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Trevor M. Penning, Ph.D.

Trevor M. Penning

faculty photo
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
Lab: (215) 898-1144
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

Zanetti KA, Wang Z, Aldrich M, Amos CI, Blot WJ, Bowman ED, Burdette L, Cai Q, Caporaso N, Chung CC, Gillanders EM, Haiman CA, Hansen HM, Henderson BE, Kolonel LN, Marchand LL, Li S, McNeill LH, Ryan BM, Schwartz AG, Sison JD, Spitz MR, Tucker M, Wenzlaff AS, Wiencke JK, Wilkens L, Wrensch MR, Wu X, Zheng W, Zhou W, Christiani D, Palmer JR, Penning TM, Rieber AG, Rosenberg L, Ruiz-Narvaez EA, Su L, Vachani A, Wei Y, Whitehead AS, Chanock SJ, Harris CC.: Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population. Lung Cancer. 98: 33-42, Aug 2016.

Huang M, Zhang L, Mesaros C, Hackfeld LC, Hodge RP, Blair IA, Penning TM.: Metabolism of an Alkylated Polycyclic Aromatic Hydrocarbon 5-Methylchrysene in Human Hepatoma (HepG2) Cells. Chem Res Toxicol. 28(10): 2045-58, Oct 2015.

Hendriks CM, Penning TM, Zang T, Wiemuth D, Gründer S, Sanhueza IA, Schoenebeck F, Bolm C.: Pentafluorosulfanyl-containing flufenamic acid analogs: Syntheses, properties and biological activities. Bioorg Med Chem Lett. 25(20): 4437-4440, Oct 2015.

Jemielita T, Gerton GL, Neidell M, Chillrud S, Yan B, Stute M, Howarth M, Saberi P, Fausti N, Penning TM, Roy J, Propert KJ, Panettieri RA Jr.: Unconventional Gas and Oil Drilling Is Associated with Increased Hospital Utilization Rates. PLoS One. 10(7): e0131093. july 2015.

Chen M, Jin Y, Penning TM.: The rate-determining steps of aldo-keto reductases (AKRs), a study on human steroid 5β-reductase (AKR1D1). Chem Biol Interact 234: 360-365, Jun 2015.

Zang T, Verma K, Chen M, Jin Y, Trippier PC, Penning TM.: Screening baccharin analogs as selective inhibitors against type 5 17β-hydroxysteroid dehydrogenase (AKR1C3). Chem Biol Interact. 234: 339-48, Jun 2015.

Tamae D, Mostaghel E, Montgomery B, Nelson PS, Balk SP, Kantoff PW, Taplin ME, Penning TM.: The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer. Chem Biol Interact. 234: 332-338, Jun 2015.

Jin Y, Chen M, Penning TM, Miller WL: Electron transfer by human wild-type and A287P mutant P450 oxidoreductase assessed by transient kinetics: functional basis of P450 oxidoreductase deficiency. Biochem. J. 468(1): 25-31, May 2015.

Taplin, M.E., Montgomery, B., Logothetis, C.J., Bubley, G.J., Richie, J.P., Dalkin, B.L., Sanda, M.G., Davis, J.W., Loda, M., True, L.D., Troncoso, P., Ye, H., Lis, R.T., Marck, B.T., Matsumoto, A.M., Balk, S.P., Mostaghel, EA, Penning, T.M., Nelson, P.S., Xie, W., Jiang, Z., Haqq, C.M., Tamae, D., Tran, N., Peng, W., Kheoh, T., Molina, A., Kantoff, P.W: Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study. J. Clin. Oncol. 32(33): 360-365, Nov 2014.

Mostaghel, E.A., Nelson, P.S., Lange, P., Lin, D.W., Taplin, M.E., Balk, S., Ellis, W., Kantoff, P., Marck, B., Tamae, D., Matsumoto, A.M., True, L.D., Vessella, R., Penning, T., Hunter Merrill, R., Gulati, R., Montgomery, B: Targeted androgen pathway suppression in localized prostate cancer: a pilot study. Journal clinical oncology 32: 229-37, 2014.

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Last updated: 09/15/2016
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