Received for publication July 31, 2006.
Revised September 8, 2006.
Accepted for publication September 13, 2006.

Metabolic Aromatization of N-Alkyl-1,2,3,4-Tetrahydroquinoline Substructures to Quinolinium by Human Liver Microsomes and Horseradish Peroxidase

Abstract

Metabolic aromatization of xenobiotics is an unusual reaction with some documented examples. For instance, the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the neurotoxic pyridinium ion metabolite 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO) B in the brain has been of interest to a number of investigators. It has also been reported that, while the aromatization of N-methyl-tetrahydroisoquinoline occurs with MAO B, the metabolism does not proceed for its isomer, N-methyl-tetrahydroquinoline, by the same enzyme. The aromatization of an N-alkyl-tetrahydroquinoline substructure was identified during in vitro metabolite profiling of compound A - designed as a potent renin inhibitor for the treatment of hypertension. The N-alkylquinolinium metabolite of compound A was identified by LC-MS/MS of human liver microsomal incubates and proton NMR of the isolated metabolite. Further in vitro metabolism studies with a commercially available chemical (compound B), containing the same substructure, also generated an N-alkylquinolinium metabolite. In vitro cytochrome P450 (CYP) reaction phenotyping of compound A revealed that the metabolism was catalyzed exclusively by CYP3A4. Although compound B was a substrate for several CYP isoforms, its quinolinium metabolite was also generated predominantly by CYP3A4. Neither compound A nor B was a substrate of MAOs. The quinolinium metabolites were readily produced by horseradish peroxidase, suggesting that aromatization of the N-alkyltetrahydroquinoline could occur via a mechanism involving single electron transfer from nitrogen. Although dihydro intermediates from the tetrahydroquinoline substrates were not observed in the formation of quinolinium metabolites, cyanide trapping results indicated the occurrence of iminium intermediates.

Key words: cytochrome P450 catalyzed oxidations, human CYP enzymes, liver microsomes, metabolite identification, P450 mechanism

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