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Trevor M. Penning, Ph.D.

Trevor M. Penning, Ph.D.

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Molinoff Professor
Department: Pharmacology

Contact information
Department of Pharmacology
University of Pennsylvania Perelman School of Medicine
1315 BRB II/III
421 Curie Blvd
Philadelphia, PA 19104-6160
Office: (215) 898-9445
Fax: (215) 573-0200
Education:
B.Sc. (Physiology and Biochemistry)
(First Class Honors) Southampton University, UK, 1972.
Ph.D. (Biochemistry)
Southampton University, UK, 1976.
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Description of Research Expertise

Research Summary
Steroid Hormone Transforming Aldo-Keto Reductases.
The aldo-keto reductase (AKR) superfamily contains mammalian hydroxysteroid dehydrogenases (HSDs). For each sex steroid there are a pair of HSDs, which by acting as reductases or oxidases can convert potent steroid hormones into their cognate inactive metabolites or vice versa. When found in steroid target tissues they can regulate the occupancy and trans-activation of steroid hormone receptors, providing a pre-receptor regulation of steroid hormone action. Many HSDs are considered therapeutic targets. For example, aldo-keto reductase AKR1C3 (type 5 17beta-hydroxysteroid dehydrogenase) catalyses the formation of the potent androgens, testosterone and 5alpha-dihydrotestosterone, in castrate resistant prostate cancer (CRPC). CRPC is dependent upon intratumoral androgen biosynthesis that reactivate the androgen receptor and is uniformly fatal. Structure-based inhibitor design is being used to develop selective AKR1C3 inhibitors for the treatment of CRPC. In another area structure-function studies on steroid 5beta-reductase (AKR1D1)are being pursued. This enzyme catalyzes a pivotal step in bile-acid biosynthesis and natural mutations are causal in bile-acid deficiency syndromes which are often neonatal fatal. In both areas we use the following techniques: site-directed mutagenesis, x-ray crystallography, transient and steady state kinetics, and transfection studies in prostate cancer cell lines.

Dihydrodiol Dehydrogenases and Polycyclic Aromatic Hydrocarbon (PAH) Activation
Dihydrodiol dehydrogenases are members of the AKR superfamily. They convert PAH-trans-dihydrodiols (proximate carcinogens) to reactive and redox active o-quinones. By entering into futile redox-cycles the o-quinones can amplify the production of reactive oxygen species (e.g., superoxide anion, hydrogen peroxide and hydroxyl radical). The pro-oxidant state may provide a mechanism by which PAH can act as complete carcinogens. Similar metabolic activation has been observed for the structurally related catechol estrogens and diethylstilbestrol. The cytotoxicity and genotoxicity of PAH o-quinones are being studied in human lung cells as it pertains to causality in human lung cancer. Methods include cell culture, high-resolution NMR, EPR, mass-spectrometry, PAH-DNA adduct chemistry, and mutagenesis paradigms.

Laboratory Personnel
Dr. Yi Jin, Research Assistant Professor
Ms. Ling Duan, Laboratory Manager

Postdoctoral Fellows:
Dr. Adegoke Adeniji
Dr. Mo Chen
Dr. Meng Huang
Dr. Daniel Tamae
Dr. Li Zhang



Also, visit www.med.upenn.edu/akr

Selected Publications

Sinreih Maša, Sosič Izidor, Beranič Nataša, Turk Samo, Adeniji Adegoke O, Penning Trevor M, Rižner Tea Lanišnik, Gobec Stanislav: N-Benzoyl anthranilic acid derivatives as selective inhibitors of aldo-keto reductase AKR1C3. Bioorganic & medicinal chemistry letters 22(18): 5948-51, Sep 2012.

Brožič Petra, Turk Samo, Adeniji Adegoke O, Konc Janez, Janežič Dušanka, Penning Trevor M, Lanišnik Rižner Tea, Gobec Stanislav: Selective Inhibitors of Aldo-Keto Reductases AKR1C1 and AKR1C3 Discovered by Virtual Screening of a Fragment Library. Journal of medicinal chemistry Aug 2012.

Sen Sushmita, Bhojnagarwala Pratik, Francey Lauren, Lu Ding, Penning Trevor M, Field Jeffrey: p53 Mutagenesis by Benzo[a]pyrene Derived Radical Cations. Chemical research in toxicology Aug 2012.

Zhang Li, Huang Meng, Blair Ian A, Penning Trevor M: Detoxication of Benzo[a]pyrene-7,8-dione by Sulfotransferases (SULTs) in Human Lung Cells. The Journal of biological chemistry 287(35): 29909-20, Aug 2012.

Chen Mo, Adeniji Adegoke O, Twenter Barry M, Winkler Jeffrey D, Christianson David W, Penning Trevor M: Crystal structures of AKR1C3 containing an N-(aryl)amino-benzoate inhibitor and a bifunctional AKR1C3 inhibitor and androgen receptor antagonist. Therapeutic leads for castrate resistant prostate cancer. Bioorganic & medicinal chemistry letters 22(10): 3492-7, May 2012.

Byrns Michael C, Mindnich Rebekka, Duan Ling, Penning Trevor M: Overexpression of aldo-keto reductase 1C3 (AKR1C3) in LNCaP cells diverts androgen metabolism towards testosterone resulting in resistance to the 5α-reductase inhibitor finasteride. The Journal of steroid biochemistry and molecular biology 130(1-2): 7-15, May 2012.

Chen Mo, Drury Jason E, Christianson David W, Penning Trevor M: Conversion of human steroid 5β-reductase (AKR1D1) into 3β-hydroxysteroid dehydrogenase by single point mutation E120H: example of perfect enzyme engineering. The Journal of biological chemistry 287(20): 16609-22, May 2012.

Huang Meng, Liu Xiaojing, Basu Sankha S, Zhang Li, Kushman Mary E, Harvey Ronald G, Blair Ian A, Penning Trevor M: Metabolism and distribution of benzo[a]pyrene-7,8-dione (B[a]P-7,8-dione) in human lung cells by liquid chromatography tandem mass spectrometry: detection of an adenine B[a]P-7,8-dione adduct. Chemical research in toxicology 25(5): 993-1003, May 2012.

Jin Yi, Duan Ling, Chen Mo, Penning Trevor M, Kloosterboer Helenius J: Metabolism of the synthetic progestogen norethynodrel by human ketosteroid reductases of the aldo-keto reductase superfamily. The Journal of steroid biochemistry and molecular biology 129(3-5): 139-44, Apr 2012.

Sun Lianli, Chen Yixin, Rajendran Chitra, Mueller Uwe, Panjikar Santosh, Wang Meitian, Mindnich Rebekka, Rosenthal Cindy, Penning Trevor M, Stöckigt Joachim: Crystal structure of perakine reductase, founding member of a novel aldo-keto reductase (AKR) subfamily that undergoes unique conformational changes during NADPH binding. The Journal of biological chemistry 287(14): 11213-21, Mar 2012.

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Last updated: 01/18/2013
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