Aldo-Keto Reductases and the Metabolic Activation of Polycyclic

Chapter 6

Aldo-Keto Reductases and the Metabolic Activation of Polycyclic Aromatic Hydrocarbons 1

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Downloaded by PENNSYLVANIA STATE UNIV on July 17, 2012 | http://pubs.acs.org Publication Date: October 13, 2003 | doi: 10.1021/bk-2003-0865.ch006

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Trevor M . Penning , Nisha T. Palackal , Seon-Hwa Lee , Ian Blair , Deshan Yu , Jesse A. Berlin , Jeffrey M . Field , and Ronald G. Harvey 3

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Departments of Pharmacology and Biochemistry and Biophysics, and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA 19104 The Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637 1

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Polycyclic aromatic hydrocarbons (PAH) are suspect human lung carcinogens that are metabolically activated. Five human aldo-keto reductases [AKR1A1 (aldehyde reductase) and AKR1C1-AKR1C4] are implicated in this process since they oxidize PAH-trans-dihydrodiol proximate carcinogens to yield reactive and redox-active PAH-ortho-quinones. These ortho— quinones enter into futile redox-cycles to amplify reactive oxygen species (ROS) and cause DNA-lesions. AKR1C1 is highly overexpressed in non-small cell lung carcinoma patients (1) and in the human lung adenocarcinoma cell line A-549. AKR1C activity in these cells is sufficient to convert dimethylbenz[α]anthracene (DMBA)-3,4-diol to DMBA-3,4dione. We show that A K R derived PAH ortho-quinones produce sufficient ROS to mutate the major lung tumor suppressor gene (p53) in vitro. These mutations eliminate the transcriptional competency of p53 in a yeast-reporter system and this change-in-function results from G to T transversions (p 200 8-oxo-dGu/10 dG (26,27). If unrepaired, 8-oxo-dGuo will mispair with adenine, providing an additional straightforward route to a G to T transversion. Fourth, ROS production can lead to hydroxyl radical attack of deoxyribose leading to DNA strand scission and the formation of base propenals which hydrolyze to yield malondialdehyde, which is highly mutagenic (28). DNAstrand scission mediated by PAH o-quinones has been observed under redoxcycling conditions using poly-dC.dG,