faculty photo

Trevor M. Penning, Ph.D.

Molinoff Professor
Department: Pharmacology

Contact information
Department of Systems Pharmacology & Translational Therapeutics
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
Lab: (215) 898-1144
Education:
B.Sc. (Physiology and Biochemistry)
(First Class Honors) Southampton University, UK, 1972.
Ph.D. (Biochemistry)
Southampton University, UK, 1976.
Post-Graduate Training
Science Research Council Postgraduate Fellowship, Southampton University, UK, 1972-1976.
Postdoctoral Fellowship, Molecular Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, 1976-1979.
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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



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

Selected Publications

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.

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.

Date, Mihir S., O’Brien, Devin, Botelho, Danielle J. Schultz, Terry W., Liebler, Daniel, C., Penning, T.M., Salvito, Daniel, T: Clustering a Chemical Inventory for Safety Assessment of Fragrance Ingredients: Identifying Read-Across Analogs to Address Data Gaps. Chem Res Toxicol 33(7): 1709–1718. Jul 2020.

Wetherbee, O, Meeker, J., DeVoto,C, Penning, TM, Moore, JH and Boland, MR : WellExplorer: an integrative resource linking hydraulic fracturing chemicals with hormonal pathways and geographic location Database (Oxford) Page: 2020:baaa053. doi: 10.1093/database/baaa053. Jan 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.

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.: Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo Metabolism 99: 67-80, Oct 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.

Nikolaou N, Gathercole LL, Kirkwood L, Dunford JE, Hughes BA, Gilligan LC, Oppermann U, Penning TM, Arlt W, Hodson L, Tomlinson JW.: AKR1D1 regulates glucocorticoid availability and glucocorticoid receptor activation in human hepatoma cells. J. Steroid Biochem. Mol. Biol. 189: [Epub ahead of print] May 2019.

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Last updated: 06/17/2021
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