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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Oxidation of PAH trans-dihydrodiols by human aldo-keto reductase AKR1B10.

Authors: Quinn, Amy M; Harvey, Ronald G; Penning, Trevor M

Published In Chem Res Toxicol, (2008 Nov)

Abstract: AKR1B10 has been identified as a potential biomarker for human nonsmall cell lung carcinoma and as a tobacco exposure and response gene. AKR1B10 functions as an efficient retinal reductase in vitro and may regulate retinoic acid homeostasis. However, the possibility that this enzyme is able to activate polycyclic aromatic hydrocarbon (PAH) trans-dihydrodiols to form reactive and redox-active o-quinones has not been investigated to date. AKR1B10 was found to oxidize a wide range of PAH trans-dihydrodiol substrates in vitro to yield PAH o-quinones. Reactions of AKR1B10 proceeded with improper stereochemistry, since it was specific for the minor (+)-benzo[a]pyrene-7S,8S-dihydrodiol diastereomer formed in vivo. However, AKR1B10 displayed reasonable activity in the oxidation of both the (-)-R,R and (+)-S,S stereoisomers of benzo[g]chrysene-11,12-dihydrodiol and oxidized the potentially relevant, albeit minor, (+)-benz[a]anthracene-3S,4S-dihydrodiol metabolite. We find that AKR1B10 is therefore likely to play a contributing role in the activation of PAH trans-dihydrodiols in human lung. AKR1B10 retinal reductase activity was confirmed in vitro and found to be 5- to 150-fold greater than the oxidation of PAH trans-dihydrodiols examined. AKR1B10 was highly expressed at the mRNA and protein levels in human lung adenocarcinoma A549 cells, and robust retinal reductase activity was measured in lysates of these cells. The much greater catalytic efficiency of retinal reduction compared to PAH trans-dihydrodiol metabolism suggests AKR1B10 may play a greater role in lung carcinogenesis through dysregulation of retinoic acid homeostasis than through oxidation of PAH trans-dihydrodiols.

PubMed ID: 18788756 Exiting the NIEHS site

MeSH Terms: Aldehyde Reductase/analysis; Aldehyde Reductase/physiology*; Carcinogens/metabolism*; Carcinoma, Non-Small-Cell Lung/enzymology; Cells, Cultured; Circular Dichroism; Dihydroxydihydrobenzopyrenes/metabolism; Humans; Lung Neoplasms/enzymology; Lung Neoplasms/etiology; Oxidation-Reduction; Polycyclic Aromatic Hydrocarbons/metabolism*; Retinaldehyde/metabolism

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