Journal of Clinical Toxicology
Open Access

Determining genetic susceptibility to food carcinogens using Saccharomyces cerevisiae (Budding Yeast)

4^th Global Summit on Toxicology

August 24-26, 2015 Philadelphia, USA

Michael Fasullo, Nick St John and Julian Freedland

Scientific Tracks Abstracts: J Clin Toxicol

Abstract :

The human response to environmental carcinogens that require bioactivation is highly variable. Environment, lifestyle, and
genetics are factors that influence bioactivation. Genetic factors include polymorphic P450 and DNA repair genes; however,
epidemiological studies may lack significance due to inadequate patient numbers. We used budding yeast as a model organism to
determine genetic susceptibility to food-associated carcinogens, including benzopyrene (BaP), aflatoxins (AFB1) and heterocyclic
aromatic amines (HAAs). Budding yeast does not contain P450s that activate these compounds, so we introduced expression vectors
that contain specific human P450 and NAT2 genes. In yeast, either CYP1A2 or CYP1A1 activates AFB1, while both CYP1A2 and
NAT2 are required for activation of IQ. To measure genotoxic effects, we measured recombination and mutation frequencies, Rad51
foci, growth inhibition and DNA adducts, as in a previous publication concerning CYP1A2 polymorphisms. Here, we analyzed two
CYP1A1 polymorphisms, T461N and I462V, correlated with breast and lung cancer. Although some studies have suggested that these
polymorphisms confer reduced activity, both CYP1A1 polymorphisms are highly efficient at activating the AFB1and benzo[a]pyrene
dihydrodiol (BaP-DHD). To determine resistance genes, we used a high throughput approach for screening the yeast deletion library
expressing specific P450 genes. Screens for aflatoxin resistance identified checkpoint and RNA metabolism genes that are mutated in
cancers. We are now performing screens to identify genes involved in resistance to 2-amino-3-methylimidazo [4,5-f] quinoline (IQ).
Preliminary data identified both recombinational repair and DNA damage tolerance genes. Further high throughput analysis will be
performed using other food carcinogens, including 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) and 2-amino-3,8-
dimethylimidazo [4,5-f] quinoxaline (MeIQx).

Biography :

Michael Fasullo earned his PhD at Stanford University School of Medicine, Department of Biochemistry, and completed his Postdoctoral studies at Columbia University
in the field of DNA repair and recombination. He has published over 25 papers in the field of DNA damage response, radiation repair and environmental toxicology. His
current interest centers on high throughput screening for resistance to P450-activated carcinogens. He is currently an Associate Professor at the State University of New
York Polytechnic Institute, Albany, NY.