Aldo-keto reductases (AKR) and the metabolic activation of trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-dihydrodiol) in human lung adenocarcinoma (A549) cells

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Trevor Martin Penning, penning@pharm.med.upenn.edu, Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, Jong-Heum Park, Pharmacology, University of Pennsylvania School of Medicine, 132 John Morgan Bldg, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, Kirk A. Tacka, Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, 135 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, Amy M. Quinn, aquinn@mail.med.upenn.edu, Department of Pharmacology, University of Pennsylvania School of Medicine, 135 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, Dipti Mangal, dipti@mail.med.upenn.edu, Department of Pharmacology, Center for Cancer Pharmacology, University of Pennsylvania, 421, Curie Blvd, 846, Biomedical Research Building, Philadelphia, PA 19104, and Ian A Blair, ian@spirit.gcrc.upenn.edu, Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, 854 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104.
One pathway of polycyclic aromatic hydrocarbon (PAH) activation involves the AKR catalyzed oxidation of PAH trans-dihydrodiols to yield reactive and redox-active o-quinones. Evidence for this pathway is presented in A549 cells which constitutively express AKR1A1, and AKR1C1-AKR1C3. Cells treated with PAH trans-dihydrodiols form the corresponding o-quinones as measured by LC/MS. Upon treatment with B[a]P-7,8-dihydrodiol (AKR substrate) and B[a]P-7,8-dione (AKR product), cells produce reactive-oxygen species (measured by increases in in cell fluorescence and FACS analysis using dichlorofluorescein diacetate), undergo changes in redox state (measured by increases in GSSG : GSH and NADP+ : NADPH), undergo increased single-strand-DNA breaks (measured by Comet assay coupled to the base-excision repair enzyme hOGG1), and produce 8-oxo-dGuo (measured by stable isotope dilution LC/MS). These effects were enhanced by a COMT inhibitor and were not seen with B[a]P-4,5-dihydrodiol or anti-B[a]PDE. These studies support a role for AKRs in PAH-lung carcinogenesis. Supported by P01CA092537, P30ES013508 and R01CA39504.
 

General Papers
1:00 PM-4:45 PM, Wednesday, August 22, 2007 BCEC -- 258C, Oral

Division of Chemical Toxicology

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007