Fluoro-substituted N-nitrosamines. 8. N-Nitrosodibutylamine and ω-fluorinated analogues: in vivo metabolism in relation to the induction of urinary bladder cancer in the rat

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Abstract
Urinary excretion of N-nitrosodibutylamine (NDBA) and of two ω-fluorinated analogues [N-nitroso-4, 4, 4-trifluorobutyl-butylamine, NDBA-F3; N-nitroso-bis(4, 4, 4-trifluorobutyl)-amine, NDBA-F6] was studied in male Sprague-Dawley (SD) rats. After oral application of equimolar doses (0.44 and 1.32 mmol/kg body wt.) urines were collected (48 h) and analyzed for parent compounds, and for nitrosamine metabolites by gas chromatography/Thermal Energy Analyzer (GC/TEA) and gas chromatography/mass spectrometry (GC/MS). After administration of NDBA the known major metabolites N-nitroso-3- hydroxybutylbutylamine (3-OH-NDBA) and N-nitroso-3-carboxypropylbutylamine (BCPN) were excreted in urine. After application of the ω-fluorinated analogue NDBA-F6, however, urinary and biliary nitrosamine metabolites were detected only in trace amounts. This finding demonstrates a strong inhibitory effect of fluorine substitution on oxidations at ω, (ω-1) and β-positions. Confirmation of this inhibitory effect of ω-fluorine substitution is given from the excretion profiles of NDBA-F3 which shows metabolic oxidations only at the nonfluorinated chain: N-nitroso-3-hydroxybutyl-4, 4, 4,-trifluorobutylamine (3-OH-NDBA-F3) and N-nitroso-3-carboxypropyl-4, 4, 4-trifluoro-butylamine (BCPN-F3) were excreted as main metabolites. Our results on metabolism together with the available data on carcinogenicity of the compounds in the rat strongly support the hypothesis that ω-oxidation of one butyl-chain is a prerequisite for the induction of urinary bladder tumors with NDBA. For the induction of liver tumors, α-C-hydroxylation appears to be the crucial event.