代谢的结果，该代谢过程由细胞色素P - 450催化生成有毒代谢物2,2,2 - 三氟乙醇（TFE）。麻醉剂或TFE（0.21 g/kg）可导致白细胞计数减少、骨髓和淋巴细胞坏死、小肠干重降低，并伴有败血症。为阐明TFE对大鼠的毒性机制，我们进行了组织病理学、超微结构和细菌学研究。TFE导致肠固有层和黏膜下层严重水肿、隐窝扩张、表面上皮丧失、肠上皮细胞空泡化和坏死，以及多形核白细胞浸润至水肿的固有层。肠上皮绒毛失去细胞组织完整性。在溃疡的肠道中可见大量球杆菌。从肠道组织中分离出的溶血性大肠杆菌浓度相对于对照组增加了两个对数级。TFE处理的大鼠的血常规显示明显的白细胞减少和形态差异。血小板失去盘状形态，伸出伪足并聚集颗粒。在TFE处理的大鼠中观察到血红蛋白以海因茨小体和晶体结构形式沉淀。这些数据共同表明，TFE诱导的肠病很可能是由于TFE介导的小肠微生物群改变导致大肠杆菌沉淀所致。在给大鼠注射TFE之前，先给予对革兰氏阳性菌有活性的抗生素红霉素、对革兰氏阴性菌有活性的链霉素以及抗内毒素多粘菌素B，以通过改变肠道细菌群来区分这些机制。结果表明，TFE诱导的小肠损伤是由TFE或其代谢产物对小肠上皮的直接局灶性坏死作用引发的。TFE产生的局灶性凝固性坏死使动物易患致命性肠炎和全身性菌血症。
