Effects of dexfenfluramine on aristolochic acid nephrotoxicity in a rat model for Chinese-herb nephropathy

被引:0
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作者
Frédéric Debelle
Joëlle Nortier
Volker M. Arlt
Eric De Prez
Anne Vienne
Isabelle Salmon
David H. Phillips
Monique Deschodt-Lanckman
Jean-Louis Vanherweghem
机构
[1] Université Libre de Bruxelles,Laboratoire de Recherche sur le Métabolisme des Peptides (L.R.M.P.), Faculté de Médecine
[2] Université Libre de Bruxelles,Department of Nephrology, Hôpital Erasme
[3] Université Libre de Bruxelles,Department of Pathology, Hôpital Erasme
[4] Institute of Cancer Research,Section of Molecular Carcinogenesis
来源
Archives of Toxicology | 2003年 / 77卷
关键词
Aristolochic acid; Dexfenfluramine; Chinese-herb nephropathy; Renal fibrosis; DNA adducts;
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摘要
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 32P-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.
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页码:218 / 226
页数:8
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