Lock E A, Ishmael J
Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
Arch Toxicol. 1998 May;72(6):347-54. doi: 10.1007/s002040050513.
Recent studies have shown that tetrafluoroethylene is a renal and hepatic carcinogen in the rat. In this study, we have examined the ability of a single i.p. dose of 1,1,2,2-tetrafluoroethyl-L-cysteine (TFEC), a major metabolite of tetrafluoroethylene, to produce hepatic and renal injury in male and female rats. We have also examined the effect of blocking the renal organic anion transport system with probenecid and of inhibiting the activity of cysteine conjugate beta-lyase with aminooxyacetic acid on the extent of renal injury produced by TFEC. Doses of > or = 12.5 mg/kg TFEC produced renal tubular necrosis to the pars recta of the proximal tubules within 24 h in both male and female rats. This was associated with an increased kidney to body weight ratio and plasma urea at doses of > or = 25 mg/kg. No consistent evidence of liver injury was seen at doses up to 50 mg/kg TFEC in rats of either sex, although occasional vacuolation of hepatocytes and a small dose-related increase in liver to body weight ratio was observed. Prior treatment of female rats with probenecid completely prevented the renal injury produced by either 25 or 50 mg/kg TFEC as judged by plasma urea and histopathology. However, prior treatment of female rats with aminooxyacetic acid afforded no protection against the nephrotoxicity produced by either TFEC or the cysteine conjugate of hexachloro-1,3-butadiene. Thus no major sex difference in nephrotoxicity in the rat was seen with TFEC, while accumulation of TFEC, or its N-acetyl derived metabolite, into renal proximal tubular cells via a probenecid sensitive transport system appears to be a key event in the mechanism of nephrotoxicity. The lack of protection observed with the cysteine conjugate beta-lyase inhibitor, aminooxyacetic acid, may reflect the inability to completely inhibit the mitochondrial form of this enzyme and thereby prevent the formation of the reactive metabolite. Our acute studies provide no insight concerning the liver carcinogenicity of tetrafluoroethylene.
最近的研究表明，四氟乙烯在大鼠体内是一种肾和肝致癌物。在本研究中，我们检测了腹腔注射单剂量的1,1,2,2 - 四氟乙基-L-半胱氨酸（TFEC，四氟乙烯的一种主要代谢产物）在雄性和雌性大鼠中导致肝和肾损伤的能力。我们还检测了用丙磺舒阻断肾有机阴离子转运系统以及用氨基氧乙酸抑制半胱氨酸共轭β-裂解酶活性对TFEC所致肾损伤程度的影响。剂量≥12.5 mg/kg的TFEC在24小时内使雄性和雌性大鼠近端小管直部出现肾小管坏死。剂量≥25 mg/kg时，这与肾重/体重比增加及血浆尿素升高有关。在剂量高达50 mg/kg的TFEC处理的两性大鼠中，未观察到一致的肝损伤证据，尽管偶尔可见肝细胞空泡化以及肝重/体重比有小幅度的剂量相关增加。用丙磺舒预先处理雌性大鼠，根据血浆尿素和组织病理学判断，可完全预防25或50 mg/kg TFEC所致的肾损伤。然而，用氨基氧乙酸预先处理雌性大鼠并不能保护其免受TFEC或六氯-1,3 - 丁二烯半胱氨酸共轭物所致的肾毒性。因此，TFEC在大鼠肾毒性方面未观察到明显的性别差异，而TFEC或其N - 乙酰衍生代谢产物通过丙磺舒敏感的转运系统蓄积到肾近端小管细胞似乎是肾毒性机制中的关键事件。半胱氨酸共轭β-裂解酶抑制剂氨基氧乙酸缺乏保护作用，可能反映出无法完全抑制该酶的线粒体形式，从而无法阻止活性代谢产物的形成。我们的急性研究未提供关于四氟乙烯肝致癌性的见解。
