Alkylamines are oxidized by a number of different types of enzymes, and the low oxidation potentials favor 1-electron transfer processes and aminium radicals. We studied the mechanism of N-dealkylation by hemoproteins using the prototypic substrate N,N-dimethylaniline (with isotopic substitution on the methyl groups), since there were considerable data available from kinetic deuterium isotope studies suggesting alternative mechanisms for different hemoproteins (Miwa, G.T., Walsh, J.S., Kedderis, G.L., and Hollenberg, P. F. (1983) J. Biol. Chem. 258, 14445-14449). Cytochrome P450 2B1 (P450), chloroperoxidase, and several biomimetic metalloporphyrin systems showed low kinetic hydrogen isotope effects (D(V/K)intra < or = 2.0, T(V/K) < or = 3.4), and hemoglobin, horseradish peroxidase, and prostaglandin H synthase yielded high isotope effects (D(V parallel K)intra > or = 3.5, T(V/K) > or = 8.1), in agreement with previous studies. Dinnocenzo and Banach (Dinnocenzo, J. P., and Banach, T. E. (1989) J. Am. Chem. Soc. 111, 8646-8653) have provided evidence that the pKa for an alpha-hydrogen of the N,N-dimethylaniline aminium radical is approximately 9 and also estimated that the pKa for the 4-hydrogen of a 1,4-dihydropyridine aminium radical is approximately 3.5. The oxidations of two model 1,4-dihydropyridines showed only low kinetic hydrogen isotope effects with all of the enzymes examined (D(V/K) < or = 2.3, T(V/K) < or = 2.8). Aminium radicals derived from aminopyrine and N,N-dimethylthioanisole accumulated only with those hemoprotein systems showing the high isotope effects with N,N-dimethylaniline. We conclude that specific base catalysis of alkyl hydrogen removal from aminium radicals by the (Fe.O)2+ complex is a feature of some hemoproteins, including P450s, and that the lack of such catalysis in other hemoproteins is the basis of their high kinetic hydrogen isotope effects.