Numerous previous studies have demonstrated that the common food antioxidants BHA and BHT, as well as naturally occurring substances present in a variety of vegetables, reduce the carcinogenic and toxic effects of a variety of chemical carcinogens. Recent studies have demonstrated that phenolic antioxidants reduce the covalent binding and carcinogenicity of the potent, naturally occurring dietary carcinogen, aflatoxin B1 (AFB), by inducing glutathione-S-transferases (GST). Specific forms of this enzyme appear responsible for the species differences in sensitivity to the hepatocarcinogenic effects of AFB. Some """"""""anticarcinogenic"""""""" vegetables such as broccoli and brussel sprouts are also effective inducers of GST, but also alter oxidative biotransformation pathways. Because induction of multiple biotransformation pathways can result in highly substrate-specific alterations in xenobiotics, it is essential to determine the effects of dietary treatments on actual chemical carcinogens of importance, rather than making inferences from """"""""surrogate"""""""" substrates which may behave very differently. Methods have recently been developed which allow for the determination of both the rate of oxidative formation of AFB- epoxide (the putative carcinogenic form), as well as rates of GST inactivation of the AFB-epoxide. With these methodologies it is now possible to assess the effects of dietary factors directly on the metabolic disposition of AFB. The long-range goal of this research project is to determine the biochemical mechanisms by which dietary factors such as vegetable consumption and antioxidant exposure influence carcinogen disposition. With such an understanding of mechanisms, dietary and/or chemical interventions may be rationally developed which could lead to reduction in chemical-induced cancers.
The specific aims of this project are to: 1) rigorously examine the relationship between diet-induced changes in specific hepatic biotransformation pathways and the covalent binding of the potent hepatocarcinogen aflatoxin B1 (AFB) to hepatic DNA in vivo, utilizing a) a diet containing PCBs, b) a diet containing beta-napthoflavone, c) a diet containing various concentrations of BHA (dose-response study), d) a diet containing both BHA and beta-napthoflavone, e) a diet containing 25% freeze-dried broccoli, and f) a diet containing only indoles at the same concentration as in the broccoli diet. Additional studies are also proposed to examine the structure- activity relationship between different phenolic antioxidants, enzyme induction and inhibition of AFB-DNA binding.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003933-03
Application #
3251674
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1988-05-01
Project End
1991-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Public Health
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Eaton, D L; Gallagher, E P; Bammler, T K et al. (1995) Role of cytochrome P4501A2 in chemical carcinogenesis: implications for human variability in expression and enzyme activity. Pharmacogenetics 5:259-74
Gallagher, E P; Buetler, T M; Stapleton, P L et al. (1995) The effects of diquat and ciprofibrate on mRNA expression and catalytic activities of hepatic xenobiotic metabolizing and antioxidant enzymes in rat liver. Toxicol Appl Pharmacol 134:81-91
Chen, Z Y; White, C C; He, C Y et al. (1995) Zonal differences in DNA synthesis activity and cytochrome P450 gene expression in livers of male F344 rats treated with five nongenotoxic carcinogens. J Environ Pathol Toxicol Oncol 14:83-99
Borroz, K I; Buetler, T M; Eaton, D L (1994) Modulation of gamma-glutamylcysteine synthetase large subunit mRNA expression by butylated hydroxyanisole. Toxicol Appl Pharmacol 126:150-5
Eaton, D L; Gallagher, E P (1994) Mechanisms of aflatoxin carcinogenesis. Annu Rev Pharmacol Toxicol 34:135-72
Gallagher, E P; Wienkers, L C; Stapleton, P L et al. (1994) Role of human microsomal and human complementary DNA-expressed cytochromes P4501A2 and P4503A4 in the bioactivation of aflatoxin B1. Cancer Res 54:101-8
Chen, Z Y; Liu, Y F; He, C Y et al. (1994) Inhibition of cell proliferation by ciprofibrate in glutathione S-transferase P1-1-positive rat hepatic hyperplastic nodules. Cancer Res 54:2622-9
Hulla, J E; Chen, Z Y; Eaton, D L (1993) Aflatoxin B1-induced rat hepatic hyperplastic nodules do not exhibit a site-specific mutation within the p53 gene. Cancer Res 53:9-11
Chen, Z Y; White, C C; Eaton, D L (1993) Decreased expression of cytochrome P450 mRNAs and related steroid hydroxylation activities in hepatic hyperplastic nodules in male F344 rats. Toxicol Appl Pharmacol 123:151-9
Buetler, T M; Eaton, D L (1992) Complementary DNA cloning, messenger RNA expression, and induction of alpha-class glutathione S-transferases in mouse tissues. Cancer Res 52:314-8

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