Cruciferous vegetable feeding and inflammation: effect of GST genotypes

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): Consumption of cruciferous (i.e., broccoli-family) vegetables is associated with lower risk of several cancers, and is dependent, in part, on GSTM1/GSTT1 genotype. Isothiocyanates (ITC), the bioactive components derived from glucosinolates in crucifers, modulate enzymes that detoxify carcinogens and sex steroids, via activation of a transcription factor Nrf-2. Evidence also supports a role for ITC in another signaling pathway critical to carcinogenesis, inhibition of nuclear factor kappa-B (NF-kB). NF-kB is a transcription factor and central mediator in activation of genes involved in the inflammatory process, e.g., cytokines, chemokines, adhesion molecules and other soluble factors involved in the immune response. ITC inhibit NF-kB-mediated processes, and therefore may reduce inflammation -- a well-recognized risk factor of carcinogenesis. Higher levels of many cytokines have been associated with an increased risk of cancer. Variation in metabolism of ITC may influence ITC exposure and biologic response to these agents. Glutathione S-transferase (GST)M1 and GSTT1 metabolize ITC and genotypic differences in biologic response and ITC pharmacokinetics have been reported. However, it is not clear if the effects of these variants are on ITC metabolism or another unknown mechanism. There is a well-established literature on the modifying effects of GSTM1/GSTT1 genotypes in response to cruciferous vegetables;however the data are weak for other GST isoforms. Evidence suggests that activation of the transcription factor Nrf-2, as occurs with ITC, may diminish the pro- inflammatory cycle established via sustained NF-kB signaling. We will evaluate the role of cruciferous vegetables in inhibition of this pro-inflammatory signaling pathway relevant to carcinogenesis, and will address how variation in genes encoding enzymes that metabolize ITC alters effects of these plant foods in humans. We will examine, within our existing randomized, controlled feeding trial (R01 CA070913), effects of GSTM1 and GSTT1 genotypes and cruciferous vegetable supplementation on NF-kB-mediated serum inflammation biomarkers under defined-diet conditions. The aims are to determine whether there are effects of the vegetable diets and cruciferous-vegetable dose on serum inflammation biomarker concentrations and to measure the modifying effects of GSTM1 and GSTT1 genotype combinations on biomarker concentrations. We make efficient use of already collected samples. Participants were recruited based on GST genotype and randomized to 4 diets: a fruit- and vegetable-free basal diet and the basal diet supplemented with: 1) single- dose cruciferous vegetables;2) a double-dose;and 3) cruciferous + apiaceous vegetables. We will measure serum IL12, IL-6, IL-10, TNF-1, sTNF RI and RII, CRP, and SAA on Days 0, 7, and 14 of each period and evaluate diet and genotype effects;and examine associations between 24-h urinary ITC and these biomarkers. Results of this study will improve our understanding of the action of cruciferous vegetables on the NF-:B pathway in humans and will provide important data as to the impact of genetic variation on response. PUBLIC HEALTH RELEVANCE: In order to make accurate public health recommendations it is important to understand more fully how specific types of vegetables, such as those in the broccoli and carrot families, affect certain processes involved in cancer prevention. Moreover, it is important to test if particular genetic characteristics augment or decrease the effect of these vegetables.