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

Chem Res Toxicol. 2011 Dec 19;24(12):2153-66. doi: 10.1021/tx200294c. Epub 2011 Sep 29.


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.

Publication types

  • Research Support, N.I.H., Extramural

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


  • 4-hydroxyequilenin-o-quinone
  • Benzopyrenes
  • Polycyclic Aromatic Hydrocarbons
  • Quinones
  • Reactive Oxygen Species
  • Recombinant Proteins
  • benzo(a)pyrene-7,8-dione
  • Alcohol Oxidoreductases
  • Aldo-Keto Reductases
  • Aldehyde Reductase
  • NAD(P)H Dehydrogenase (Quinone)
  • Equilenin