Individuals with higher plant food intakes, particularly vegetables, have lower risks of almost all cancers. Studies in animals and cells have demonstrated that bioactive components of plant foods confer resistance to chemical carcinogens via induction or inhibition of biotransformation enzymes. Thus, given environmental exposure, susceptibility to carcinogens is determined, in part, by the competence of enzymatic detoxification. Diet may modulate, and genetic polymorphisms may affect, toxicity of xenobiotics by altering expression/activity of bio-transformation enzymes. The goal of this project is to continue our work on determining the role of specific botanical families of plant foods in the induction or inhibition of particular enzyme systems relevant to carcinogenesis and to address how genetic polymorphisms in the enzymes alter effects of the plant foods. We propose a randomized crossover feeding trial to identify effects of CYP1A2C734A genotypes and variants of GSTM1 and GSTT1 and cruciferous and apiaceous (i.e., carrot-family) vegetable supplementation on CYP1A2 activity, serum glutathione S- transferase-alpha (GSTalpha), and urinary isothiocyanate excretion under defined-diet conditions.
The specific aims are: 1) To test effects of CYP1A2C734A genotype on induction or inhibition of CYP1A2 activity with vegetable supplementation; 2) To test whether concurrent consumption of cruciferous and apiaceous vegetables, compared to cruciferous alone, reduces CYP1A2 activity; 3) To measure the combined effect of GSTM1 and T1 genotypes on GSTalpha response to diet; and 4) To determine whether there is a dose-response of cruciferous vegetables on GSTalpha. We will screen and recruit, based on CYP1A2C734A, GSTM1, and GSTT1 genotypes, 72 non-smoking men and women, 20-40 years of age and randomize them to four diets: a fruit- and vegetable-free basal diet and the basal diet supplemented with: 1) cruciferous vegetables; 2) a double-dose of cruciferous vegetables; and 3) cruciferous and apiaceous vegetables combined. Each diet will be fed for 14 days, with a 3-week washout between feeding periods. We will measure serum GSTalpha on Days 0, 7, 11, and 14 and CYP1A2 activity (using caffeine metabolite ratios) on Days 7 and 14. This project addresses experimentally effects of diet constituents and genotype on specific biotransformation enzymes in humans -effects that have been observed in population-based studies. These findings will improve understanding of mechanisms of action of vegetable groups in altering and, being metabolized by, biotransformation enzymes and thus, eventually, move us towards new approaches to screening and prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070913-08
Application #
6990484
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Seifried, Harold E
Project Start
1996-07-01
Project End
2008-11-30
Budget Start
2006-01-18
Budget End
2008-11-30
Support Year
8
Fiscal Year
2006
Total Cost
$672,430
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Navarro, Sandi L; Brasky, Theodore M; Schwarz, Yvonne et al. (2012) Reliability of serum biomarkers of inflammation from repeated measures in healthy individuals. Cancer Epidemiol Biomarkers Prev 21:1167-70
Brauer, Heather Ann; Libby, Tanya E; Mitchell, Breeana L et al. (2011) Cruciferous vegetable supplementation in a controlled diet study alters the serum peptidome in a GSTM1-genotype dependent manner. Nutr J 10:11
Li, Fei; Hullar, Meredith A J; Beresford, Shirley A A et al. (2011) Variation of glucoraphanin metabolism in vivo and ex vivo by human gut bacteria. Br J Nutr 106:408-16
Li, Fei; Hullar, Meredith A J; Schwarz, Yvonne et al. (2009) Human gut bacterial communities are altered by addition of cruciferous vegetables to a controlled fruit- and vegetable-free diet. J Nutr 139:1685-91
Navarro, Sandi L; Chang, Jyh-Lurn; Peterson, Sabrina et al. (2009) Modulation of human serum glutathione S-transferase A1/2 concentration by cruciferous vegetables in a controlled feeding study is influenced by GSTM1 and GSTT1 genotypes. Cancer Epidemiol Biomarkers Prev 18:2974-8
Peterson, Sabrina; Schwarz, Yvonne; Li, Shuying S et al. (2009) CYP1A2, GSTM1, and GSTT1 polymorphisms and diet effects on CYP1A2 activity in a crossover feeding trial. Cancer Epidemiol Biomarkers Prev 18:3118-25
Navarro, Sandi L; Peterson, Sabrina; Chen, Chu et al. (2009) Cruciferous vegetable feeding alters UGT1A1 activity: diet- and genotype-dependent changes in serum bilirubin in a controlled feeding trial. Cancer Prev Res (Phila) 2:345-52
Chia, Victoria M; Newcomb, Polly A; White, Emily et al. (2008) Reproducibility of serum leptin, insulin-like growth factor-I, and insulin-like growth factor-binding protein-3 measurements. Horm Res 69:295-300
Lampe, Johanna W; Chang, Jyh-Lurn (2007) Interindividual differences in phytochemical metabolism and disposition. Semin Cancer Biol 17:347-53

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