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.
Dr. Yi Jin, Research Assistant Professor
Ms. Ling Duan, Laboratory Manager
Dr. Adegoke Adeniji
Dr. Mo Chen
Dr. Meng Huang
Dr. Daniel Tamae
Dr. Li Zhang
Also, visit www.med.upenn.edu/akr
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.
Jin, Y., Chen, M., Penning, T.M. : Rate of steroid double-bond reduction catalysed by the human steroid 5β-reductase (AKR1D1) is sensitive to steroid structure: implications for steroid metabolism and bile acid synthesis. Biochemical Journal 462: 163-71, 2014.
Huang, M., Zhang, L., Mesaros, C., Zhang, S., Blaha, M.A., Blair, I.A., Penning, T.M. : Metabolism of a representative oxygenated polycyclic aromatic hydrocarbon (PAH) phenanthrene-9,10-quinone in human hepatoma (HepG2) cells. Chemical research in toxicology 27: 852-63, 2014.
Huang, M., Blair, I.A., Penning, T.M: Identification of stable benzo[a]pyrene-7,8-dione-DNA adducts in human lung cells. Chemical research in toxicology 26: 685-92, 2013.
Baldwin DA, Sarnowski CP, Reddy SA, Blair IA, Clapper M, Lazarus P, Li M, Muscat JE, Penning TM, Vachani A, Whitehead AS: Development of a genotyping microarray for studying the role of gene-environment interactions in risk for lung cancer. J Biomol Tech. 24: 198-217, 2013.
Liedtke, A.J., Adeniji, A.O., Chen, M., Byrns, M.C., Jin, Y., Christianson, D.W., Marnett, L.J., Penning TM.: Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer. J. medicinal chemistry 56: 2429-46, 2013.
Zhang L, Huang M, Blair IA, Penning TM: Interception of benzo[a]pyrene-7,8-dione by UDP glucuronosyltransferases (UGT) in human lung cells. Chemical research in toxicology 26: 1570-8, 2013.
Tamae, D., Byrns, M., Marck, B., Mostaghel, E.A., Nelson, P.S., Lange, P., Lin, D., Taplin, M.E., Balk, S., Ellis, W., True, L., Vessella, R., Montgomery, B., Blair, I.A., Penning, T.M. : Development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization/selected reaction monitoring/mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of keto-androgens in human serum. Journal of steroid biochemistry and molecular biology 138C: 281-89, 2013.
Barski, O.A., Mindnich, R., and Penning, T.M: Alternative splicing in the aldo-keto reductase superfamily: implications for protein nomenclature. Chemico-Biological Interactions 202: 153-8, 2013.
Sinreih Maša, Sosič Izidor, Beranič Nataša, Turk Samo, Adeniji Adegoke O, Penning Trevor M, Rižner Tea Lanišnik, Gobec Stanislav: N-Benzoyl anthranilic acid derivatives as selective inhibitors of aldo-keto reductase AKR1C3. Bioorganic & medicinal chemistry letters 22(18): 5948-51, Sep 2012.
back to top
Last updated: 09/05/2014
The Trustees of the University of Pennsylvania