Mechanism of the microsomal demethylation of 1-aryl-3,3-dimethyltriazenes.
The metabolism of 1-aryl-3,3-dimethyltriazenes by phenobarbital-induced rat liver microsomes results in the formation of 1-aryl-3-methyltriazenes and formaldehyde. Intermolecular kinetic deuterium isotope effects for the reaction are found to be 1.0 (+/- 0.03) in both Vmax and Vmax/Km, respectively. The intramolecular kinetic deuterium isotope effects in Vmax and Vmax/Km are found to be 4.8 (+/- 0.05). There is no correlation of Vmax or Vmax/Km with calculated ionization potentials of the triazenes. For 3-ethyl-3-methyltriazene comparison of values of Vmax and Vmax/Km for ethyl vs methyl loss give rise to values of 3.68 in Vmax and 2.02 in Vmax/Km. Thus, loss of an ethyl group is favoured. The results are discussed in terms of a mechanism in which the triazene undergoes direct hydrogen atom abstraction to form a carbon centred radical. This radical subsequently forms a hydroxymethyltriazene that collapses to formaldehyde and a monomethyltriazene.
Iley
J
J
Chemistry Department, Open University, Milton Keynes, U.K.
Ruecroft
G
G
D000818:Animals; D003640:Dealkylation; D005557:Formaldehyde / Q000737:chemistry; D005609:Free Radicals; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013268:Stimulation, Chemical; D014227:Triazines / Q000737:chemistry / Q000378:metabolism*
D005609:Free Radicals; D011725:Pyridines; D014227:Triazines; D005557:Formaldehyde; D010634:Phenobarbital