Carcinogenesis Advance Access first published online on October 19, 2006
This version published online on October 25, 2006
Carcinogenesis, doi:10.1093/carcin/bgl184
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1 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
* To whom correspondence should be addressed. 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
Received July 12, 2006
Revised September 8, 2006
Accepted September 20, 2006
CARCINOGENESIS
Mouse lung CYP1A1 catalyzes the metabolic activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
Xiaochao Ma 1, Jeffrey R. Idle 2, Michael A. Malfatti 3, Kristopher W. Krausz 1, Daniel W. Nebert 4, Chong-Sheng Chen 5, James S. Felton 3, David J. Waxman 5, and Frank J. Gonzalez 1 *
2 Institute of Pharmacology, 1st Faculty of Medicine, Charles University, 128 00 Praha 2, Czech Republic
3 Biosciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94551
4 Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267
5 Department of Biology, Boston University, Boston, MA 02215
Frank J. Gonzalez, E-mail: fjgonz{at}helix.nih.gov
Abstract 
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 (TCDD) 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.
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