Debelle Frédéric, Nortier Joëlle, Arlt Volker M, De Prez Eric, Vienne Anne, Salmon Isabelle, Phillips David H, Deschodt-Lanckman Monique, Vanherweghem Jean-Louis
Laboratoire de Recherche sur le Métabolisme des Peptides (L.R.M.P.), Faculté de Médecine, Université Libre de Bruxelles, 1070, Brussels, Belgium.
Arch Toxicol. 2003 Apr;77(4):218-26. doi: 10.1007/s00204-003-0438-y. Epub 2003 Feb 20.
Chinese-herb nephropathy (CHN) is a progressive renal interstitial fibrosis initially reported after concomitant intake of an anorexigen, (dex)fenfluramine, and a Chinese herb ( Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acid (AA). We thus tested the possible enhancing effect of the active enantiomer dexfenfluramine (DXF) on AA nephrotoxicity in a rat model for CHN. Groups of 12 salt-depleted male Wistar rats received daily subcutaneous injections of 7 mg/kg body weight DXF (DXF group), 7 mg/kg body weight AA (AA group), a combination of the same doses of AA and DXF (AA+DXF group), or vehicle (control group) for up to 35 days. Six animals per group were killed on day 10 and the remaining six on day 35. Renal function was evaluated by determining serum creatinine and urinary leucine aminopeptidase activity. Histological evaluation of kidney samples was performed and tubulointerstitial injuries were semiquantified. The DXF group did not differ from controls for any parameter. Similarly elevated serum creatinine levels, decreased leucine aminopeptidase enzymuria, and renal lesions were observed in the AA and the AA+DXF groups after both 10 and 35 days. The formation of specific AA-DNA adducts in liver and renal tissue samples was assessed by the (32)P-postlabelling method. Specific AA-DNA adduct levels were significantly increased in kidney tissues from AA+DXF rats compared with AA rats. These functional and histological data suggest that DXF does not enhance AA nephrotoxicity in a rat model for CHN. Further investigations are needed to clarify the mechanism by which DXF may enhance AA-DNA adduct formation.
中草药肾病（CHN）是一种进行性肾间质纤维化疾病，最初是在同时摄入一种食欲抑制剂（右旋）芬氟拉明和一种含有肾毒性及致癌性马兜铃酸（AA）的中草药（广防己）后被报道的。因此，我们在CHN大鼠模型中测试了活性对映体右旋芬氟拉明（DXF）对AA肾毒性可能的增强作用。将12只低盐雄性Wistar大鼠分为几组，每天皮下注射7mg/kg体重的DXF（DXF组）、7mg/kg体重的AA（AA组）、相同剂量的AA与DXF的组合（AA+DXF组）或赋形剂（对照组），持续35天。每组6只动物在第10天处死，其余6只在第35天处死。通过测定血清肌酐和尿亮氨酸氨肽酶活性来评估肾功能。对肾脏样本进行组织学评估，并对肾小管间质损伤进行半定量分析。DXF组在任何参数上与对照组均无差异。在第10天和第35天后，AA组和AA+DXF组均观察到血清肌酐水平同样升高、亮氨酸氨肽酶尿减少以及肾脏病变。通过³²P后标记法评估肝脏和肾脏组织样本中特异性AA-DNA加合物的形成。与AA大鼠相比，AA+DXF大鼠肾脏组织中的特异性AA-DNA加合物水平显著升高。这些功能和组织学数据表明，在CHN大鼠模型中DXF不会增强AA的肾毒性。需要进一步研究以阐明DXF可能增强AA-DNA加合物形成的机制。
