Presented by the Department of Pharmacology & Toxicology, University of Arizona College of Pharmacy:
Tuesday, October 15
Robert J. Turesky, PhD
Masonic Cancer Center and Department of Medicinal Chemistry, University of Minnesota, Minneapolis
“Approaches to Biomonitor Dietary Carcinogens: What Works and What Doesn't”
A gaping hole in cancer research has been the lack of valid measurements of environmental carcinogens that can be used in large epidemiological studies. Dietary and environmental toxicants or their metabolites can form covalent adducts with protein and DNA and lead to the onset of diseases, including cancer. Knowledge about the metabolism, biodisposition, and chemical reactivity of genotoxicants with macromolecules is essential to devise robust approaches for human biomonitoring. However, the identification of the cancer-causing agents and their mutation-prone DNA adducts has advanced slowly because fresh biopsy specimens are rarely available for research. There is a critical need to establish non-invasive and underutilized biospecimens develop comprehensive screening approaches to identify genotoxicants and their DNA adducts. I will discuss our research on heterocyclic aromatic amines (HAA), probable human carcinogens formed in cooked meat and tobacco smoke, and aristolochic acid (AA), upper urinary tract and bladder carcinogens found in Aristolochia herbs used for medicinal purposes. We quantified HAAs, their urinary metabolites, protein and DNA adducts, using liquid chromatography with triple quadrupole (TQ), ion trap (IT) or Orbitrap high-resolution (HR)-multistage mass spectrometry (MSn). 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is an abundant HAA formed in cooked meats. PhIP is a rodent and possible human colorectal and prostate carcinogen that accrues in human hair. We are measuring the levels of PhIP in scalp hair of prostate cancer (PC) patients, by TQ-MS, to determine if PhIP can serve as a biomarker of cooked meat consumption, PC risk, and tumor aggressiveness. Serum albumin adducts of PhIP have been characterized and measured by IT-MS, and PhIP-DNA adducts have measured in the genome of PC patients by HR-MSn. Our biomarker data reveal that PhIP undergoes metabolism and forms reactive intermediates that covalently bind to protein and DNA in humans; however, a signature mutation is still sought to link PhIP with cancer. DNA adducts of AA are frequently detected, by IT-MS3, in renal tissue of kidney cancer patients in Asia where traditional herbs are commonly used. AA-DNA adducts and the unique mutational spectrum induced by AA in cancer driver genes have provided compelling evidence for a role of AA in upper urinary tract cancer. We have shown that exfoliated urinary cells can be used to non-invasively screen for DNA adducts of AA, and studies are underway to screen for DNA adducts of genotoxicants present in tobacco smoke that contribute to bladder cancer in smokers. Fresh frozen biopsy specimens are rarely available for human biomonitoring. We have established technologies to measure multiple classes of DNA adducts in formalin-fixed paraffin embedded tissues (FFPE) with clinical diagnosis of disease. FFPE tissues are underutilized biospecimens which can be retrospectively screened for DNA adducts and mutations. Our laboratory has established non-targeted DNA adductomics methods to screen for a wide array of DNA adducts in the human genome by ion trap and HR-MSn. DNA adductomics will provide a greater understanding of the chemicals in the diet and environment that damage the genome and contribute to cancer etiology.
For future seminars, please go to: http://www.pharmacy.arizona.edu/academics/graduate-programs/seminars
Host: Xinxin Ding, PhD | Department Head, Pharmacology and Toxicology, UA College of Pharmacy
Health Sciences Innovation Building (HSIB), Room 880
University of Arizona Health Sciences Campus
1670 E. Drachman St.
Tucson, AZ 85721