Fluoro-substituted N-nitrosamines. 7. Non-genotoxic N-nitroso-bis(2,2,2-trifluoroethyl)amine and N-nitroso-bis(2,2,3,3,4,4,4-heptafluorobutyl)amine: binding to cytochrome P-450, acidity of alpha-protons and pharmacokinetic investigations.
The biologically inactive fluorinated nitrosamines N-nitroso-bis(2,2,2-trifluoroethyl)amine (NDEA-F6) and N-nitroso-bis-(2,2,3,3,4,4,4-heptafluorobutyl)amine (NDBA-F14) were investigated for binding affinity to cytochrome P-450 and for ease of alkali-induced proton abstraction at the alpha-C atom, in comparison with biologically active analogues (N-nitroso-diethylamine, NDEA; N-nitroso-2,2,2-trifluoroethylethylamine, NDEA-F3; N-nitrosodibutylamine, NDBA; N-nitroso-4,4,4-trifluorobutylbutylamine, NDBA-F3; N-nitroso-bis(4,4,4-trifluorobutyl)amine, NDBA-F6). Binding to cytochrome P-450 was studied by spectroscopic measurements (optical difference spectra with microsomal fractions); base-catalyzed deuterium exchange of alpha-hydrogen atoms was followed by 1H n.m.r. measurements. Additionally the excretion of NDEA-F6 and NDBA-F14 in expired air, urine and faeces was studied after oral application to the rat. Compared with the biologically active nitrosamine analogues, NDEA-F6 and NDBA-F14 showed higher binding affinity to cytochrome P-450. N.m.r. spectroscopy showed that NDEA-F6, NDBA-F14 and NDEA-F3 (at the fluorinated alkyl chain) were rapidly deprotonated at the alpha-C-position in sodium perdeutero methylate, in contrast to the other analogues tested. In vivo, NDEA-F6 and NDBA-F14 were excreted unchanged, mainly via exhalation. The biological inactivity of NDEA-F6 and NDBA-F14, together with the observed blocking of their microsomal activation can be reconciled with the experimental findings which indicate that homolytic alpha-C-H bond fission is more likely to be involved in alpha-C-hydroxylation of dialkylnitrosamines, than alpha-proton abstraction.
Janzowski
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C
Gottfried
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Preussmann
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Eisenbrand
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D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005243:Feces / Q000032:analysis; D007700:Kinetics; D008297:Male; D009602:Nitrosamines / Q000378:metabolism*; D011522:Protons; D051381:Rats; D011919:Rats, Inbred Strains; D013057:Spectrum Analysis; D005466:Fluorocarbons
D003577:Cytochrome P-450 Enzyme System; D009602:Nitrosamines; D011522:Protons; C044516:N-nitrosobis(2,2,2-trifluoroethyl)amine; C044517:N-nitrosobis(2,2,3,3,4,4,4-heptafluorobutyl)amine; D005466:Fluorocarbons