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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

Research Summary:
Aldo-Keto Reductases Role 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) which 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 and molecular modeling), 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. Earlier work focused on a rat homolg (3α-HSD) enabled the group to elucidate the crystal structures for the apoenzyme, the E!NADP+ and the E!NADP+ testosterone complexes. These structures have provided valuable insight into the structure-function of the human enzymes. This information is being exploited to design 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 reactive 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). Similar metabolic activation has been observed for the structurally related catechol estrogens and diethylstilbestrol. The cytotoxicity and genotoxicity of PAH ο-quinones are being studied. Methods include human lung cell culture, metabolic profiling with LC/MS, high-resolution NMR, EPR, PAH-DNA adduct chemistry, and mutagenesis paradigms.