Glutathione transferases in humans: dietary influences

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

PROJECT SUMMARY Higher consumption of cruciferous (i.e., broccoli-family) vegetables is associated with lower risk of several cancers. Isothiocyanates (ITC), the bioactive components derived from glucosinolates in cruciferous vegetables, have been shown to modulate enzymes that metabolize exogenous compounds (e.g., carcinogens) and endogenous compounds (e.g., sex steroid hormones) implicated in cancer risk. Genetic variants and differences in gut microbial community, in combination with types of cruciferous vegetables consumed by different populations, may contribute to observed differences in the modifying effect of glutathione S-transferase (GST)M1 genotype on associations between cruciferous vegetable consumption and cancer risk in Western and Asian populations. Cruciferous vegetables have different glucosinolate profiles. ITC availability from cooked cruciferous vegetables is dependent on gut microbial hydrolysis of glucosinolates. Further, depending on the chemical structure, an ITC may be more or less readily metabolized by GST and vary in capacity to induce biotransformation enzymes. Our goal is to continue to define the role of cruciferous vegetables in induction or inhibition of enzyme systems relevant to carcinogenesis, and to address how genetic variants in the enzymes that metabolize ITC, as well as differences in gut microbial community, alter effects of these plant foods. We propose a randomized crossover feeding trial of broccoli and green cabbage supplementation on measures of CYP1A2, GST-[unreadable], and UGT1A1, and ITC excretion under defined-diet conditions. The specific aims are: 1) To test the effect of broccoli and green cabbage (sources of different ITC) on caffeine metabolite ratios (CYP1A2 activity), serum GST-[unreadable], and serum bilirubin (UGT1A1 activity);2) To compare the enzyme responses to diet by GSTM1 genotype (GSTM1+ and GSTM1null);3) To compare responses to diet between East Asian and Caucasian participants;and 4) To compare the effects of the controlled diets on gut microbial community (i.e., gut microbial composition of Eubacteria, total bacterial biomass). We will screen and recruit 96 non-smoking men and women, 20-40 years of age, based on GSTM1 genotype and East Asian and Caucasian background. Participants will receive 3 controlled diets in assigned random order: 1) a fruit-and vegetable-free basal diet;2) basal diet + broccoli;and 3) basal diet + green cabbage. Each diet will be fed for 14 days, with a 3-week washout between feeding periods. We will measure serum GST[unreadable] and bilirubin on Days 0, 7, 11, and 14 and caffeine metabolite ratios on Days 1 and 15. Fecal samples will be collected at the end of each period. Results of this study will improve understanding of mechanisms of action of different crucifers on biotransformation enzymes, in different genetic and racial populations, and will address the contribution of gut bacterial metabolism to this response.