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Cancer Prevention through Dietary Compounds - Influence of Naturally Ooccurring Flavonoids on Polycyclic Aromatic Hydrocarbon-Metabolizing Enzymes and DNA-Binding using a Fish ModelEPA Grant Number: FP916431
Title: Cancer Prevention through Dietary Compounds - Influence of Naturally Ooccurring Flavonoids on Polycyclic Aromatic Hydrocarbon-Metabolizing Enzymes and DNA-Binding using a Fish Model
Investigators: Tsuji, Petra A.
Institution: Medical University of South Carolina
EPA Project Officer: Manty, Dale
Project Period: January 1, 2004 through December 31, 2006
Project Amount: $109,507
RFA: STAR Graduate Fellowships (2004) RFA Text | Recipients Lists
Research Category: Fellowship - Toxicology , Academic Fellowships , Health Effects
The objective of this research project is to investigate the chemopreventive potential and mechanism of the flavonoid 5,7-dimethoxyflavone (DMF) in inhibiting adverse biological effects exerted by environmental pollutants, such as Benzo[a]pyrene (BaP), using fish models.
Exposure to polycyclic aromatic hydrocarbons (PAHs) is known to predispose cancer development in several organs (e.g., lung in humans and liver in fish). For PAHs to bind to DNA and thus initiate carcinogenic processes, these chemicals need bioactivation by enzymes such as cytochrome P450 (CYP) and epoxide hydrolase (EH). Bioactivation of BaP by these enzymes results in the highly reactive ultimate carcinogenic metabolite BaP-7,8-diol-9,10-oxide, which binds to cellular macromolecules such as proteins and, more importantly, DNA. Other enzymes, such as UDP-glucuronosyl-transferase (UGT) and glutathione-S-transferase (GST), may be protective by inactivating the ultimate carcinogenic form. It is the balance between these bioactivating and bioinactivating enzymes that determines the extent of DNA-binding and thus presumably the risk of developing cancer.
Dietary flavonoids represent a completely new group of naturally occurring, nontoxic chemicals capable of preventing DNA-binding, and/or down-regulating enzymes involved in the bioactivation of procarcinogens. It is the goal of this research proposal to determine the protective properties of the flavonoid DMF on the DNA-binding of BaP as well as on expression and catalytic activity of BaP-bioactivating and BaP-bioinactivating enzymes, including the mechanisms involved, in cultured fish hepatocytes and in the marine teleost Fundulus heteroclitus after in vivo exposure to DMF. Experiments in our laboratory indicate that hepatic microsomal-induced DNA-binding of BaP is as much as 45-fold higher, CYP1A1 activity more than 10-fold, and EH activity more than 3-fold higher in F. heteroclitus than in humans, making this fish a sensitive model to investigate chemically-induced carcinogenesis. Our investigations showed that in vitro incubation of fish liver microsomes with DMF resulted in a dramatically decreased DNA-binding of 3H-BaP. Using sensitive fish models provides an efficient and unique angle to elucidate pathways of chemical carcinogenesis and a potential prevention technique that may contribute to the increase in quality and years of healthy life in humans.