Specific induction of hepatic cytochrome P4501a-2 in C57BL/6 and DBA/2 mice treated with 2-amino-3-methylimidazo[4,5-f]quinoline (IQ).

Abstract

The food mutagen/carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is activated by cytochrome p4501a-2 via N-hydroxylation; various P450s may contribute to detoxification via ring hydroxylation. Alterations in P450 levels by IQ treatment might therefore influence its toxicity. To examine the role of Ah locus genotype on the biochemical effects of IQ, C57BL/6 (AhbAhb; p450Ia-1/2 inducible) and DBA/2 (AhdAhd, noninducible) mice of both sexes were given IQ at varying doses, with different vehicles and routes of administration. Livers taken after 24 hours were assessed for total cytochrome p450 and activities of ethoxyresorufin-O-deethylase (EROD, a p4501a-1 activity, inducible in Ahb mice), methoxyresorufin-O-demethylase (MROD, a p4501a-2 activity), and benzyloxyresorufin-O-dealkylase (BzROD, an activity of p4502b). There was little effect on total cytochrome p450, but all three enzyme activities were often induced, a maximum of 2.5-fold, in both sexes and in DBA/2 as well as C57BL/6 mice. However, Western immunoblot analysis with monoclonal antibodies demonstrated an increase only in p4501a-2 protein. p4501a-1 remained undetectable. A monoclonal antibody to p4502-b recognized one protein band in liver microsomes from males and two bands in female mice of both strains. Amounts of these proteins were not altered by IQ treatment. Thus, IQ specifically, if moderately, induces its activating enzyme, p4501a-2, in a process that was not clearly related to Ah responsiveness.