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, transfection studies and si-RNA.

Aldo-Keto Reductases and the Metabolic Activation of Chemical Carcinogens
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.

Laboratory Personnel
Ms. Ling Duan, MS Laboratory Manager

Postdoctoral Fellows:
Dr. Guannan (Tiffany) Zhang
Dr. Nuria Camina Garcia

Predoctoral Fellows:
Ms. Andrea Detlefsen
Ms. Nicole Kerstetter
Mr. Ryan Paulukinas



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