THE EFFECT OF AROMATIC FLUORINE SUBSTITUTION ON THE NEPHROTOXICITY AND METABOLISM OF N-(3,5-DICHLOROPHENYL)SUCCINIMIDE IN FISCHER-344 RATS

N-(3,5-Difluorophenyl)succinimide (DFPS) is a non-toxic analogue of th e nephrotoxic fungicide N-(3,5-dichorophenyl)succinimide (NDPS). Altho ugh NDPS must be metabolized to produce renal damage, the metabolic fa te of DFPS is unknown. These studies were therefore designed to examin e the nephrotoxic potential of putative DFPS metabolites and to determ ine if DFPS is metabolized differently from NDPS. Male Fischer-344 rat s were administered (1.0 mmol/kg, i.p. in corn oil) DFPS, N-(3,5-diflu orophenyl)succinamic acid (DFPSA), N-(3,5-difluorophenyl)-2-hydroxysuc cinimide (DFHS), N-(3,5-difluorophenyl)-2- or -3-hydroxysuccinamic aci ds (2- and 3-DFHSA, respectively), N-(3,5-difluoro-4-hydroxyphenyl) su ccinimide (DFHPS), N-(3,5-difluoro-4-hydroxyphenyl) succinamic acid (D FHPSA) or corn oil only (1.2 ml/kg). Although some of the compounds pr oduced changes in renal function and histology, these alterations were not indicative of irreversible kidney damage. DFPSA, 2-DFHSA, 3-DFHSA and DFHPSA were detected in the urine of rats 3 h after administratio n of 0.2 mmol/kg [C-14]DFPS. The same metabolites were produced by iso lated rat hepatocytes, but not by renal proximal tubule cells. Formati on of the oxidative metabolites in vitro was prevented by the cytochro me P450 inhibitor 1-aminobenzotriazole. It appears that DFPS undergoes hepatic biotransformation similar to NDPS and that some of its metabo lites have reversible effects on renal proximal tubules. Copyright (C) 1997 Elsevier Science Ireland Ltd.