Human akrs display quinone reductase activity with pah o-quinones

TOXI 73

Carol A. Shultz, cashultz@mail.med.upenn.edu, Department of Biochemistry and Biophysics, University of Pennsylvania, 3620 Hamilton Walk, 135 John Morgan Building, Philadelphia, PA 19104, Amy M. Quinn, aquinn@mail.med.upenn.edu, Department of Pharmacology, Center for Cancer Pharmacology, and Center of Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, PA 19104, and Trevor M. Penning, penning@pharm.med.upenn.edu, Center for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, PA 19104.
Human aldo-keto reductases (AKRs) metabolically activate pro-carcinogenic polycyclic aromatic hydrocarbon trans-dihydrodiols to highly reactive o-quinones. However, the quinone reductase (QR) activity of human AKRs, where o-quinones are reduced back to the catechol, has not been previously studied. QR activity could either detoxify o-quinones or increase futile redox cycling, amplifying reactive oxygen species (ROS). In this study, we now show that recombinant human AKR1C1, 1C2, 1C2, 1C3, 1C4, 1B1, and 1B10 have substantial QR activity. The enzymatic reduction of o-quinones completely oxidized NADPH, implying that all the catechol formed auto-oxidized back to the o-quinone. In each case, enzymatic o-quinone redox cycling greatly exceeded the rate of PAH trans-dihydrodiol oxidation catalyzed by the respective enzyme. The exception was AKR7A2, which had the highest QR activity, but did not oxidize trans-dihydrodiols. The QR activity of AKRs may increase PAH-mediated oxidative stress. (Supported by PO1 CA92354, RO1 CA39504, P30-ES013508 awarded to T. M. P.)
 

Poster Session and Awards
6:00 PM-10:00 PM, Tuesday, August 21, 2007 BCEC -- 204 A/B, Poster

Division of Chemical Toxicology

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