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Symposium: Testing the Cruciferous Vegetable-Cancer Relationship: From Basic Science to Observational Studies and Back

Interindividual differences in response to cruciferous vegetable diets: Implications for cancer risk.

Fred Hutchinson Cancer Research Center, Seattle, WA

Abstract

SY18-04

Glucosinolates (ß-thioglycoside N-hydroxysulfates) in cruciferous vegetables are hydrolyzed by the plant enzyme myrosinase when the cells in plants are damaged (e.g., cut, ground, or chewed), releasing the biologically active isothiocyanates (ITC). If myrosinase has been inactivated (e.g., with cooking), intestinal microbial metabolism of glucosinolates also contributes to ITC exposure, albeit at a lower level (1). Within the Brassica genus and species, different glucosinolates predominate and yield distinct ITC (2). The primary route of in vivo metabolism of ITC is by the mercapturic acid pathway, a major pathway for elimination of many xenobiotics (3). Thiol conjugates of ITC are formed by conjugation with glutathione, catalyzed by GST. Subsequent, stepwise cleavage of glutamine and glycine yields L-cysteine-ITC, which are acetylated to produce N-acetyl-L-cysteine ITC conjugates (mercapturic acids); these are excreted in urine. Thus, the natural variation in glucosinolate content of cruciferous vegetables, the range of methods used to prepare these foods (i.e., degree of myrosinase inactivation), and the activity level of the consumers’ dentition and colonic microbes all contribute to an individual's isothiocyanate exposure and potentially level of chemoprotection. Moreover, relationships between cruciferous vegetable intake and cancer risk may be influenced by genetic polymorphisms in biotransformation enzymes that metabolize ITC (e.g., GSTs), as well as possibly in receptors and transcription factors that interact with these compounds.

Investigators have hypothesized that individuals who are null for GST and who therefore less readily conjugate and excrete ITC, would have greater amounts of isothiocyanates at the tissue level, and hence would experience a greater protective effect (4). Results of one population-based study of ITC excretion among Chinese showed that urinary ITC was higher among GSTT1-positive, relative to GSTT1-null, individuals, but that GSTM1 and P1 genotypes had no effect (5). A recent pharmacokinetic study of sulforaphane disposition showed that GSTM1-null, relative to GSTM1+, individuals, had greater areas under the curve for plasma sulforaphane metabolite concentrations, faster rates of urinary sulforaphane metabolite excretion in the first 6 hours following consumption, and higher total excretion of sulforaphane and its metabolites over 24 h (6). Whether these differential responses are a function of differences in the varieties of ITC present in broccoli versus crucifers commonly consumed in China remains to be established (6); however, they speak to the further need to understand how genotype influences ITC disposition.

Several studies also suggest that polymorphisms in ITC-metabolizing enzymes may affect response of other biotransformation enzymes to ITC exposure. In one cross-sectional study, among frequent consumers of broccoli, GSTM1-null, relative to GSTM1+, individuals had a 21% higher CYP1A2 activity (7). This relationship was not observed in a controlled feeding study designed to test a priori the effect of GSTM1 genotype on response to a diet high in cruciferous vegetables; increased CYP1A2 activity on the crucifer-containing diet was not affected by GSTM1 genotype (8). However, in this same feeding study (9), serum GST concentration, a surrogate measure of hepatic GST and an enzyme also induced by ITC, increased significantly in response to cruciferous vegetable feeding, but only in GSTM1-null individuals.

Polymorphisms that affect the interaction of ITC with promoter regions or transcription factors also have the potential to influence cancer risk. UDP-glucuronosyltransferase (UGT) 1A1 is a conjugating enzyme that maintains levels of endogenous compounds (e.g., bilirubin) and handles exogenous compounds, including carcinogens. The UGT1A1*28 polymorphism results in decreased UGT1A1 promoter activity due to 7 thymine-adenine (TA) repeats instead of the commonly found 6 repeats. An inverse association between serum bilirubin concentrations (measure of UGT1A1 activity) and the interaction of UGT1A1*28 genotype with crucifer intake in a cross-sectional study suggests that constituents of the Cruciferae family may more efficiently induce UGT1A1 gene expression when there are 7 TA repeats; individuals with the 7/7 genotype had reduced bilirubin concentrations with increased intake of cruciferous vegetables, whereas individuals with the 6/6 or 6/7 genotype did not (10).

In conclusion, few human intervention studies designed to test the effects of a crucifer-rich diet on biomarkers of cancer susceptibility and risk have examined the effects of genotype on response to these diets. Understanding the relationships between genotype and ITC disposition and action in the context of controlled diets may aid in the interpretation of the epidemiologic findings related to cruciferous vegetable intake and cancer risk.