Regioselective differences in C8- and N-oxidation of 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline by human and rat liver microsomes and cytochromes P450 1A2

The metabolism of the mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated with human and rat liver microsomes, recombinant human cytochrome P450 1A2 (P450 1A2) expressed in Escherichia coli cells, and rat P450 1A2. Human liver microsomes and human P450 1A2 catalyzed the oxidation of the exocyclic amine group of MeIQx to form the genotoxic product 2-(hydroxyamino)-3,8-dimethylimidazo[4,5-f]quinoxaline (HONH-MeIQx). Human P450 1A2 also catalyzed the oxidation of C8-methyl group of MeIQx to form 2-amino-(8-hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH2OH-IQx), 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carbaldehyde (IQx-8-CHO), and 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic acid (IQx-8-COOH). Thus, chemically stable C8-oxidation products of MeIQx may be useful biomarkers of P450 1A2 activity in humans. Rat liver microsomes were 10−15-fold less active than the human counterpart at both N-oxidation and C8-oxidation of MeIQx when expressed as nanomoles of product...