Morel Georges, Ban Masarin, Bonnet Pierre, Zissu Danièle, Brondeau Marie-Thérèse
Institut National de Recherche et de Sécurité, Avenue de Bourgogne, BP 27, 54501 Vandoeuvre, France.
J Appl Toxicol. 2005 Mar-Apr;25(2):153-65. doi: 10.1002/jat.1048.
The role of cytochrome P450 activity in the nephrotoxicity of chlorotrifluoroethylene (CTFE) and 1,1-dichloro-2,2-difluoroethylene (DCDFE) was investigated in the male rat. Hepatic cytochrome P450 1A1 and principally P450 2B1/2 were induced by beta-naphthoflavone and phenobarbital, respectively. Nephrotoxicity was evaluated by investigating urine biochemical parameters, kidney histochemistry and histopathological modifications. Both CTFE and DCDFE induce severe nephrotoxicity in rats after 4 h of exposure to 200 and 100 ppm, respectively. Compared with controls, activity levels of gamma-glutamyltranspeptidase (gamma GT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and N-acetyl-beta-D-glucosaminidase (NAG) in 24-h urine were increased similarly, but urinary excretion of glucose, proteins and beta2-microglobulin (beta2-m) and serum urea and creatinine levels were increased. Histopathological and histochemical examinations of kidney sections of CTFE- and DCDFE-exposed rats revealed cellular necrosis and tubular lesions 24 h after exposure. Beta-naphthoflavone-pretreated rats were afforded some protection against the nephrotoxicity of CTFE and DCDFE. Phenobarbital did not modify DCDFE nephrotoxicity but afforded some protection against CTFE nephrotoxicity. In conclusion, CTFE and DCDFE are strong nephrotoxins. Cytochrome P450 1A1 is implicated in CTFE and DCDFE metabolism and one or several cytochromes induced by phenobarbital are implicated in CTFE metabolism. The P450 cytochromes involved in CTFE and DCDFE metabolism probably constitute detoxication metabolic pathways. The nephrotoxicity of CTFE and DCDFE is therefore subordinated to the cytochrome P450 activity involved in their metabolism.
在雄性大鼠中研究了细胞色素P450活性在三氟氯乙烯（CTFE）和1,1 - 二氯 - 2,2 - 二氟乙烯（DCDFE）肾毒性中的作用。β - 萘黄酮和苯巴比妥分别诱导肝细胞色素P450 1A1和主要是P450 2B1/2。通过研究尿液生化参数、肾脏组织化学和组织病理学改变来评估肾毒性。分别在暴露于200 ppm和100 ppm的CTFE和DCDFE 4小时后，二者均在大鼠中诱导了严重的肾毒性。与对照组相比，24小时尿液中γ - 谷氨酰转肽酶（γGT）、天冬氨酸转氨酶（AST）、碱性磷酸酶（ALP）和N - 乙酰 - β - D - 氨基葡萄糖苷酶（NAG）的活性水平同样升高，但葡萄糖、蛋白质和β2 - 微球蛋白（β2 - m）的尿排泄量以及血清尿素和肌酐水平升高。对暴露于CTFE和DCDFE的大鼠肾脏切片进行组织病理学和组织化学检查发现，暴露24小时后出现细胞坏死和肾小管病变。经β - 萘黄酮预处理的大鼠对CTFE和DCDFE的肾毒性有一定的保护作用。苯巴比妥未改变DCDFE的肾毒性，但对CTFE肾毒性有一定的保护作用。总之，CTFE和DCDFE是强肾毒素。细胞色素P450 1A1参与CTFE和DCDFE的代谢，苯巴比妥诱导的一种或几种细胞色素参与CTFE的代谢。参与CTFE和DCDFE代谢的P450细胞色素可能构成解毒代谢途径。因此，CTFE和DCDFE的肾毒性从属于参与其代谢的细胞色素P450活性。
