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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Specificity of human aldo-keto reductases, NAD(P)H:quinone oxidoreductase, and carbonyl reductases to redox-cycle polycyclic aromatic hydrocarbon diones and 4-hydroxyequilenin-o-quinone.

Authors: Shultz, Carol A; Quinn, Amy M; Park, Jong-Heum; Harvey, Ronald G; Bolton, Judy L; Maser, Edmund; Penning, Trevor M

Published In Chem Res Toxicol, (2011 Dec 19)

Abstract: Polycyclic aromatic hydrocarbons (PAHs) are suspect human lung carcinogens and can be metabolically activated to remote quinones, for example, benzo[a]pyrene-1,6-dione (B[a]P-1,6-dione) and B[a]P-3,6-dione by the action of either P450 monooxygenase or peroxidases, and to non-K region o-quinones, for example B[a]P-7,8-dione, by the action of aldo keto reductases (AKRs). B[a]P-7,8-dione also structurally resembles 4-hydroxyequilenin o-quinone. These three classes of quinones can redox cycle, generate reactive oxygen species (ROS), and produce the mutagenic lesion 8-oxo-dGuo and may contribute to PAH- and estrogen-induced carcinogenesis. We compared the ability of a complete panel of human recombinant AKRs to catalyze the reduction of PAH o-quinones in the phenanthrene, chrysene, pyrene, and anthracene series. The specific activities for NADPH-dependent quinone reduction were often 100-1000 times greater than the ability of the same AKR isoform to oxidize the cognate PAH-trans-dihydrodiol. However, the AKR with the highest quinone reductase activity for a particular PAH o-quinone was not always identical to the AKR isoform with the highest dihydrodiol dehydrogenase activity for the respective PAH-trans-dihydrodiol. Discrete AKRs also catalyzed the reduction of B[a]P-1,6-dione, B[a]P-3,6-dione, and 4-hydroxyequilenin o-quinone. Concurrent measurements of oxygen consumption, superoxide anion, and hydrogen peroxide formation established that ROS were produced as a result of the redox cycling. When compared with human recombinant NAD(P)H:quinone oxidoreductase (NQO1) and carbonyl reductases (CBR1 and CBR3), NQO1 was a superior catalyst of these reactions followed by AKRs and last CBR1 and CBR3. In A549 cells, two-electron reduction of PAH o-quinones causes intracellular ROS formation. ROS formation was unaffected by the addition of dicumarol, suggesting that NQO1 is not responsible for the two-electron reduction observed and does not offer protection against ROS formation from PAH o-quinones.

PubMed ID: 21910479 Exiting the NIEHS site

MeSH Terms: Alcohol Oxidoreductases/genetics; Alcohol Oxidoreductases/metabolism*; Aldehyde Reductase; Aldo-Keto Reductases; Benzopyrenes/chemistry; Benzopyrenes/toxicity; Biocatalysis; Cell Line, Tumor; Equilenin/analogs & derivatives*; Equilenin/chemistry; Equilenin/metabolism; Equilenin/toxicity; Humans; Isomerism; NAD(P)H Dehydrogenase (Quinone)/genetics; NAD(P)H Dehydrogenase (Quinone)/metabolism*; Oxidation-Reduction/drug effects; Polycyclic Aromatic Hydrocarbons/chemistry; Polycyclic Aromatic Hydrocarbons/metabolism*; Polycyclic Aromatic Hydrocarbons/toxicity; Quinones/chemistry; Quinones/metabolism*; Quinones/toxicity; Reactive Oxygen Species/metabolism; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Substrate Specificity

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