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.
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