Trevor M. Penning, Ph.D.

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Molinoff Professor
Member, Abramson Cancer Center
Member, Center for Research and Reproduction and Women's Health (CRRWH)
Director Center of Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine
Co-Leader, Tobacco and Environmental Carcinogenesis Program, The Abramson Cancer Center
Director Certificate Program in Environmental Health Sciences, Perelman School of Medicine
Director Translational Research Training Program in Environmental Health Sciences, Perelman School of Medicine, University of Pennsylvania
Department: Systems Pharmacology and Translational Therapeutics

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
Dr. Steven Eichelbaum, Research Specialist

Postdoctoral Fellows:
Dr. Catia Marques

Predoctoral Fellows:
Ms. Andrea Andress Huacachino

Selected Publications

Detlefsen AJ, Mesaros CA, Duan L, Penning TM.: AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol Cancer Res Commun. 3(1888-1898), Sep 2023.

Paulukinas RD, Penning TM.: Insulin-Induced AKR1C3 Induces Fatty Acid Synthase in a Model of Human PCOS Adipocytes Endocrinology 164(5): doi: 10.1210/endocr/bqad033. Mar 2023.

Su AL, Penning TM.: Role of Human Aldo-Keto Reductases and Nuclear Factor Erythroid 2-Related Factor 2 in the Metabolic Activation of 1-Nitropyrene via Nitroreduction in Human Lung Cells Chem Res Toxicol. 36(2): 270-280, Feb 2023.

Su AL, Mesaros CA, Krzeminski J, El-Bayoumy K, Penning TM.: Role of Human Aldo-Keto Reductases in the Nitroreduction of 1-Nitropyrene and 1,8-Dinitropyrene Chem Res Toxicol. 35(12): 2296-2309, Nov 2022.

Sakata Y, Cheng K, Mayama M, Seita Y, Detlefsen AJ, Mesaros CA, Penning TM, Shishikura K, Yang W, Auchus RJ, Strauss JF 3rd, Sasaki K.: Reconstitution of human adrenocortical specification and steroidogenesis using induced pluripotent stem cells. Dev Cell. 57(22): 2566-2583, Nov 2022.

Paulukinas RD, Mesaros CA, Penning TM.: Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes Endocrinology 163(7): doi: 10.1210/endocr/bqac068. Jul 2022.

Detlefsen AJ, Wangtrakuldee P, Penning TM.: Characterization of the major single nucleotide polymorphic variants of aldo-keto reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase) J Steroid Biochem Mol Biol. 221, April 2022.

Appanna N, Gibson H, Gangitano E, Dempster NJ, Morris K, George S, Arvaniti A, Gathercole LL, Keevil B, Penning TM, Storbeck KH, Tomlinson JW, Nikolaou N: Differential activity and expression of human 5β-reductase (AKR1D1) splice variants. J Mol Endocrinol. 66(3): 181-194, March 2021.

McKeon TP, Hwang WT, Ding Z, Tam V, Wileyto P, Glanz K, Penning TM: Environmental exposomics and lung cancer risk assessment in the Philadelphia metropolitan area using ZIP code-level hazard indices Environ Sci Pollut Res Int. Page: doi: 10.1007/s11356-021-12884-z. Ahead of print, Feb 2021.

Zhu Y, McKeon TP, Tam V, Vachani A, Penning TM, Hwang WT: Geographic Differences in Lung Cancer Incidence: A Study of a Major Metropolitan Area within Southeastern Pennsylvania. Int J Environ Res Public Health 17(24): 9498. doi: 10.3390/ijerph17249498, Dec 2020.

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Last updated: 07/03/2024
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