Carcinogenesis Advance Access originally published online on October 19, 2006
Carcinogenesis 2007 28(3):732-737; doi:10.1093/carcin/bgl184
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Published by Oxford University Press 2006
Mouse lung CYP1A1 catalyzes the metabolic activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
1 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106 Bethesda, MD 20892, USA
2 Institute of Pharmacology, 1st Faculty of Medicine, Charles University 12800 Praha 2, Czech Republic
3 Biosciences Directorate, Lawrence Livermore National Laboratory Livermore, CA 94551, USA
4 Department of Environmental Health, University of Cincinnati Medical Center Cincinnati, OH 45267, USA
5 Department of Biology, Boston University Boston, MA 02215, USA
*To whom correspondence should be addressed. Tel: +1 301 496 9067; Fax: +1 301 496 8419; E-mail: fjgonz{at}helix.nih.gov
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) carcinogenesis is initiated by N2-hydroxylation, mediated by several cytochromes P450, including CYP1A1. However, the role of CYP1A1 in PhIP metabolic activation in vivo is unclear. In this study, Cyp1a1-null and wild-type (WT) mice were used to investigate the potential role of CYP1A1 in PhIP metabolic activation in vivo. PhIP N2-hydroxylation was actively catalyzed by lung homogenates of WT mice, at a rate of 14.9 ± 5.0 pmol/min/g tissue, but <1 pmol/min/g tissue in stomach and small intestine, and almost undetectable in mammary gland and colon. PhIP N2-hydroxylation catalyzed by lung homogenates of Cyp1a1-null mice was 
10-fold lower than that of WT mice. In contrast, PhIP N2-hydroxylation activity in lung homogenates of Cyp1a2-null versus WT mice was not decreased. Pretreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin increased lung Cyp1a1 mRNA and lung homogenate PhIP N2-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 in Cyp1a1-null mice, but not in Cyp1a2-null mice, were significantly lower (P = 0.0028) than in WT mice. These results reveal that mouse lung has basal and inducible PhIP N2-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).
Abbreviations: PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; N-OH-PhIP, N2-hydroxy-PhIP; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Received July 12, 2006; revised September 8, 2006; accepted September 20, 2006.
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