ae
d
a8
d
4c
8
1b
2d
8
27
8
8
18
49
16
9
19
1
49
2
8
1b
1d
18
36
37
1d
2 29
1d
25
Trevor M. Penning, Ph.D.
78
37
Molinoff Professor
28
55
3
8a
Member, Abramson Cancer Center
9f
Director Center of Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine
8e
Co-Leader, Tobacco and Environmental Carcinogenesis Program, The Abramson Cancer Center
91
Director Certificate Program in Environmental Health Sciences, Perelman School of Medicine
a8
Co-Director Translational Research Training Program in Environmental Health Sciences, Perelman School of Medicine
7a
Member, Center for Women's Health and Reproductive Medicine (CWHRM)
a5
Director Translational Research Training Program in Environmental Health Sciences, Perelman School of Medicine
11
Department: Systems Pharmacology and Translational Therapeutics
4
1
b
1d
46
Contact information
6d
4
3
23
6d
Department of Systems Pharmacology & Translational Therapeutics
3e University of Pennsylvania Perelman School of Medicine
17 1315 BRB II/III
36 421 Curie Blvd
Philadelphia, PA 19104-6160
26
3e University of Pennsylvania Perelman School of Medicine
17 1315 BRB II/III
36 421 Curie Blvd
Philadelphia, PA 19104-6160
30
Office: (215) 898-9445
34 Fax: (215) 573-0200
34 Lab: (215) 898-1144
18
83
34 Fax: (215) 573-0200
34 Lab: (215) 898-1144
18
Email:
PENNING@UPENN.EDU
12
PENNING@UPENN.EDU
1f
Graduate Group Affiliations
8
a
3
1d
18
Publications
23 a
3
2
4
b
1f
23 a
13
Education:
21 a B.Sc. 28 (Physiology and Biochemistry) c
48 (First Class Honors) Southampton University, UK, 1972.
21 a Ph.D. 19 (Biochemistry) c
33 Southampton University, UK, 1976.
c
3
27
21 a B.Sc. 28 (Physiology and Biochemistry) c
48 (First Class Honors) Southampton University, UK, 1972.
21 a Ph.D. 19 (Biochemistry) c
33 Southampton University, UK, 1976.
c
Links
9a Search PubMed for articles
74 The aldo-keto reductase superfamily homepage
51 Pharmacological Sciences graduate group faculty webpage.
91 Biochemistry and Molecular Biophysics graduate group faculty webpage.
81 Primary Work Website
71 Center of Excellence in Environmental Toxicology
c
5
3
3
8b
Permanent link9a Search PubMed for articles
74 The aldo-keto reductase superfamily homepage
51 Pharmacological Sciences graduate group faculty webpage.
91 Biochemistry and Molecular Biophysics graduate group faculty webpage.
81 Primary Work Website
71 Center of Excellence in Environmental Toxicology
c
2 29
21
1e
1d
24
5e
3a Steroid Hormone Transforming Aldo-Keto Reductases.
578 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.
8
51 Aldo-Keto Reductases and the Metabolic Activation of Chemical Carcinogens
371 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.
8
23 Laboratory Personnel
2c Ms. Ling Duan, MS Laboratory Manager
32 Dr. Steven Eichelbaum, Research Specialist
8
1d Postdoctoral Fellows:
19 Dr. Catia Marques
8
8
1c Predoctoral Fellows:
24 Ms. Andrea Andress Huacachino
26 29
27
Description of Research Expertise
28 Research Summary3a Steroid Hormone Transforming Aldo-Keto Reductases.
578 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.
8
51 Aldo-Keto Reductases and the Metabolic Activation of Chemical Carcinogens
371 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.
8
23 Laboratory Personnel
2c Ms. Ling Duan, MS Laboratory Manager
32 Dr. Steven Eichelbaum, Research Specialist
8
1d Postdoctoral Fellows:
19 Dr. Catia Marques
8
8
1c Predoctoral Fellows:
24 Ms. Andrea Andress Huacachino
26 29
23
59 Gardner S, Vogt A, Penning TM, Marmorstein, R 76 : Substrate specificity and kinetic mechanism of 3-hydroxy-Δ5-C27-steroid oxidoreductase J. Biol. Chem. 2 3b Page: Online ahead of print. Nov 2024.
162 Jonnalagadda SK, Duan L, Dow LF, Boligala GP, Kosmacek E, McCoy K, Oberley-Deegan R, Chhonker YS, Murry DJ, Reynolds CP, Maurer BJ, Penning TM, Trippier PC.: Coumarin-Based Aldo-Keto Reductase Family 1C (AKR1C) 2 and 3 Inhibitors. ChemMedChem. 19(21): e202400081, September 2024.
116 Carmona AV, Jonnalagadda S, Case AM, Maddeboina K, Jonnalagadda SK, Dow LF, Duan L, Penning TM, Trippier PC.: Discovery of an Aldo-Keto reductase 1C3 (AKR1C3) degrader. Commun Chem. 7(1): 95, April 2024.
137 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.
f9 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.
131 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.
115 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.
167 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.
120 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.
2c
7
1d
1f
Selected Publications
13a Huacachino AA, Chung A, Sharp K, Penning TM.: Specific and potent inhibition of steroid hormone pre-receptor regulator AKR1C2 by perfluorooctanoic acid: Implications for androgen metabolism J Steroid Biochem Mol Biol. 246: 106641, Feb 2025.59 Gardner S, Vogt A, Penning TM, Marmorstein, R 76 : Substrate specificity and kinetic mechanism of 3-hydroxy-Δ5-C27-steroid oxidoreductase J. Biol. Chem. 2 3b Page: Online ahead of print. Nov 2024.
162 Jonnalagadda SK, Duan L, Dow LF, Boligala GP, Kosmacek E, McCoy K, Oberley-Deegan R, Chhonker YS, Murry DJ, Reynolds CP, Maurer BJ, Penning TM, Trippier PC.: Coumarin-Based Aldo-Keto Reductase Family 1C (AKR1C) 2 and 3 Inhibitors. ChemMedChem. 19(21): e202400081, September 2024.
116 Carmona AV, Jonnalagadda S, Case AM, Maddeboina K, Jonnalagadda SK, Dow LF, Duan L, Penning TM, Trippier PC.: Discovery of an Aldo-Keto reductase 1C3 (AKR1C3) degrader. Commun Chem. 7(1): 95, April 2024.
137 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.
f9 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.
131 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.
115 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.
167 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.
120 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.
2c