Bayer Tanja, Amberg Alexander, Bertermann Rüdiger, Rusch George M, Anders M W, Dekant Wolfgang
Institut für Toxikologie, Universität Würzburg, Versbacher Strasse 9, 97078, Germany.
Chem Res Toxicol. 2002 May;15(5):723-33. doi: 10.1021/tx025505c.
1,1,1,3,3-Pentafluoropropane (HFC-245fa) is being developed as a CFC substitute. 1,1,1,3,3-Pentafluoropropane has a low potential for toxicity: the only remarkable toxic effect seen in rats after inhalation exposure to 1,1,1,3,3-pentafluoropropane in concentrations of up to 50,000 ppm for 90 days was an increased incidence of diffuse myocarditis. To elucidate the possible role of biotransformation in 1,1,1,3,3-pentafluoropropane-induced cardiotoxicity, the biotransformation of 1,1,1,3,3-pentafluoropropane was investigated in rats after inhalation exposure and in rat and human liver microsomes. Male and female rats were exposed by inhalation to 50 000, 10 000, and 2000 ppm 1,1,1,3,3-pentafluoropropane for 6 h, urine was collected for 72 h, and metabolites excreted were identified by 19F NMR spectroscopy and quantified by GC/MS. Trifluoroacetic acid and inorganic fluoride were identified as major urinary metabolites of 1,1,1,3,3-pentafluoropropane; 3,3,3-trifluoropropanoic acid and 1,1,1,3,3-pentafluoropropane-2-ol were minor metabolites. The extent of 1,1,1,3,3-pentafluoropropane biotransformation after inhalation was dependent on exposure concentrations. Neither 3,3,3-trifluoropropanoic acid nor 3,3,3-trifluoropyruvic acid were metabolized to trifluoroacetic acid in vitro or in rats. In rat and human liver microsomes, 1,1,1,3,3-pentafluoropropane was biotransformed by a cytochrome P450-dependent reaction to trifluoroacetic acid and 3,3,3-trifluoropropanoic acid. Rates of trifluoroacetic acid formation were 99.2 +/- 20.5 pmol (mg of protein)(-)(1) min(-)(1) and of 3,3,3-trifluoropropanoic acid formation were 17.5 +/- 4.0 pmol (mg of protein)(-)(1) min(-)(1) in liver microsomes from male rats. In human liver microsomes, rates of trifluoroacetic acid formation ranged from 0 to 11.6 pmol (mg of protein)(-)(1) min(-)(1), and rates of 3,3,3-trifluoropropanoic acid formation ranged from 0.7 to 7.6 pmol (mg of protein)(-)(1) min(-)(1). The results show that 1,1,1,3,3-pentafluoropropane is metabolized at low rates in vivo and in vitro. The toxic effects of 1,1,1,3,3-pentafluoropropane may be associated with the formation of the minor metabolite 3,3,3-trifluoropropanoic acid, which is highly toxic in rats.
1,1,1,3,3 - 五氟丙烷（HFC - 245fa）正在被开发作为一种氟氯化碳替代品。1,1,1,3,3 - 五氟丙烷的毒性潜力较低：在大鼠吸入浓度高达50000 ppm的1,1,1,3,3 - 五氟丙烷90天后，唯一显著的毒性作用是弥漫性心肌炎的发病率增加。为了阐明生物转化在1,1,1,3,3 - 五氟丙烷诱导的心脏毒性中可能的作用，对大鼠吸入暴露后以及大鼠和人肝微粒体中1,1,1,3,3 - 五氟丙烷的生物转化进行了研究。雄性和雌性大鼠吸入50000、10000和2000 ppm的1,1,1,3,3 - 五氟丙烷6小时，收集尿液72小时，并通过19F核磁共振光谱鉴定排泄的代谢产物，通过气相色谱/质谱法定量。三氟乙酸和无机氟化物被鉴定为1,1,1,3,3 - 五氟丙烷的主要尿代谢产物；3,3,3 - 三氟丙酸和1,1,1,3,3 - 五氟丙烷 - 2 - 醇是次要代谢产物。吸入后1,1,1,3,3 - 五氟丙烷的生物转化程度取决于暴露浓度。在体外或大鼠体内，3,3,3 - 三氟丙酸和3,3,3 - 三氟丙酮酸均未代谢为三氟乙酸。在大鼠和人肝微粒体中，1,1,1,3,3 - 五氟丙烷通过细胞色素P450依赖性反应生物转化为三氟乙酸和3,3,3 - 三氟丙酸。雄性大鼠肝微粒体中三氟乙酸的形成速率为99.2±20.5 pmol（mg蛋白质）-1 min -1，3,3,3 - 三氟丙酸的形成速率为17.5±4.0 pmol（mg蛋白质）-1 min -1。在人肝微粒体中，三氟乙酸的形成速率范围为0至11.6 pmol（mg蛋白质）-1 min -1，3,3,3 - 三氟丙酸的形成速率范围为0.7至7.6 pmol（mg蛋白质）-1 min -1。结果表明，1,1,1,3,3 - 五氟丙烷在体内和体外的代谢速率较低。1,1,1,3,3 - 五氟丙烷的毒性作用可能与次要代谢产物3,3,3 - 三氟丙酸的形成有关，3,3,3 - 三氟丙酸在大鼠中具有高毒性。
