Relationships between the regioselectivity of the hydroxylation of C4-substituted 2-fluoroaniline derivatives and their toxic endpoints.
The in vitro and in vivo metabolic profiles of a series of C4-substituted 2-fluoroanilines were determined and compared to their capacity to induce methemoglobinemia and nephrotoxicity in male Wistar rats. Qualitative and quantitative relationships between the biotransformation and the toxic endpoint of the halogenated anilines were defined. The rate of in vitro N-hydroxylation of the aniline derivatives correlated with the capacity of the compounds to induce methemoglobinemia (r = 0.96). In the experiments on the nephrotoxicity, attention was focused on the relative importance of the C4- and C6-hydroxylated metabolites of the C4-substituted 2-fluoroanilines. In vivo, the formation of 4-aminophenol metabolites was demonstrated to vary in the opposite order as the formation of the 6-aminophenol metabolites. 1H-NMR urinalysis and characterization of a set of conventional biochemical urinary parameters revealed the occurrence of nephrotoxicity upon exposure to the aniline derivatives and were most consistent with damage at the proximal tubular site. Comparison of the extent of nephrotoxicity to the extent of formation of the 4-aminophenol and/or 6-aminophenol metabolites, respectively, indicates a predominant role for the C4-hydroxylation route, not the C6-hydroxylation route, in the induction of nephrotoxic effects. Thus, a qualitative relationship is observed for the extent of C4-hydroxylation of the aniline derivatives and the extent of their in vivo nephrotoxicity. In addition, comparison of the extent of 4-aminophenol formation and nephrotoxicity of both 2-fluoroaniline and 2,4-difluoroaniline pointed at a possible role for a bioactivation pathway through oxidative dehalogenation, resulting in direct formation of a 1,4-benzoquinoneimine as the primary metabolite in the case of 2,4-difluoroaniline. Altogether, it is concluded that a decrease in C4-hydroxylation in the series of aniline derivatives results in a metabolic switch to C6- and N-hydroxylation and, consequently, a shift in the type of toxic endpoint observed, i.e., from nephrotoxicity to methemoglobinemia.
Cnubben
N H
NH
Department of Biochemistry, Agricultural University, Dreijenlaan, Wageningen, The Netherlands.
van den Berg
C L
CL
Rietjens
I M
IM
D000814:Aniline Compounds / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D006900:Hydroxylation; D007668:Kidney / Q000187:drug effects; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D000814:Aniline Compounds; C066212:2-fluoroaniline