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Abstract
1. N-Methyl-N-alkyl-p-chlorobenzamides (alkyl=Me, Et, nPr, nBu, PhCH2, isoPr and cylcoPr) underwent mono-N-dealkylation exclusively with phenobarbital-induced rat liver microsomes; with each compound both demethylation and dealkylation occurred.
2. The time-courses showed bilinear kinetics, but there was no evidence for general suicide-substrate activity with the cyclopropyl amide, and product ratios did not vary with time.
3. The demethylation/dealkylation ratio varied from 0.3 to 2.0 among the primary alkyl groups but was ca. 40 when the alkyl group was isoPr or cycloPr. Dealkylation of the benzyl substituent was 2–3 times more favourable than for any other primary alkyl group. Despite wide variations in the demethylation/dealkylation ratios, at near-saturating concentrations of substrates the rates of total oxidation (demethylation plus dealkylation) varied little across the entire series.
4. The results of this study are consistent with a kinetic mechanism involving significant commitment to catalysis, substituent-induced metabolic switching at the product-determining step, a non-catalytic step which is partly rate-limiting in turnover, and a chemical mechanism involving H-atom abstraction as opposed to electron abstraction.