Trevor M. Penning, Ph.D.

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Molinoff Professor
Department: Pharmacology

Contact information
Department of Systems Pharmacology & Translational Therapeutics
University of Pennsylvania Perelman School of Medicine
421 Curie Blvd
Philadelphia, PA 19104-6160
Office: (215) 898-9445
Fax: (215) 573-0200
Lab: (215) 898-1144
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, transfection studies and si-RNA.

Aldo-Keto Reductases and the Metabolic Activation of Chemical Carcinogens
Human AKRs are involved in the metabolic activation of pyrogenic, petrogenic and nitro-polycyclic aromatic hydrocarbons (PAH). For pyrogenic PAH his group identified a novel pathway of PAH activation involving the formation of redox-active o-quinones, which has become widely accepted as an alternative pathway to diol-epoxide formation. His work on petrogenic PAH has led to the identification of the first potential human biomarkers of oil exposure. In work on the metabolic activation of nitroarenes, his group showed that 3-nitrobenzanthrone is metabolically activated by both AKRs and NQO1, and that the metabolic activation is dependent on the Nrf2-Keap1 pathway using CRISPER/Cas9 gene editing. Methods include cell culture, high-resolution NMR, EPR, mass-spectrometry, PAH-DNA adduct chemistry, mutagenesis assays, and epigenetic signaling through the Nrf2 pathway.

Laboratory Personnel
Ms. Ling Duan, MS Laboratory Manager

Postdoctoral Fellows:
Dr. Guannan (Tiffany) Zhang
Dr. Nuria Camina Garcia

Predoctoral Fellows:
Ms. Andrea Detlefsen
Ms. Nicole Kerstetter
Mr. Ryan Paulukinas

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Selected Publications

Lee I, Zhang G, Mesaros C, Penning TM.: Estrogen receptor-dependent and independent roles of benzo[a]pyrene in Ishikawa cells J. Endocrinology 247: 139-151, Nov 2020.

Murray JR, de la Vega L, Hayes JD, Duan L, Penning TM.: Induction of the Antioxidant Response by the Transcription Factor NRF2 Increases Bioactivation of the Mutagenic Air Pollutant 3-Nitrobenzanthrone in Human Lung Cells. Chem. Res. Toxicol. 32(12): 2538-2551, Dec 2019.

Chen M, Wangtrakuldee P, Zang T, Duan L, Gathercole LL, Tomlinson JW, Penning TM.: Human and murine steroid 5β-reductases (AKR1D1 and AKR1D4): insights into the role of the catalytic glutamic acid. Chem. Biol. Interact. 305: 163-170, May 2019.

Verma K, Zang T, Penning TM, Trippier PC.: Potent and Highly Selective Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors Act as Chemotherapeutic Potentiators in Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia. J. Med. Chem. 62(7): 3590-3916, April 2019.

Mostaghel EA, Zhang A, Hernandez S, Marck BT, Zhang X, Tamae D, Biehl HE, Tretiakova M, Bartlett J, Burns J, Dumpit R, Ang L, Matsumoto AM, Penning TM, Balk SP, Morrissey C, Corey E, True LD, Nelson PS.: Contribution of Adrenal Glands to Intratumor Androgens and Growth of Castration-Resistant Prostate Cancer. Clin.Cancer Res. 25(1): 426-439, Jan 2019.

Wangtrakuldee P, Adeniji AO, Zang T, Duan L, Khatri B, Twenter BM, Estrada MA, Higgins TF, Winkler JD, Penning TM.: A 3-(4-nitronaphthen-1-yl) amino-benzoate analog as a bifunctional AKR1C3 inhibitor and AR antagonist: Head to head comparison with other advanced AKR1C3 targeted therapeutics. J. Steroid Biochem. Mol. Biol. Epub ahead of Print: doi: 10.1016/j.jsbmb.2019.01.001, Jan 2019.

Nikolaou N, Gathercole LL, Marchand L, Althari S, Dempster NJ, Green CJ, van de Bunt M, McNeil C, Arvaniti A, Hughes BA, Sgromo B, Gillies RS, Marschall HU, Penning TM, Ryan J, Arlt W, Hodson L, Tomlinson JW.: AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease. Metabolism 99: 67-80, 2019.

Murray JR, Mesaros CA, Arlt VM, Seidel A, Blair IA, Penning TM.: Role of Human Aldo-Keto Reductases in the Metabolic Activation of the Carcinogenic Air Pollutant 3-Nitrobenzanthrone. Chem. Res. Toxicol. 11 : 1277-1288, Nov 2018.

Sullivan J, Croisant S, Howarth M, Rowe GT, Fernando H, Phillips-Savoy A, Jackson D, Prochaska J, Ansari GAS, Penning TM, Elferink C; Community Partner Authors: Louisiana Environmental Action Network, United Houma Nation, Bayou Interfaith Shared Community Organizing, Dustin Nguyen-Vietnamese Community Partner, Center for Environmental & Economic Justice, and Alabama Fisheries Cooperative Project Community Scientist Author: Wilma Subra.: Building and Maintaining a Citizen Science Network With Fishermen and Fishing Communities Post Deepwater Horizon Oil Disaster Using a CBPR Approach. New Solutions 28(3): 416-447, Nov 2018.

Verma K, Gupta N, Zang T, Wangtrakluldee P, Srivastava SK, Penning TM, Trippier PC.: AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells. Mol Cancer Ther. 17(9): 1833-1845, Epub 2018 Jun 11 2018.

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Last updated: 10/11/2020
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