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2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) carcinogenesis is initiated byN  2-hydroxylation, mediated by several cytochromes P450, including CYP1A1. However, the role of CYP1A1 in PhIP metabolic activationin vivois unclear. In this study,Cyp1a1-null and wild-type (WT) mice were used to investigate the potential role of CYP1A1 in PhIP metabolic activationin vivo. PhIPN  2-hydroxylation was actively catalyzed by lung homogenates of WT mice, at a rate of 14.9 ± 5.0 pmol/min/g tissue, but &lt;1 pmol/min/g tissue in stomach and small intestine, and almost undetectable in mammary gland and colon. PhIPN  2-hydroxylation catalyzed by lung homogenates ofCyp1a1-null mice was ∼10-fold lower than that of WT mice. In contrast, PhIPN  2-hydroxylation activity in lung homogenates ofCyp1a2-null versus WT mice was not decreased. Pretreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin increased lungCyp1a1mRNA and lung homogenate PhIPN  2-hydroxylase activity ∼50-fold in WT mice, where the activity was substantially inhibited (70%) by monoclonal antibodies against CYP1A1.In vivo, 30 min after oral treatment with PhIP, PhIP levels in lung were similar to those in liver. After a single dose of 0.1 mg/kg [14C]PhIP, lung PhIP-DNA adduct levels inCyp1a1-null mice, but not inCyp1a2-null mice, were significantly lower (P= 0.0028) than in WT mice. These results reveal that mouse lung has basal and inducible PhIPN  2-hydroxylase activity predominantly catalyzed by CYP1A1. Because of the high inducibility of human CYP1A1, especially in cigarette smokers, the role of lung CYP1A1 in PhIP carcinogenesis should be considered. (237 words).

Mouse lung CYP1A1 catalyzes the metabolic activation of 2-amino-1-methyl-6-phenylimidazo[4,5- b ]pyridine (PhIP)