Professor, Eppley Institute
Director of the Animal Care Facility and Cell Culture Facility
PhD - University of Leeds, 1967
My research concerns the molecular epidemiology of chemically-induced cancer in humans, specifically Non-Hodgkin’s lymphoma, pancreas and prostate cancer. This will be expanded to include a study of head and neck cancer in 2002. The premise upon which this research is based is that each of these cancers may be induced by exposure to a class of chemical carcinogens, heterocyclic amines, formed when meat is cooked to high temperatures. Since heterocyclic amines require metabolism to be both activated and detoxified, that metabolism is a determinant of susceptibility to the carcinogenic action of these amines. Some measure of this susceptibility is thus available. The expression of the genes for the following carcinogen-metabolizing enzymes is being measured in patients, and appropriate controls, with the above mentioned cancers, arylamine N–acetyltransferase (NAT1 and NAT2), cytochrome P4501A2 (CYP1A2), and glutathione S-transferase (GSTM1, GSTP1, and GSTT1).
The laboratory component of my research focuses on the impact of the genetic polymorphic expression of carcinogen metabolizing enzymes in human prostate epithelial cells (HuPrEC) on the ability of these cells to metabolize a representative heterocyclic amine PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) to mutagenic species. Mutagenicity is the preferred biological end-point in all our studies. To date (9/13/01) we have shown that HuPrEC from several donors can metabolize PhIP to mutagenic species and that the pattern of expression of NAT1 plus GST, particularly GSTP1, influences the extent of metabolism.
I propose to continue this aspect of these studies to fully establish the role(s) of both NAT1 and the GST isoforms as determinants of susceptibility. Furthermore this model is ideally suited to (i) examine the influence of agricultural chemicals on prostate cancer, which is significantly higher in rural areas of the US, and (ii) examine the role of the CYP3A4 variant 3A4V in prostate cancer. CYP3A4V is found in a much higher level in prostate cancer patients than in comparable, disease-free controls.