Trapping of metabolically generated electrophilic species with cyanide ion: metabolism of methapyrilene

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Abstract
The popular antihistamine methapyrilene [N,N-dimethyl-N''-(2-pyridyl)-N''-(2-thienylmethyl)-1,2-ethanediamine] recently was shown to be a potent hepatocarcinogen. Metabolic studies with rabbit liver 100,000 g microsomal preparations resulted in the partial characterization of the in vitro metabolic profile of methapyrilene. Evidence for the formation of the N-oxide and the 3 possible carbinolamines resulting from the NADPH-dependent oxidation of the (dimethylamino)ethyl side chain N and C atoms of methapyrilene is presented. Attempts to trap iminium ion intermediates with electrophilic alkylating potential by coincubating methapyrilene with sodium cyanide have led to the isolation of N-(cyanomethyl)normethapyrilene. The possibility of characterizing the iminium ion intermediate that would result from the oxidative deamination of the dimethylamino moiety was precluded by the chemical instability of the corresponding .alpha.-cyano amine, which undergoes a spontaneous retro-Michael reaction and hydrolysis to the corresponding amide. The results are discussed in terms of the metabolic activation of methapyrilene to potential alkylating species.