Trevor M. Penning, Ph.D.
Professor of Pharmacology
Professor of Biochemistry & Biophysics
Professor of Obstetrics-Gynecology
Director, Center for Excellence in 
Environmental
Toxicology (CEET)
Member, Graduate Group in Pharmacological Sciences
Member, Biochemistry & Molecular Biophysics Graduate
Group
Department of Pharmacology
130 C John Morgan Building
University of Pennsylvania School of Medicine
3620 Hamilton Walk
Philadelphia, PA 19104-6084
Telephone: 215-898-9445
Fax: 215-573-2236 or 215-898-7180
Email: penning@upenn.edu
Links: http://www.med.upenn.edu/akr
http://www.med.upenn.edu/ceet
Department of Pharmacology
Trevor M. Penning, Ph.D.
Education:| 1969-1972 | B.Sc. (Physiology, Biochemistry) | Southampton University, UK First Class Honors |
| 1972-1976 | Ph.D. (Biochemistry) | Southampton University, UK |
Aldo-Keto Reductases: Roles in Hormonal and Chemical Carcinogenesis
Hormonal Carcinogenesis: Prostate and breast cancer are hormone dependent malignancies of the aging male and female that require the local production of steroid hormones for their growth. The aldo-keto reductase (AKR) superfamily (www.med.upenn.edu/akr) contains hydroxysteroid dehydrogenases (HSDs) can regulate the local production of sex hormones. 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. 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. By developing selective inhibitors for these enzymes tissue specific responses to steroid hormones should be achievable. We call these inhibitors "selective intracrine modulators (SIMs)". Dr. Penning’s group is conducting structure-function (crystallography, molecular modeling and site-directed mutagenesis), and mechanistic studies (steady state, transient state, and kinetic isotope effect studies) on four human AKRs that regulate ligand occupancy of the androgen, estrogen and progesterone receptor. The group has determined the crystal structures of several steroid hormone transforming AKRs to guide mutagenesis and the design of SIMs for prostate and breast cancer intervention.
Chemical Carcinogenesis: Polycyclic aromatic hydrocarbons are ubiquitous environmental pollutants, they are constituents of tobacco smoke and are suspect human lung carcinogens. Aldo-keto reductases of the 1A and 1C subfamilies convert PAH-trans-dihydrodiols (proximate carcinogens) to electrophilic and redox active ο-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 (initiators and promoters). Current work is aimed at elucidating the importance of this pathway of PAH activation in lung cancer causation, and whether variants in the genes that can intercept the quinones determine genetic susceptibility to this disease. Methods include human lung cell culture, transcript profiling, metabolic profiling with LC/MS, high-resolution NMR, EPR, PAH-DNA adduct chemistry, and mutagenesis assays.
Di Costanzo, L., Drury, J.E., Penning, T.M., Christianson, D.W.: Crystal structure of human liver Delta4-3-ketosteroid 5beta-reductase (AKR1D1) and implications for substrate binding and catalysis. J. Biol. Chem. 283: 16830-16839, 2008. (Paper of the week)
Cooper WC, Jin Y, Penning TM: Elucidation of a complete kinetic mechanism for a mammalian hydroxysteroid dehydrogenase (HSD) and identification of all enzyme forms on the reaction coordinate: The example of rat liver 3alpha-HSD (AKR1C9). J Biol Chem 282: 33484-33493, 2007.
Byrns MC, Steckelbroeck S, Penning TM: An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies. Biochem Pharmacol 75: 484-493, 2008.
Shultz CA, Palackal NT, Mangal D, Harvey RG, Blair IA, Penning TM: Fjord-region benzo[g]chrysene-11,12-dihydrodiol and benzo[c]phenanthrene-3,4-dihydrodiol as substrates for rat liver dihydrodiol dehydrogenase (AKR1C9): structural basis for stereochemical preference. Chem Res Toxicol 21: 668-677, 2008. (Profiled: “In this Issue”)
Jiang, H., Gelhaus, S.L., Mangal, D., Harvey, R.G., Blair, I.A., Penning, T.M. Metabolism of benzo[a]pyrene in human bronchoalveolar H358 cells using liquid chromatography-mass spectrometry. Chem. Res. Toxicol. 20: 1331-41, 2007. (Listed as a most cited article in ACS 2007).
Park J-H, Mangal D, Tacka KA, Quinn AM, Harvey RG, Blair IA, Penning TM: Evidence for the aldo-keto reductase pathway of polycyclic aromatic trans-dihydrodiol activation in human lung A549 cells. Proc Natl Acad Sci USA 105: 6846-6851, 2008. (Profiled in the Editorial as: “Lung Cancer Enablers”)
Park, J-H., Gelhaus, S., Vedantam, S., Olivia, A., Batra, A., Blair, I.A., Field, J., Penning, T.M. : The pattern of p53 mutations caused by PAH o-quinones is driven by 8-oxo-dGuo formation while the spectrum of mutations is determined by biological selection for dominance. Chem. Res. Toxicol. 21: 1039-49, 2008. (Profiled: “In this Issue”)
Awards, Honors, Membership in Honorary Societies:| • | B.Sc. (First Class Honors) (1972) |
| • | Alberta Heritage Foundation for Medical Research, Visiting Lecturer (1981) |
| • | Pharmaceutical Manufacturers Association Foundation, Research Starter Grant (1983) |
| • | The Albert Ethelbert Ebert Prize and Medal, awarded by the American Pharmaceutical Association (l986) |
| • | Honorary Masters Degree, University of Pennsylvania (1988) |
| • | Research Career Development Award, National Cancer Institute (1988-93) |
| • | Commendation for Outstanding Teaching, Class of '92 (1990) |
| • | Dean's Award for Excellence in Graduate Education (1997) |
| • | Elected to the Johns Hopkins Society of Scholars (1998) |
| • | Ad Hoc Reviewer, Biochemical Endocrinology Study Section, NIH |
| • | Ad Hoc Reviewer, Biochemistry Program, National Science Foundation |
| • | Ad Hoc Reviewer, March of Dimes Research Foundation |
| • | Ad Hoc Reviewer, United States-Israel Binational Science Foundation |
| • | Ad Hoc Reviewer, The Wellcome Trust |
| • | Chemical Pathology Site-Visit Team, National Cancer Institute |
| • | START, Program Fonds zur Forderung Der wissenchaftlichen Furschung Austria |
| • | Chair, Special Emphasis Panel, Chemical Pathology, NIH |
| • | Member, Chemical Pathology Study Section, NIH |
| • | Member, Cancer Etiology Study Section, NIH |
| • | Consultant, WHO International Agency for Research in Cancer |
| • | Biochemical Journal (Editorial Advisory Board) |
| • | Steroids |
| • | Chemical Research in Toxicology |
|
• |
Journal of Biological Chemistry |
| • | Journal of Steroid Biochemistry & Molecular Biology |
|
Michael Byrns, Ph.D. Postdoctoral Researcher mbyrns@mail.med.upenn.edu |
Ling Duan Research Specialist lduan@mail.med.upenn.edu |
| Yi Jin, Ph.D. Research Assistant Professor jinyi@pharm.med.upenn.edu |
Mary Kushman, Ph.D. Postdoctoral Researcher mkushman@mail.med.upenn.edu |
| Rebekka Mindnich, Ph.D. Postdoctoral Researcher mire@mail.med.upenn.edu |
Gagan Sarawgi Research Specialist gags@mail.med.upenn.edu |
| Li Zhang Postdoctoral Researcher zhangli2@mail.med.upenn.edu |
Department of Pharmacology
102/135 John Morgan Building
University of Pennsylvania School of Medicine
3620 Hamilton Walk
Philadelphia, PA 19104-6084
Lab Telephone: 215-898-1144 Lab Fax: 215-573-2236
Links:
www.med.upenn.edu/akr
www.med.upenn.edu/ceet