faculty photo

Trevor M. Penning, Ph.D.

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 Translational Research Training Program in Environmental Health Sciences, Perelman School of Medicine, University of Pennsylvania
Deputy Director Penn Superfund Research Program, University of Pennsylvania
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.
Permanent link
 
> Perelman School of Medicine   > Faculty   > Details

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
Ms. Ling Duan, MS Laboratory Manager

Postdoctoral Fellows:
Dr. Tianzhu (Indy) Zang
Dr. Juliette Aka

Predoctoral Fellows:
Ms. Jessica Murray
Ms. Isabelle Lee



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

Selected Publications

Zang T, Tamae D, Mesaros C, Wang Q, Huang M, Blair IA, Penning TM.: Simultaneous quantitation of nine hydroxy-androgens and their conjugates in human serum by stable isotope dilution liquid chromatography electrospray ionization tandem mass spectrometry. J. Steroid Biochem. Mol. Biol. 165: 7431-44, 2017.

Mostaghel EA, Cho E, Zhang A, Alyamani M, Kaipainen A, Green S, Marck BT, Sharifi N, Wright JL, Gulati R, True LD, Loda M, Matsumoto AM, Tamae D, Penning TN, Balk SP, Kantoff PW, Nelson PS, Taplin ME, Montgomery RB. : Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer. Clin. Cancer Res. 23: 4592-4601, 2017.

Huang M, Mesaros C, Hackfeld LC, Hodge RP, Zang T, Blair IA, Penning TM. : Potential Metabolic Activation of a Representative C4-Alkylated Polycyclic Aromatic Hydrocarbon Retene (1-Methyl-7-isopropyl-phenanthrene) Associated with the Deepwater Horizon Oil Spill in Human Hepatoma (HepG2) Cells. Chem. Res. Toxicol. 30: 1093-1101, 2017.

Winterbottom CJ, Shah RJ, Patterson KC, Kreider ME, Panettieri RA Jr, Rivera-Lebron B, Miller WT, Litzky LA, Penning TM, Heinlen K, Jackson T, Localio AR, Christie JD.: Exposure to Ambient Particulate Matter is Associated With Accelerated Functional Decline in Idiopathic Pulmonary Fibrosis. Chest Page: doi: 10.1016/j.chest.2017.07.034. 2017.

Zang, T., Taplin, M.E., Tamae, D., Xie, W., Mesaros, C., Zhang, Z., Bubley, G., Montgomery, B., Balk, S.P., Mostaghel, E.A., Blair, I.A. and Penning, T.M. : Testicular versus Adrenal Sources of Hydroxyandrogens in Prostate Cancer. Endocr Relat Cancer. 24: 393-404, 2017.

Verma K, Zang T, Gupta N, Penning TM, Trippier PC. : Selective AKR1C3 Inhibitors Potentiate Chemotherapeutic Activity in Multiple Acute Myeloid Leukemia (AML) Cell Lines. ACS Med. Chem. Lett. American Chemical Society, 7: 774-9, 2016.

Huang M, Mesaros C, Zhang S, Blair IA, Penning TM.: Potential Metabolic Activation of a Representative C2-Alkylated Polycyclic Aromatic Hydrocarbon 6-Ethylchrysene Associated with the Deepwater Horizon Oil Spill in Human Hepatoma (HepG2) Cells. Chem. Res. Toxicol. 29: 991-1002, 2016 Notes: ACS Editor's Choice.

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, 2016.

Adeniji A, Uddin MJ, Zang T, Tamae D, Wangtrakuldee P, Marnett LJ, Penning TM.: Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor. J. Med. Chem. American Chemical Society, 59, 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: 2045-58, 2015.

back to top
Last updated: 10/11/2017
The Trustees of the University of Pennsylvania