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Carcinogenesis Advance Access published online on January 16, 2004
Carcinogenesis, doi:10.1093/carcin/bgh078
© 2004 by Oxford University Press
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© 2004 Oxford University Press

CARCINOGENESIS

Benzo[a]pyrene phenols are more potent inducers of CYPlAl, CYP1B1 and COX-2 than benzo[a]pyrene glucuronides in cell lines derived from the human aerodigestive tract

Taghreed Almahmeed 1, Jay O. Boyle 1, Erik G. Cohen 1, John F. Carew 2, Baoheng Du 3, Nasser K. Altorki 4, Levy Kopelovich 5, Jia-Long Fang 6, Philip Lazarus 6, Kotha Subbaramaiah 3, and Andrew J. Dannenberg 3*

1 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10021
2 Department of Otorhinolaryngology, Weill Medical College of Cornell University and Strang Cancer Prevention Center, New York, NY 10021
3 Department of Medicine, Weill Medical College of Cornell University and Strang Cancer Prevention Center, New York, NY 10021
4 Departments of Cardiothoracic Surgery, Weill Medical College of Cornell University and Strang Cancer Prevention Center, New York, NY 10021
5 CADRG, DCP, National Cancer Institute, Bethesda, MD 20892
6 Divisions of Cancer Control and Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612

* Corresponding author. E-mail: ajdannen{at}med.cornell.edu.

Received 9 May 2003 ; revised 7 December 2003 ; accepted 6 January 2004

Abstract

Several UDP-glucuronosyltransferases (UGTs) including UGT1A7 and UGT1A10 detoxify metabolites of the polycyclic aromatic hydrocarbon, benzo[a]pyrene (B[a]P). Recently, genetic variants of both UGT1A7 and UGT1A10 were linked to increased risk of head and neck cancer. To elucidate the mechanisms that account for this increased risk, we investigated whether B[a]P, and three of its hydroxylated metabolites (3-, 7- and 9-OH-B[a]P) induced three aryl hydrocarbon responsive genes (CYP1AI, CYP1B1, COX-2) that have been linked to mutagenesis and carcinogenesis. In premalignant and malignant cell lines from the aerodigestive tract, B[a]P and its hydroxylated metabolites induced CYP1A1 mRNA, protein and xenobiotic responsive element (XRE)-luciferase activity. In addition, marked induction of CYP1B1 was detected. B[a]P and its hydroxylated metabolites also induced COX-2 mRNA, protein and prostaglandin biosynthesis. Treatment with the corresponding B[a]P glucuronides caused less induction of CYP1A1, CYP1B1 and COX-2. B[a]P phenols were also more potent inducers of XRE-luciferase activity than B[a]P glucuronides. These results indicate that metabolites of B[a]P that are predicted to accumulate in individuals with low-activity UGT variants induce the expression of genes (CYP1A1, CYP1B1, COX-2) that have been implicated in carcinogen activation and carcinogenesis.


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