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Expression and Characterization of Four Recombinant Human Dihydrodiol Dehydrogenase Isoforms:  Oxidation of trans-7,8-Dihydroxy-7,8-dihydrobenzo[a]pyrene to the Activated o-Quinone Metabolite Benzo[a]pyrene-7,8-dione,

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Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084, and The Ben May Institute, University of Chicago, Chicago, Illinois 60637
Cite this: Biochemistry 1998, 37, 19, 6781–6790
Publication Date (Web):April 22, 1998
https://doi.org/10.1021/bi972725u
Copyright © 1998 American Chemical Society

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    Abstract

    The bioactivation of polycyclic aromatic hydrocarbons (PAHs) to their ultimate carcinogenic forms proceeds via the formation of proximate carcinogen trans-dihydrodiols. Previous studies demonstrated that rat liver 3α-hydroxysteroid dehydrogenase/dihydrodiol dehydrogenase (3α-HSD/DD), a member of the aldo−keto reductase (AKR) superfamily, oxidizes PAH trans-dihydrodiols to redox-cycling o-quinones. Multiple closely related AKRs exist in human liver; however, it is unclear which, if any, participate in PAH activation by catalyzing the NADP+-dependent oxidation of PAH trans-dihydrodiols. In this study, cDNAs encoding four human DD isoforms were isolated from HepG2 cells using isoform-selective RT-PCR. The recombinant proteins were overexpressed in Escherichia coli, purified to homogeneity, and kinetically characterized. Calculation of KM and kcat values of each isoform for model substrates revealed that they possessed enzymatic activities assigned to native human liver DD1, DD2, DD4, and type 2 3α-HSD (DDX) proteins. The ability of human DDs to oxidize the potent proximate carcinogen (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-diol) was then examined. A reverse phase HPLC radiochemical assay demonstrated that all four isoforms oxidize (±)-BP-diol in the following rank order:  DD2 > DD1 > DD4 > DDX. Each DD consumed the entire racemic BP-diol mixture, indicating that both the minor (+)-S,S- and major (−)-R,R-stereoisomers formed in vivo are substrates. First-order decay plots showed that DD1 and DD2 displayed preferences for one of the stereoisomers, and circular dichroism spectroscopy indicated that this isomer was the (+)-7S,8S-enantiomer. The products of these reactions were trapped as either glycine or thiol ether conjugates of benzo[a]pyrene-7,8-dione (BPQ), indicating that the initial oxidation product was the reactive BPQ. Thus, human liver possesses multiple AKRs which contribute to PAH activation by catalyzing the NADP+-dependent oxidation of PAH trans-dihydrodiols to redox-active o-quinones.

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     This work was supported by NCI Grants CA39504 and CA55711 awarded to T.M.P., ACS Grant CN-22 and NCI Grant CA67937 awarded to R.G.H., and a Pharmaceutical Research and Manufacturers of America Foundation Advanced Predoctoral Fellowship awarded to M.E.B.

     A preliminary account of this work was presented at the eighty-eighth annual meeting of the American Association for Cancer Research, San Diego, CA, April 13−16, 1997.

    §

     University of Pennsylvania School of Medicine.

     University of Chicago.

    *

     Address for correspondence:  Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104-6084. Telephone:  (215) 898-9445. Fax:  (215) 573-2236. E-mail:  [email protected].

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    72. Yu-Min Shen, Andrea B. Troxel, Srilakshmi Vedantam, Trevor M. Penning, Jeffrey Field. Comparison of p53 Mutations Induced by PAH o -Quinones with Those Caused by anti -Benzo[ a ]pyrene Diol Epoxide in Vitro:  Role of Reactive Oxygen and Biological Selection. Chemical Research in Toxicology 2006, 19 (11) , 1441-1450. https://doi.org/10.1021/tx0601206
    73. Masatsugu Ueda, Yao-Ching Hung, Jin-Tang Chen, Shiow-Her Chiou, Hsuan-Hua Huang, Tze-Yi Lin, Yoshito Terai, Kuan-Chih Chow. Infection of human papillomavirus and overexpression of dihydrodiol dehydrogenase in uterine cervical cancer. Gynecologic Oncology 2006, 102 (2) , 173-181. https://doi.org/10.1016/j.ygyno.2005.12.009
    74. Qian Ruan, Hye‐Young H. Kim, Hao Jiang, Trevor M. Penning, Ronald G. Harvey, Ian A. Blair. Quantification of benzo[ a ]pyrene diol epoxide DNA‐adducts by stable isotope dilution liquid chromatography/tandem mass spectrometry. Rapid Communications in Mass Spectrometry 2006, 20 (8) , 1369-1380. https://doi.org/10.1002/rcm.2457
    75. Kamalesh K. Sharma, Annika Lindqvist, Xin J. Zhou, Richard J. Auchus, Trevor M. Penning, Stefan Andersson. Deoxycorticosterone inactivation by AKR1C3 in human mineralocorticoid target tissues. Molecular and Cellular Endocrinology 2006, 248 (1-2) , 79-86. https://doi.org/10.1016/j.mce.2005.10.024
    76. Shur-Hueih Cherng, Shih-Lan Hsu, Jia-Ling Yang, Chang-Tze Ricky Yu, Huei Lee. Suppressive effect of 1-nitropyrene on benzo[a]pyrene-induced CYP1A1 protein expression in HepG2 cells. Toxicology Letters 2006, 161 (3) , 236-243. https://doi.org/10.1016/j.toxlet.2005.10.002
    77. Stephan Steckelbroeck, Busola Oyesanmi, Yi Jin, Seon-Hwa Lee, Helenius J. Kloosterboer, Trevor M. Penning. Tibolone Metabolism in Human Liver Is Catalyzed by 3α/3β-Hydroxysteroid Dehydrogenase Activities of the Four Isoforms of the Aldo-Keto Reductase (AKR)1C Subfamily. Journal of Pharmacology and Experimental Therapeutics 2006, 316 (3) , 1300-1309. https://doi.org/10.1124/jpet.105.091587
    78. Trevor M. Penning, Stephan Steckelbroeck, David R. Bauman, Meredith W. Miller, Yi Jin, Donna M. Peehl, Kar-Ming Fung, Hseuh-Kung Lin. Aldo-keto reductase (AKR) 1C3: Role in prostate disease and the development of specific inhibitors. Molecular and Cellular Endocrinology 2006, 248 (1-2) , 182-191. https://doi.org/10.1016/j.mce.2005.12.009
    79. Jun Gao, Andrew A. Voss, Isaac N. Pessah, Fredine T. Lauer, Trevor M. Penning, Scott W. Burchiel. Ryanodine Receptor-Mediated Rapid Increase in Intracellular Calcium Induced by 7,8-Benzo(a)Pyrene Quinone in Human and Murine Leukocytes. Toxicological Sciences 2005, 87 (2) , 419-426. https://doi.org/10.1093/toxsci/kfi265
    80. Jean‐François Couture, Karine Pereira De Jésus‐Tran, Anne‐Marie Roy, Line Cantin, Pierre‐Luc Côté, Pierre Legrand, Van Luu‐The, Fernand Labrie, Rock Breton. Comparison of crystal structures of human type 3 3α‐hydroxysteroid dehydrogenase reveals an “induced‐fit” mechanism and a conserved basic motif involved in the binding of androgen. Protein Science 2005, 14 (6) , 1485-1497. https://doi.org/10.1110/ps.051353205
    81. David R. Bauman, Stephen I. Rudnick, Lawrence M. Szewczuk, Yi Jin, Sridhar Gopishetty, Trevor M. Penning. Development of Nonsteroidal Anti-Inflammatory Drug Analogs and Steroid Carboxylates Selective for Human Aldo-Keto Reductase Isoforms: Potential Antineoplastic Agents That Work Independently of Cyclooxygenase Isozymes. Molecular Pharmacology 2005, 67 (1) , 60-68. https://doi.org/10.1124/mol.104.006569
    82. Rémi Thibaut, Cinta Porte. Effects of endocrine disrupters on sex steroid synthesis and metabolism pathways in fish. The Journal of Steroid Biochemistry and Molecular Biology 2004, 92 (5) , 485-494. https://doi.org/10.1016/j.jsbmb.2004.10.008
    83. Hsueh-Kung Lin, Stephan Steckelbroeck, Kar-Ming Fung, Amy N. Jones, Trevor M. Penning. Characterization of a monoclonal antibody for human aldo-keto reductase AKR1C3 (type 2 3α-hydroxysteroid dehydrogenase/type 5 17β-hydroxysteroid dehydrogenase); immunohistochemical detection in breast and prostate. Steroids 2004, 69 (13-14) , 795-801. https://doi.org/10.1016/j.steroids.2004.09.014
    84. Stephan Steckelbroeck, Yi Jin, Busola Oyesanmi, Helenius J. Kloosterboer, Trevor M. Penning. Tibolone Is Metabolized by the 3α/3β-Hydroxysteroid Dehydrogenase Activities of the Four Human Isozymes of the Aldo-Keto Reductase 1C Subfamily: Inversion of Stereospecificity with a Δ 5(10) -3-Ketosteroid. Molecular Pharmacology 2004, 66 (6) , 1702-1711. https://doi.org/10.1124/mol.104.004515
    85. Xu Xu, Junfeng Zhang, Lin Zhang, Weili Liu, Clifford P. Weisel. Selective detection of monohydroxy metabolites of polycyclic aromatic hydrocarbons in urine using liquid chromatography/triple quadrupole tandem mass spectrometry. Rapid Communications in Mass Spectrometry 2004, 18 (19) , 2299-2308. https://doi.org/10.1002/rcm.1625
    86. Liang‐Shun Wang, Kuan‐Chih Chow, Yu‐Chung Wu, Tze‐Yi Lin, Wing‐Yin Li. Inverse expression of dihydrodiol dehydrogenase and glutathione‐ S ‐transferase in patients with esophageal squamous cell carcinoma. International Journal of Cancer 2004, 111 (2) , 246-251. https://doi.org/10.1002/ijc.11650
    87. Narayanan Balu, William T. Padgett, Guy R. Lambert, Adam E. Swank, Ann M. Richard, Stephen Nesnow. Identification and Characterization of Novel Stable Deoxyguanosine and Deoxyadenosine Adducts of Benzo[ a ]pyrene-7,8-quinone from Reactions at Physiological pH. Chemical Research in Toxicology 2004, 17 (6) , 827-838. https://doi.org/10.1021/tx034207s
    88. Stephan Steckelbroeck, Yi Jin, Sridhar Gopishetty, Busola Oyesanmi, Trevor M. Penning. Human Cytosolic 3α-Hydroxysteroid Dehydrogenases of the Aldo-keto Reductase Superfamily Display Significant 3β-Hydroxysteroid Dehydrogenase Activity. Journal of Biological Chemistry 2004, 279 (11) , 10784-10795. https://doi.org/10.1074/jbc.M313308200
    89. T.M. Penning, Y. Jin, S. Steckelbroeck, T. Lanišnik Rižner, M. Lewis. Structure–function of human 3α-hydroxysteroid dehydrogenases: genes and proteins. Molecular and Cellular Endocrinology 2004, 215 (1-2) , 63-72. https://doi.org/10.1016/j.mce.2003.11.006
    90. Trevor M. Penning. Aldo-Keto Reductases and Formation of Polycyclic Aromatic Hydrocarbon o-Quinones. 2004, 31-67. https://doi.org/10.1016/S0076-6879(04)78003-9
    91. Jean-François Couture, Pierre Legrand, Line Cantin, Van Luu-The, Fernand Labrie, Rock Breton. Human 20α–Hydroxysteroid Dehydrogenase: Crystallographic and Site-directed Mutagenesis Studies Lead to the Identification of an Alternative Binding Site for C21-steroids. Journal of Molecular Biology 2003, 331 (3) , 593-604. https://doi.org/10.1016/S0022-2836(03)00762-9
    92. Tea Lanišnik Rižner, Hsueh K. Lin, Donna M. Peehl, Stephan Steckelbroeck, David R. Bauman, Trevor M. Penning. Human Type 3 3α-Hydroxysteroid Dehydrogenase (Aldo-Keto Reductase 1C2) and Androgen Metabolism in Prostate Cells. Endocrinology 2003, 144 (7) , 2922-2932. https://doi.org/10.1210/en.2002-0032
    93. Trevor M Penning, Yi Jin, Vladi V Heredia, Mitchell Lewis. Structure–function relationships in 3α-hydroxysteroid dehydrogenases: a comparison of the rat and human isoforms. The Journal of Steroid Biochemistry and Molecular Biology 2003, 85 (2-5) , 247-255. https://doi.org/10.1016/S0960-0760(03)00236-X
    94. Yi Jin, William C Cooper, Trevor M Penning. Examination of the differences in structure–function of human and rat 3α-hydroxysteroid dehydrogenase. Chemico-Biological Interactions 2003, 143-144 , 383-392. https://doi.org/10.1016/S0009-2797(02)00207-7
    95. Takeshi Ozeki, Yoshiki Takahashi, Kazuo Nakayama, Masato Funayama, Kazuo Nagashima, Takao Kodama, Tetsuya Kamataki. Hepatocyte nuclear factor-4??/?? and hepatocyte nuclear factor-1?? as causal factors of interindividual difference in the expression of human dihydrodiol dehydrogenase 4 mRNA in human livers. Pharmacogenetics 2003, 13 (1) , 49-53. https://doi.org/10.1097/00008571-200301000-00007
    96. Takeshi Ozeki, Yoshiki Takahashi, Kazuo Nakayama, Tetsuya Kamataki. Hepatocyte nuclear factor (HNF)-4α/γ, HNF-1α, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. Archives of Biochemistry and Biophysics 2002, 405 (2) , 185-190. https://doi.org/10.1016/S0003-9861(02)00384-3
    97. Nisha T. Palackal, Seon Hwa Lee, Ronald G. Harvey, Ian A. Blair, Trevor M. Penning. Activation of Polycyclic Aromatic Hydrocarbontrans-Dihydrodiol Proximate Carcinogens by Human Aldo-keto Reductase (AKR1C) Enzymes and Their Functional Overexpression in Human Lung Carcinoma (A549) Cells. Journal of Biological Chemistry 2002, 277 (27) , 24799-24808. https://doi.org/10.1074/jbc.M112424200
    98. Hanaa H. Abdel-Baky, E. M. Gouda ., A. N. El-Behairy ., Gamal S. El-Baroty .. Chemoprevention of Penzo[a]pyrene-induced Carcinogen and Lipid Peroxidation in Mice by Lipophilic Algae Extracts (Phycotene). Journal of Medical Sciences 2002, 2 (4) , 185-193. https://doi.org/10.3923/jms.2002.185.193
    99. Shixiang Yan, Robert Shapiro, Nicholas E. Geacintov, Suse Broyde. Stereochemical, Structural, and Thermodynamic Origins of Stability Differences between Stereoisomeric Benzo[ a ]pyrene Diol Epoxide Deoxyadenosine Adducts in a DNA Mutational Hot Spot Sequence. Journal of the American Chemical Society 2001, 123 (29) , 7054-7066. https://doi.org/10.1021/ja0043035
    100. Laurie Tsuruda, Yong-tai Hou, Trevor M. Penning. Stable Expression of Rat Dihydrodiol Dehydrogenase (AKR1C9) in Human Breast MCF-7 Cells Results in the Formation of PAH- o -Quinones and Enzyme Mediated Cell Death. Chemical Research in Toxicology 2001, 14 (7) , 856-862. https://doi.org/10.1021/tx0100035
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