TREVOR PENNING

Summary

Affiliation: University of Pennsylvania
Country: USA

Publications

  1. pmc Polycyclic aromatic hydrocarbon (PAH) o-quinones produced by the aldo-keto-reductases (AKRs) generate abasic sites, oxidized pyrimidines, and 8-oxo-dGuo via reactive oxygen species
    Jong Heum Park
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Chem Res Toxicol 19:719-28. 2006
  2. ncbi request reprint Molecular determinants of steroid recognition and catalysis in aldo-keto reductases. Lessons from 3alpha-hydroxysteroid dehydrogenase
    T M Penning
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104 6084, USA
    J Steroid Biochem Mol Biol 69:211-25. 1999
  3. pmc Identification of the molecular switch that regulates access of 5alpha-DHT to the androgen receptor
    Trevor M Penning
    Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Mol Cell Endocrinol 265:77-82. 2007
  4. pmc Human aldo-keto reductases: Function, gene regulation, and single nucleotide polymorphisms
    Trevor M Penning
    Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, 130 C John Morgan Bldg, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Arch Biochem Biophys 464:241-50. 2007
  5. pmc Pre-receptor regulation of the androgen receptor
    Trevor M Penning
    Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104 6084, USA
    Mol Cell Endocrinol 281:1-8. 2008
  6. ncbi request reprint Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors
    Trevor M Penning
    Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104 6084, USA
    Mol Cell Endocrinol 248:182-91. 2006
  7. ncbi request reprint AKR1B10: a new diagnostic marker of non-small cell lung carcinoma in smokers
    Trevor M Penning
    Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Clin Cancer Res 11:1687-90. 2005
  8. ncbi request reprint Structure-function of human 3 alpha-hydroxysteroid dehydrogenases: genes and proteins
    T M Penning
    Department of Pharmacology, University of Pennsylvania School of Medicine, 130C John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Mol Cell Endocrinol 215:63-72. 2004
  9. ncbi request reprint Structure-function relationships in 3alpha-hydroxysteroid dehydrogenases: a comparison of the rat and human isoforms
    Trevor M Penning
    Department of Pharmacology, School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA
    J Steroid Biochem Mol Biol 85:247-55. 2003
  10. ncbi request reprint Hydroxysteroid dehydrogenases and pre-receptor regulation of steroid hormone action
    Trevor M Penning
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Hum Reprod Update 9:193-205. 2003

Research Grants

Collaborators

Detail Information

Publications76

  1. pmc Polycyclic aromatic hydrocarbon (PAH) o-quinones produced by the aldo-keto-reductases (AKRs) generate abasic sites, oxidized pyrimidines, and 8-oxo-dGuo via reactive oxygen species
    Jong Heum Park
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Chem Res Toxicol 19:719-28. 2006
    ..However, in the presence of Fe(III)-mediated PAH o-quinone redox-cycling, the *OH radical scavengers and sodium azide consistently attenuated their formation, indicating that the ROS responsible was *OH...
  2. ncbi request reprint Molecular determinants of steroid recognition and catalysis in aldo-keto reductases. Lessons from 3alpha-hydroxysteroid dehydrogenase
    T M Penning
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104 6084, USA
    J Steroid Biochem Mol Biol 69:211-25. 1999
    ..Exploitation of these findings using steroidal and nonsteroidal mechanism based inactivators may lead to selective and broad based AKR inhibitors...
  3. pmc Identification of the molecular switch that regulates access of 5alpha-DHT to the androgen receptor
    Trevor M Penning
    Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Mol Cell Endocrinol 265:77-82. 2007
    ..Our studies suggest that aldo-keto reductase (AKRs) and SDRs function as reductases and oxidases, respectively, to control ligand access to nuclear receptors...
  4. pmc Human aldo-keto reductases: Function, gene regulation, and single nucleotide polymorphisms
    Trevor M Penning
    Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, 130 C John Morgan Bldg, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Arch Biochem Biophys 464:241-50. 2007
    ..This suggests that there will be inter-individual variation in endogenous and xenobiotic metabolism which in turn affect susceptibility to nuclear receptor signaling and chemical carcinogenesis...
  5. pmc Pre-receptor regulation of the androgen receptor
    Trevor M Penning
    Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104 6084, USA
    Mol Cell Endocrinol 281:1-8. 2008
    ..Inhibition of AKR1C2 would be desirable in cases of androgen insufficiency and inhibition of RL-HSD might be desirable in benign prostatic hyperplasia...
  6. ncbi request reprint Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors
    Trevor M Penning
    Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104 6084, USA
    Mol Cell Endocrinol 248:182-91. 2006
    ..These compounds can now be used to determine the role of AKR1C3 in producing two proliferative signals in the prostate namely testosterone and 9alpha,11beta-PGF2...
  7. ncbi request reprint AKR1B10: a new diagnostic marker of non-small cell lung carcinoma in smokers
    Trevor M Penning
    Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Clin Cancer Res 11:1687-90. 2005
  8. ncbi request reprint Structure-function of human 3 alpha-hydroxysteroid dehydrogenases: genes and proteins
    T M Penning
    Department of Pharmacology, University of Pennsylvania School of Medicine, 130C John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Mol Cell Endocrinol 215:63-72. 2004
    ..AKR1C4 is virtually liver specific, while AKR1C2 and AKR1C3 are dominantly expressed in prostate and mammary gland. AKR1C genes are highly conserved in structure and may be transcriptionally regulated by steroid hormones and stress...
  9. ncbi request reprint Structure-function relationships in 3alpha-hydroxysteroid dehydrogenases: a comparison of the rat and human isoforms
    Trevor M Penning
    Department of Pharmacology, School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA
    J Steroid Biochem Mol Biol 85:247-55. 2003
    ..Instead the low k(cat) seen in AKR1C2 (50-fold less than AKR1C9) may be due to substrate "wobble" at the plastic active site...
  10. ncbi request reprint Hydroxysteroid dehydrogenases and pre-receptor regulation of steroid hormone action
    Trevor M Penning
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Hum Reprod Update 9:193-205. 2003
    ..Crystal structures exist for HSDs in both families, making rational design of SIMs a reality. Broad-based criteria have been established which must be fulfilled to validate each HSD isoform as a potential SIM target...
  11. ncbi request reprint Characterization of the substrate binding site in rat liver 3alpha-hydroxysteroid/dihydrodiol dehydrogenase. The roles of tryptophans in ligand binding and protein fluorescence
    J M Jez
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 271:30190-8. 1996
    ..A model of how androstanedione binds in the apolar cleft is developed. These data provide further evidence that loop structures in members of the aldoketoreductase superfamily are critical determinants of ligand binding...
  12. ncbi request reprint Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3)
    T M Penning
    Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Mol Cell Endocrinol 171:137-49. 2001
    ..With regards to transition state analogs steroid carboxylates and pyrazoles may be preferred while 3alpha, 17beta or 20alpha-spiro-oxiranes may act as mechanism-based inactivators...
  13. pmc Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones
    T M Penning
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6084, USA
    Biochem J 351:67-77. 2000
    ..These studies are in stark contrast with those in rat where only a single AKR with positional- and stereo-specificity for 3alpha-hydroxysteroids exists...
  14. pmc Aldo-keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer
    Michael C Byrns
    Centers of Excellence in Environmental Toxicology and Cancer Pharmacology, Department of Pharmacology, University of Pennsylvania School of Medicine, 130C John Morgan Bldg, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, United States
    J Steroid Biochem Mol Biol 118:177-87. 2010
    ....
  15. ncbi request reprint Activation of polycyclic aromatic hydrocarbon trans-dihydrodiol proximate carcinogens by human aldo-keto reductase (AKR1C) enzymes and their functional overexpression in human lung carcinoma (A549) cells
    Nisha T Palackal
    Departments of Biochemistry and Biophysics and Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 277:24799-808. 2002
    ..The ability to measure DMBA-3,4-dione formation in A549 cells implicates the AKR pathway in the metabolic activation of PAH in human lung...
  16. ncbi request reprint Alanine scanning mutagenesis of the testosterone binding site of rat 3 alpha-hydroxysteroid dehydrogenase demonstrates contact residues influence the rate-determining step
    Vladi V Heredia
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Biochemistry 43:5832-41. 2004
    ..These findings support the concept of enzyme catalysis in which the correct positioning of reactants is essential; otherwise, k(cat) will be limited by the chemical event...
  17. pmc Fjord-region benzo[g]chrysene-11,12-dihydrodiol and benzo[c]phenanthrene-3,4-dihydrodiol as substrates for rat liver dihydrodiol dehydrogenase (AKR1C9): structural basis for stereochemical preference
    Carol A Shultz
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Chem Res Toxicol 21:668-77. 2008
    ..The similarity between rates of trans-dihydrodiol oxidation by the rat and human liver specific AKRs (AKR1C9 and AKR1C4) implicate these enzymes in hepatocarcinogenesis in rats observed with the fjord-region PAH...
  18. ncbi request reprint Transcript profiling of the androgen signal in normal prostate, benign prostatic hyperplasia, and prostate cancer
    David R Bauman
    Department of Pharmacology, Center of Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, 130C John Morgan Building, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104 6084, USA
    Endocrinology 147:5806-16. 2006
    ..280 in normal PSC) were maintained in PEC and PSC in diseased prostate. These data suggest that CaP may be more responsive to an ERbeta agonist and BPH may be more responsive to androgen ablation...
  19. ncbi request reprint Human type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells
    Tea Lanisnik Rizner
    Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Endocrinology 144:2922-32. 2003
    ..Neither AKR1C2, retinol dehydrogenase/3alpha-HSD nor 11-cis-retinol dehydrogenase is a source of 5alpha-DHT in PC-3 cells...
  20. ncbi request reprint Tibolone metabolism in human liver is catalyzed by 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four isoforms of the aldo-keto reductase (AKR)1C subfamily
    Stephan Steckelbroeck
    Department of Pharmacology, University of Pennsylvania School of Medicine, 130C John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    J Pharmacol Exp Ther 316:1300-9. 2006
    ..The low hepatic formation of 3alpha-hydroxytibolone suggests that AKR1C4 is not the primary source of this metabolite and instead it maybe formed by an intestinal or enterobacterial 3alpha-HSD...
  21. pmc Evidence for the aldo-keto reductase pathway of polycyclic aromatic trans-dihydrodiol activation in human lung A549 cells
    Jong Heum Park
    Center of Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6084, USA
    Proc Natl Acad Sci U S A 105:6846-51. 2008
    ..We conclude that activation of PAH-trans-dihydrodiols by AKRs in lung cells leads to ROS-mediated genotoxicity and contributes to lung carcinogenesis...
  22. pmc Aldo-keto reductases and formation of polycyclic aromatic hydrocarbon o-quinones
    Trevor M Penning
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA
    Methods Enzymol 378:31-67. 2004
  23. pmc An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone indepe
    Michael C Byrns
    Center for Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, United States
    Biochem Pharmacol 75:484-93. 2008
    ..The identification of CBM as a specific inhibitor of AKR1C3 will aid the investigation of its roles in steroid hormone and prostaglandin signaling and the resultant effects on cancer development...
  24. ncbi request reprint 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
    David R Bauman
    Department of Pharmacology, University of Pennsylvania School of Medicine, 130C John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Mol Pharmacol 67:60-8. 2005
    ..These compounds can be used to dissect the role of the AKR1C isozymes in neoplastic diseases and may have cancer chemopreventive roles independent of COX inhibition...
  25. pmc Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism
    Yi Jin
    Centers of Excellence in Environmental Toxicology and Cancer Pharmacology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    J Biol Chem 284:10013-22. 2009
    ....
  26. pmc Type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogs
    Michael C Byrns
    Department of Pharmacology, Center of Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6084, United States
    Chem Biol Interact 178:221-7. 2009
    ..Both strategies are informed by crystal structures of ternary AKR1C3.NADP(+).NSAID complexes. The identification of NSAID analogs as specific inhibitors of AKR1C3 will help validate its role in the proliferation of breast cancer cells...
  27. ncbi request reprint Resveratrol is a peroxidase-mediated inactivator of COX-1 but not COX-2: a mechanistic approach to the design of COX-1 selective agents
    Lawrence M Szewczuk
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 279:22727-37. 2004
    ..We propose that resveratrol inactivates COX-1 by a "hit-and-run" mechanism, and offers a basis for the design of selective COX-1 inactivators that work through a mechanism-based event at the peroxidase active site...
  28. pmc Oxidation of PAH trans-dihydrodiols by human aldo-keto reductase AKR1B10
    Amy M Quinn
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Chem Res Toxicol 21:2207-15. 2008
    ....
  29. ncbi request reprint Identification of the major oxidative 3alpha-hydroxysteroid dehydrogenase in human prostate that converts 5alpha-androstane-3alpha,17beta-diol to 5alpha-dihydrotestosterone: a potential therapeutic target for androgen-dependent disease
    David R Bauman
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Mol Endocrinol 20:444-58. 2006
    ..The data show that the major oxidative 3alpha-HSD in normal human prostate is RL-HSD and may be a new therapeutic target for treating prostate diseases...
  30. ncbi request reprint Steroid-binding site residues dictate optimal substrate positioning in rat 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD or AKR1C9)
    Vladi V Heredia
    Departments Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104, USA
    Chem Biol Interact 143:393-400. 2003
    ..These results highlight the importance of steroid binding site residues in dictating the proper orientation of substrates to achieve high catalytic turnover while having minimal effects on hormone affinity...
  31. ncbi request reprint Characterization of a monoclonal antibody for human aldo-keto reductase AKR1C3 (type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase); immunohistochemical detection in breast and prostate
    Hsueh Kung Lin
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19018, USA
    Steroids 69:795-801. 2004
    ..The reagent thus has utility to access the localized expression of AKR1C3 in hormonal dependent malignancies of the breast and prostate...
  32. ncbi request reprint Tibolone is metabolized by the 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo-keto reductase 1C subfamily: inversion of stereospecificity with a delta5(10)-3-ketosteroid
    Stephan Steckelbroeck
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Mol Pharmacol 66:1702-11. 2004
    ....
  33. ncbi request reprint Dissection of the physiological interconversion of 5alpha-DHT and 3alpha-diol by rat 3alpha-HSD via transient kinetics shows that the chemical step is rate-determining: effect of mutating cofactor and substrate-binding pocket residues on catalysis
    Vladi V Heredia
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Biochemistry 43:12028-37. 2004
    ..Thus, residues in the cofactor and steroid-binding site can alter the rate-determining step in the NADP(+)-dependent oxidation of 3alpha-diol to make chemistry rate-limiting overall...
  34. pmc Multiple steps determine the overall rate of the reduction of 5alpha-dihydrotestosterone catalyzed by human type 3 3alpha-hydroxysteroid dehydrogenase: implications for the elimination of androgens
    Yi Jin
    Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Biochemistry 45:13054-63. 2006
    ..12 s(-1)), the release of the steroid product (0.081 s(-1)), and the release of the cofactor product (0.21 s(-1)), combine to yield the overall observed low turnover number...
  35. ncbi request reprint Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3beta-hydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action
    Stephan Steckelbroeck
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    J Biol Chem 279:10784-95. 2004
    ....
  36. doi request reprint Comparisons of (+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol activation by human cytochrome P450 and aldo-keto reductase enzymes: effect of redox state and expression levels
    Amy M Quinn
    Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Chem Res Toxicol 21:1086-94. 2008
    ..These data suggest that AKR enzymes may effectively compete with P450 1A1/1B1 for PAH trans-dihydrodiol activation in human lung cells...
  37. pmc Crystal structure of human liver Delta4-3-ketosteroid 5beta-reductase (AKR1D1) and implications for substrate binding and catalysis
    Luigi Di Costanzo
    Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104 6323, USA
    J Biol Chem 283:16830-9. 2008
    ..The locations of disease-linked mutations thought to be responsible for bile acid deficiency are also revealed...
  38. pmc Aldo-keto reductases in which the conserved catalytic histidine is substituted
    Luigi Di Costanzo
    Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, PA 19104 6323, United States
    Chem Biol Interact 178:127-33. 2009
    ....
  39. ncbi request reprint Molecular docking simulations of steroid substrates into human cytosolic hydroxysteroid dehydrogenases (AKR1C1 and AKR1C2): insights into positional and stereochemical preferences
    Yi Jin
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, 19104 6084, USA
    Steroids 71:380-91. 2006
    ..Favorable nonproductive modes were observed with all substrates in both enzymes in which the steroid was bound at a "near-entry" position and/or an "in-middle" position, which may influence the reaction coordinate...
  40. ncbi request reprint Competing roles of aldo-keto reductase 1A1 and cytochrome P4501B1 in benzo[a]pyrene-7,8-diol activation in human bronchoalveolar H358 cells: role of AKRs in P4501B1 induction
    Hao Jiang
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Chem Res Toxicol 19:68-78. 2006
    ....
  41. pmc Liquid chromatography-mass spectrometry (LC-MS) of steroid hormone metabolites and its applications
    Trevor M Penning
    Centers of Excellence in Environmental Toxicology and Cancer Pharmacology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6084, USA
    J Steroid Biochem Mol Biol 121:546-55. 2010
    ..Our LC-MS methods have sufficient sensitivity to detect steroid hormone levels in prostate and breast tumors and should aid their molecular diagnosis and treatment...
  42. ncbi request reprint Viniferin formation by COX-1: evidence for radical intermediates during co-oxidation of resveratrol
    Lawrence M Szewczuk
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Nat Prod 68:36-42. 2005
    ..Methoxy-resveratrol analogues, in which either the m-hydroquinone or the phenol moiety were protected as methyl ethers, were used to confirm the proposed mechanism of viniferin production by COX-1...
  43. ncbi request reprint The roles of aldo-keto reductases in steroid hormone action
    David R Bauman
    Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, 135 John Morgan Building, Philadelphia, Pennsylvania 19104, USA
    Drug News Perspect 17:563-78. 2004
    ..Consequently, they are potential targets in treating prostate cancer, breast cancer, endometriosis and endometrial cancer...
  44. pmc Steroid hormone transforming aldo-keto reductases and cancer
    Trevor M Penning
    Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Ann N Y Acad Sci 1155:33-42. 2009
    ..This proproliferative signaling may stimulate the growth of hormone-dependent and -independent prostate and breast cancer...
  45. pmc Inhibition of human steroid 5beta-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex
    Jason E Drury
    Center of Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    J Biol Chem 284:19786-90. 2009
    ..This is the first reported structure of finasteride bound to an enzyme involved in steroid hormone metabolism...
  46. ncbi request reprint Polycyclic aromatic hydrocarbon o-quinones inhibit the activity of the catalytic fragment of protein kinase C
    Deshan Yu
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6084, USA
    Biochemistry 41:11888-94. 2002
    ..These data suggest that PAH o-quinones, generated by AKRs, may affect cellular signaling through suppression of the activity of PKC isoforms...
  47. pmc New frontiers in androgen biosynthesis and metabolism
    Trevor M Penning
    University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Curr Opin Endocrinol Diabetes Obes 17:233-9. 2010
    ..To summarize recent advances in androgen biosynthesis and metabolism in peripheral tissues (e.g., liver and prostate) and how these can be exploited therapeutically...
  48. pmc Targeted androgen pathway suppression in localized prostate cancer: a pilot study
    Elahe A Mostaghel
    Elahe A Mostaghel, Rachel Hunter Merrill, and Roman Gulati, Fred Hutchinson Cancer Research Center Elahe A Mostaghel, Peter S Nelson, Paul Lange, Daniel W Lin, William Ellis, Robert Vessella, and Bruce Montgomery, University of Washington Brett Marck, Alvin M Matsumoto, and Lawrence D True, Veterans Affairs Puget Sound Health Care System, Seattle, WA Mary Ellen Taplin and Philip Kantoff, Dana Farber Cancer Institute, Harvard Medical School Steven Balk, Beth Israel Deaconess Medical Center, Boston, MA and Daniel Tamae and Trevor Penning, University of Pennsylvania, Philadelphia, PA
    J Clin Oncol 32:229-37. 2014
    ..The failure to completely ablate tissue androgens may limit suppression of PCa growth. We evaluated combinations of CYP17A and 5-α-reductase inhibitors for reducing prostate androgen levels, AR signaling, and PCa volumes...
  49. ncbi request reprint Aldo-keto reductase- and cytochrome P450-dependent formation of benzo[a]pyrene-derived DNA adducts in human bronchoalveolar cells
    Qian Ruan
    Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6160, USA
    Chem Res Toxicol 20:424-31. 2007
    ..These data raise the intriguing possibility that P450 1A1/P450 1B1 and AKR1A1 may be protective against (+)-B[a]PDE-mediated DNA damage...
  50. ncbi request reprint Reactive oxygen species generated by PAH o-quinones cause change-in-function mutations in p53
    Deshan Yu
    Department of Pharmacology, Biostatistics University of Pennsylvania School of Medicine, Philadelphia 19104, USA
    Chem Res Toxicol 15:832-42. 2002
    ..Together these data suggest that PAH o-quinones generate an endogenous mutagen (ROS) which leads to p53 inactivation. These observations provide an alternative route to G to T transversions that dominate in p53 in lung cancer...
  51. ncbi request reprint Examination of the differences in structure-function of human and rat 3alpha-hydroxysteroid dehydrogenase
    Yi Jin
    Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Chem Biol Interact 143:383-92. 2003
    ..The results suggest that cofactor binding or release for the human and rat 3alpha-HSDs are similar and do not account for the observed differences in k(cat)...
  52. pmc Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer
    Karen E Knudsen
    Kimmel Cancer Center, Department of Cancer Biology and Department of Urology, Thomas Jefferson University, Philadelphia, PA 19107, USA
    Trends Endocrinol Metab 21:315-24. 2010
    ..In this report, the mechanisms underlying the lethal pairing of AR deregulation and aberrant androgen synthesis in prostate cancer progression will be discussed...
  53. ncbi request reprint Role of human type 3 3alpha-hydroxysteroid dehydrogenase (AKR1C2) in androgen metabolism of prostate cancer cells
    Tea Lanisnik Rizner
    Department of Pharmacology, University of Pennsylvania, School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Chem Biol Interact 143:401-9. 2003
    ..Based on these findings AKR1C2 may diminish 5alpha-DHT and prevent this ligand from activating the androgen receptor in situ...
  54. ncbi request reprint Benzo[a]pyrene-7,8-dihydrodiol promotes checkpoint activation and G2/M arrest in human bronchoalveolar carcinoma H358 cells
    M Cecilia Caino
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6160, USA
    Mol Pharmacol 71:744-50. 2007
    ..Our data suggest that a p53-independent pathway operates in lung epithelial cells in response to BPD that involves P450 induction and subsequent activation of the ATR/ATM/Chk1 damage check-point pathway and cell cycle arrest in G2/M...
  55. ncbi request reprint Elucidation of a complete kinetic mechanism for a mammalian hydroxysteroid dehydrogenase (HSD) and identification of all enzyme forms on the reaction coordinate: the example of rat liver 3alpha-HSD (AKR1C9)
    William C Cooper
    Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    J Biol Chem 282:33484-93. 2007
    ..The kinetic Haldane and free energy diagram confirmed that K(eq) was governed by ligand binding terms that favored the reduction reactants. Thus, HSDs in the aldo-keto reductase superfamily thermodynamically favor ketosteroid reduction...
  56. ncbi request reprint Aldo-keto reductases and bioactivation/detoxication
    Yi Jin
    Department of Pharmacology, Center of Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Annu Rev Pharmacol Toxicol 47:263-92. 2007
    ..g., aflatoxin, endogenous toxicants, and those formed from the breakdown of lipid peroxides. AKRs are stress-regulated genes and play a central role in the cellular response to osmotic, electrophilic, and oxidative stress...
  57. ncbi request reprint Mechanism-based inactivation of COX-1 by red wine m-hydroquinones: a structure-activity relationship study
    Lawrence M Szewczuk
    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Nat Prod 67:1777-82. 2004
    ..These findings imply that resveratrol is not the sole agent responsible for the antiplatelet activity of red wine and suggest that all dietary m-hydroquinones should be examined for cardioprotective effects...
  58. pmc Metabolism of benzo[a]pyrene in human bronchoalveolar H358 cells using liquid chromatography-mass spectrometry
    Hao Jiang
    Centers of Excellence in Environmental Toxicology and Cancer Pharmacology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6084, USA
    Chem Res Toxicol 20:1331-41. 2007
    ..It also provides evidence that each of the pathways of PAH activation yields their distinctive metabolites in H358 human lung cells and that each pathway may contribute to the carcinogenic process...
  59. pmc Aldo-keto reductase (AKR) superfamily: genomics and annotation
    Rebekka D Mindnich
    Department of Pharmacology, Center for Excellence in Environmental Toxicology, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104 6084, USA
    Hum Genomics 3:362-70. 2009
    ..Recent developments in the annotation of SNP and transcript variance in AKRs are also summarised...
  60. pmc Structure and catalytic mechanism of human steroid 5beta-reductase (AKR1D1)
    Luigi Di Costanzo
    Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104 6323, USA
    Mol Cell Endocrinol 301:191-8. 2009
    ..It participates with Y58 to create a "superacidic" oxyanion hole for polarization of the C3 ketone. A role for K87 in the proton relay proposed using the AKR1D1-NADP(+)-5beta-dihydroprogesterone structure is not supported...
  61. pmc Characterization of disease-related 5beta-reductase (AKR1D1) mutations reveals their potential to cause bile acid deficiency
    Jason E Drury
    Department of Pharmacology, University of PennsylvaniaSchool of Medicine, Center of Excellence in Environmental Toxicology, Philadelphia, Pennsylvania 19104 6084, USA
    J Biol Chem 285:24529-37. 2010
    ..Our findings show that the reported mutations in AKR1D1 in patients with 5beta-reductase lead to significantly decreased levels of active enzyme and could be causal in the development of bile acid deficiency syndrome...
  62. pmc Formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo) by PAH o-quinones: involvement of reactive oxygen species and copper(II)/copper(I) redox cycling
    Jong Heum Park
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Chem Res Toxicol 18:1026-37. 2005
    ....
  63. ncbi request reprint Competing roles of cytochrome P450 1A1/1B1 and aldo-keto reductase 1A1 in the metabolic activation of (+/-)-7,8-dihydroxy-7,8-dihydro-benzo[a]pyrene in human bronchoalveolar cell extracts
    Hao Jiang
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Chem Res Toxicol 18:365-74. 2005
    ..These model systems provide a cellular context in which the dominant DNA adducts/lesions formed by either pathway may be compared...
  64. pmc 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
    Yu Min Shen
    Department of Pharmacology, Center of Excellence in Environmental Toxicology and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Chem Res Toxicol 19:1441-50. 2006
    ..The resultant 8-oxo-dGuo yields a pattern of mutations but not a spectrum consistent with that seen in lung cancer; we suggest that the emergence of the spectrum requires biological selection...
  65. pmc Analysis of 7,8-dihydro-8-oxo-2'-deoxyguanosine in cellular DNA during oxidative stress
    Dipti Mangal
    Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania, 854 BRB II III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104 6160, USA
    Chem Res Toxicol 22:788-97. 2009
    ..In keeping with this concept, inhibition of catechol-O-methyl transferase (COMT)-mediated detoxification of B[a]P-7,8-catechol with Ro 410961 caused increased 8-oxo-dGuo formation in the H358 cell DNA...
  66. pmc Aryl hydrocarbon receptor facilitates DNA strand breaks and 8-oxo-2'-deoxyguanosine formation by the aldo-keto reductase product benzo[a]pyrene-7,8-dione
    Jong Heum Park
    Center of Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    J Biol Chem 284:29725-34. 2009
    ..We conclude that the AhR shuttles PAH o-quinone genotoxins to the nucleus and enhances oxidative DNA damage...
  67. ncbi request reprint Quantification of benzo[a]pyrene diol epoxide DNA-adducts by stable isotope dilution liquid chromatography/tandem mass spectrometry
    Qian Ruan
    Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, 854 BRB II III, 421 Curie Boulevard, Philadelphia, PA 19104 6160, USA
    Rapid Commun Mass Spectrom 20:1369-80. 2006
    ..Also, the adduct profile suggests that this occurs by binding of (+)-anti-B[a]PDE to DNA in a manner that facilitates covalent binding to dGuo rather than dAdo residues...
  68. ncbi request reprint Synthesis of the o-quinones and other oxidized metabolites of polycyclic aromatic hydrocarbons implicated in carcinogenesis
    Ronald G Harvey
    The Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637, USA
    J Org Chem 69:2024-32. 2004
    ..The latter include the corresponding o-catechols, trans-dihydrodiols, and the corresponding anti- and syn-diol epoxides...
  69. pmc Fluorogenic metabolic probes for direct activity readout of redox enzymes: Selective measurement of human AKR1C2 in living cells
    Dominic J Yee
    Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA
    Proc Natl Acad Sci U S A 103:13304-9. 2006
    ..Similarly, inhibitor potency of physiological (ursodeoxycholate) and synthetic inhibitors (flufenamic acid, ibuprofen, and naproxen) was also readily evaluated...
  70. ncbi request reprint Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer
    Michael Stanbrough
    Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
    Cancer Res 66:2815-25. 2006
    ..These results indicate that enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone is a mechanism by which prostate cancer cells adapt to androgen deprivation and suggest new therapeutic targets...
  71. ncbi request reprint AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer
    Tea Lanisnik Rizner
    Institute of Biochemistry, Medical Faculty, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
    Mol Cell Endocrinol 248:126-35. 2006
    ..It is suggested that the expression of AKR1C1 and AKR1C3 in endometrial cancer will govern the ratio of P:E2...
  72. ncbi request reprint Deoxycorticosterone inactivation by AKR1C3 in human mineralocorticoid target tissues
    Kamalesh K Sharma
    Department of Obstetrics Gynecology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Mol Cell Endocrinol 248:79-86. 2006
    ..Our findings suggest that AKR1C3 protects the mineralocorticoid receptor from activation by DOC in mineralocorticoid target cells of the kidney and colon, analogous to cortisol inactivation by 11beta-hydroxysteroid dehydrogenase type 2...
  73. pmc The pattern of p53 mutations caused by PAH o-quinones is driven by 8-oxo-dGuo formation while the spectrum of mutations is determined by biological selection for dominance
    Jong Heum Park
    Department of Pharmacology, Centers for Excellence in Environmental Toxicology and Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Chem Res Toxicol 21:1039-49. 2008
    ..These observations, if extended to mammalian cells, suggest that mutagenesis can drive the pattern of mutations but that biological selection for dominant mutations drives the spectrum of mutations observed in p53 in lung cancer...
  74. ncbi request reprint The aldo-keto reductase superfamily homepage
    David Hyndman
    Protein Function Discovery Facility, Queen s University, Ont, K7L 3N6, Kingston, Canada
    Chem Biol Interact 143:621-31. 2003
    ..The current nomenclature is recognized by the Human Genome Project (HUGO) and the Web site provides a link to genomic information including chromosomal localization, gene boundaries, human ESTs and SNPs and much more...
  75. ncbi request reprint Anatomical and cellular localization of neuroactive 5 alpha/3 alpha-reduced steroid-synthesizing enzymes in the spinal cord
    Christine Patte-Mensah
    Laboratoire de Neurophysiologie Cellulaire et Intégrée, Unité Mixte de Recherche 7519 Centre National de la Recherche Scientifique, Universite Louis Pasteur, 67084 Strasbourg, France
    J Comp Neurol 477:286-99. 2004
    ..These results are the first demonstrating that oligodendrocytes and neurons of the SC possess the key enzymatic complex for synthesizing potent neuroactive steroids that may control spinal sensorimotor processes...
  76. doi request reprint Strategies for synthesis of adducts of omicron-quinone metabolites of carcinogenic polycyclic aromatic hydrocarbons with 2'-deoxyribonucleosides
    Chongzhao Ran
    The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois 60637, USA
    J Org Chem 73:992-1003. 2008
    ..The copper-mediated method offers advantages of economy, adaptability to large-scale preparation, utility for synthesis of (13)C- or (15)N-labeled analogues, and nonformation of bis-adducts as secondary products...

Research Grants2

  1. Symposium on Aldo-Keto Reductases & Toxicant Metabolism
    TREVOR PENNING; Fiscal Year: 2002
    ..abstract_text> ..
  2. Molecular Mechanisms of Multistage Carcinogenesis
    TREVOR PENNING; Fiscal Year: 2006
    ..By studying the discrete molecular events responsible for the causation of cancer this Program may lead to the early prevention and intervention of this disease. ..