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The Ubiquitous Aldehyde Reductase (AKR1A1) Oxidizes Proximate Carcinogen trans-Dihydrodiols to o-Quinones:  Potential Role in Polycyclic Aromatic Hydrocarbon Activation

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Departments of Biochemistry and Biophysics and Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and The Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637
Cite this: Biochemistry 2001, 40, 36, 10901–10910
Publication Date (Web):August 14, 2001
Copyright © 2001 American Chemical Society

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    Polycyclic aromatic hydrocarbons (PAHs) are metabolized to trans-dihydrodiol proximate carcinogens by human epoxide hydrolase (EH) and CYP1A1. Human dihydrodiol dehydrogenase isoforms (AKR1C1−AKR1C4), members of the aldo−keto reductase (AKR) superfamily, activate trans-dihydrodiols by converting them to reactive and redox-active o-quinones. We now show that the constitutively and widely expressed human AKR, aldehyde reductase (AKR1A1), will oxidize potent proximate carcinogen trans-dihydrodiols to their corresponding o-quinones. cDNA encoding AKR1A1 was isolated from HepG2 cells, overexpressed in Escherichia coli, purified to homogeneity, and characterized. AKR1A1 oxidized the potent proximate carcinogen (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene with a higher utilization ratio (Vmax/Km) than any other human AKR. AKR1A1 also displayed a high Vmax/Km for the oxidation of 5-methylchrysene-7,8-diol, benz[a]anthracene-3,4-diol, 7-methylbenz[a]anthracene-3,4-diol, and 7,12-dimethylbenz[a]anthracene-3,4-diol. AKR1A1 displayed rigid regioselectivity by preferentially oxidizing non-K-region trans-dihydrodiols. The enzyme was stereoselective and oxidized 50% of each racemic PAH trans-dihydrodiol tested. The absolute stereochemistries of the reactions were assigned by circular dichroism spectrometry. AKR1A1 preferentially oxidized the metabolically relevant (−)-benzo[a]pyrene-7(R),8(R)-dihydrodiol. AKR1A1 also preferred (−)-benz[a]anthracene-3(R),4(R)-dihydrodiol, (+)-7-methylbenz[a]anthracene-3(S),4(S)-dihydrodiol, and (−)-7,12-dimethylbenz[a]anthracene-3(R),4(R)-dihydrodiol. The product of the AKR1A1-catalyzed oxidation of (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene was trapped with 2-mercaptoethanol and characterized as a thioether conjugate of benzo[a]pyrene-7,8-dione by LC/MS. Multiple human tissue expression array analysis showed coexpression of AKR1A1, CYP1A1, and EH, indicating that trans-dihydrodiol substrates are formed in the same tissues in which AKR1A1 is expressed. The ability of this general metabolic enzyme to divert trans-dihydrodiols to o-quinones suggests that this pathway of PAH activation may be widespread in human tissues.

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     This research was supported by NIH Grant CA39504 to T.M.P. N.T.P. received a Bristol Myers Squibb Young Investigator Award for a preliminary account of this work at the 90th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA, April 10−14, 1999.

     University of Pennsylvania School of Medicine.


     Current address:  Wyeth Ayerst Research, Genetics Institute, One Burtt Rd, Andover MA 01810.

     University of Chicago.


     To whom correspondence and requests for reprints should be addressed at the Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104-6084. Tel:  (215) 898-9445. Fax:  (215) 573-2236. E-mail:  [email protected].

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