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,3
* Interdisciplinary Graduate Program in Nutritional Sciences, Department of Epidemiology, University of Washington, Seattle, WA and
Fred Hutchinson Cancer Research Center, Seattle, WA 98109
3To whom correspondence should be addressed. E-mail: jlampe{at}fhcrc.org.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • UGT1A1 • polymorphism • chemoprevention • Cruciferae • bilirubin
UDP-glucuronosyltransferases (UGTs)4 are a superfamily of phase II biotransformation enzymes that catalyze the transfer of the glucuronyl group from 5'-disphosphoglucuronic acid to endogenous molecules and exogenous substrates, producing less toxic and more easily excreted molecules. UGT1A1 is the major UGT enzyme responsible for glucuronidation of bilirubin (1), an endogenous antioxidant hypothesized to modulate susceptibility to oxidative damage and cancer [discussed by Grant and Bell in (2)]. UGT1A1 also conjugates 17ß-estradiol (the most biologically active estrogen) and estriol, as well as exogenous compounds such as phenols, anthraquinones, and flavones, many of which are found in the diet (3). Thus UGTs play an important role in the maintenance of steady-state levels of endogenous compounds and the handling of exogenous compounds, both toxic and potentially beneficial.
Genetic variants in the UGT1 family alter UGT activity (4,5). A polymorphic site in the promoter sequence upstream of UGT1A1 is characterized by variation in the number of thymine-adenine repeats (TA). UGT1A1*1 is the most commonly found allele with 6 TA repeats. The presence of only 5 TA repeats has been associated with increased transcription (6) whereas the presence of 7 (UGT1A1*28) or 8 TA repeats has been associated with decreased transcription (6–8) and is the genetic basis for benign unconjugated hyperbilirubinemia associated with reduced hepatic UGT conjugation of bilirubin (Gilbert syndrome) (4,8). Increased numbers of TA repeats are inversely correlated with UGT1A1 promoter activity (4,8) and directly with total serum bilirubin concentrations (4). Caucasian homozygous wild-type UGT1A1*1 (6/6) or heterozygous 6/7 have been shown to have approximately half the total serum bilirubin concentration compared to 7/7 homozygotes (UGT1A1*28) (9). Corroborating these in vivo differences, enzyme studies with human liver tissue demonstrated that bilirubin-glucuronide formation by UGT1A1 was 
80% and 50% for the 6/7 and 7/7 genotypes, respectively, compared to the 6/6 genotype (10). Fang and Lazarus (11) also found significantly decreased bilirubin-glucuronide formation for the 7/7 genotype only. Regarding potential effects on estrogen metabolism, a significant inverse association between the 6/7 and 7/7 genotypes and endometrial cancer risk has been reported (12). The 6/7 and 7/7 genotypes also show decreased glucuronidation of benzo(a)pyrene (11) and heterocyclic amines (13). Taken together, polymorphisms in UGT1A1 may influence bilirubin clearance, endogenous estrogenic load, and exposure to xenobiotics.
Dietary constituents also influence UGT activity. Sulforaphane, a phytochemical derived from cruciferous vegetables (cabbage, broccoli), increases UGT1A1 mRNA and protein levels in human HepG2 and HT29 cells (14). In rodents, soy protein and soy isoflavones increase hepatic UGT activity (15–17). Dietary monoterpenes (e.g., limonene in citrus oils) significantly increase the activity of both methylcholanthrene-inducible and phenobarbital-inducible UGTs in rats (18) and onion powder and allyl sulfides in garlic increase hepatic UGT activity in rats (19,20).
Human studies indicate dietary modulation of UGT activity, though the studies have been small and have not considered genetic polymorphisms that affect enzyme activity. Using acetaminophen as a drug probe, Pantuck et al. (21) demonstrated that 10 d of supplemental cruciferous vegetables (500 g/d) increased the formation of acetaminophen-glucuronyl conjugates and increased the ratio of acetaminophen glucuronide to free acetaminophen. Another report showed elevated UGT activity following consumption of 56.8 g of watercress (a cruciferous vegetable) at each meal for 3 d (22). Consistent with the animal data, Gwilt et al. (23) demonstrated slightly increased acetaminophen glucuronidation after 12 wk of garlic-extract supplementation (equivalent to 6–7 cloves/d). Strengthening the above observations is the evidence that UGT1A1 can be induced by the aryl hydrocarbon receptor and extracellular signal-regulated kinase, both of which have been shown to interact with phytochemicals from plant foods (24,25).
Our objective was to determine in an observational study if foods in the botanical groups Cruciferae (e.g., cabbage, broccoli), Rutaceae (citrus), Liliaceae (e.g., garlic, onions), and Leguminosae (legumes), within the context of habitual dietary intake, were associated with increased UGT1A1 activity using serum bilirubin as an endogenous indicator of UGT1A1 activity. We also wanted to test whether the association varied by UGT1A1 promoter genotype.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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2.5 or 
4.5 servings/d of fruits and vegetables during an initial telephone interview. To avoid biasing the dietary self-report, participants were not informed of the exact purpose of the original study. Exclusion criteria included liver disease, ulcerative colitis, Crohn disease, diabetes, wt change of >4.5 kg within the past y, major changes in eating habits within the past y, exercise regimens requiring significant short-term dietary changes, use of antibiotics within the past 3 mo, body wt > 150% of ideal, current use of prescription medications (excluding topical agents), chronic nonsteroidal anti-inflammatory drug use, alcohol intake > 2 drinks/d (2 drinks are equivalent to 720 mL of beer, 240 mL of wine, or 90 mL of spirits), occupational exposure to smoke (tobacco, wood, and so forth) or organic solvents, chronic exposure to second-hand tobacco smoke, intake of pharmacological doses of dietary supplements, and serum alanine aminotransferase concentrations above normal range. Participants were instructed to avoid all medication for 7 d prior to and during the study. All procedures were approved by the Institutional Review Board of the Fred Hutchinson Cancer Research Center. Participants gave informed written consent prior to the start of the study. Data and sample collection. Participants completed a demographic survey, health history, and food records on 3 d consecutively. All participants had venous blood samples drawn for genomic DNA collection and measurement of serum bilirubin.
Food records. Collection and analysis of participant food records has been previously described (26). Briefly, participants were instructed on how to collect food records by a trained nutritionist who also reviewed returned records for accuracy and completeness. Records were analyzed using the University of Minnesota Nutrition Data System (Nutrition Coordinating Center, University of Minnesota; Food Database version 12A, release date November 1996, Nutrient Database version 27, release date November 1996). Servings/d of fruits and vegetables were calculated using a scheme developed by the Nutrition Assessment Shared Resource at the Fred Hutchinson Cancer Research Center. Excluding herbs, spices, and grains (except for sweet corn), this classification scheme includes all edible plant tissues included in the Nutrition Data System Food Database. Servings/d of fruits and vegetables are calculated based on standardized serving sizes (1 cup raw, 1/2 cup cooked or canned, 1 cup juice, etc.) similar to those specified in the Dietary Guidelines for Americans (27), classified by culinary form (e.g., juice, fresh, fried) and further classified into 63 botanical families. In this investigation, we limited analysis a priori to 4 botanical groups: Cruciferae, Rutaceae, Liliaceae, and Leguminosae.
Determination of UGT1A1 promoter genotypes and serum bilirubin measurement. Genotyping of the UGT1A1 promoter TA-repeat and bilirubin measurements have been fully described elsewhere (9,28). Briefly, a fragment containing the TA-repeat was PCR-amplified in the presence of a 32P-labeled primer. Amplified fragments were separated on a denaturing polyacrylamide gel and exposed to X-ray film. Serum total and direct bilirubin were measured using a Cobas MIRA Plus centrifugal analyzer (Roche Diagnostic Systems). Indirect (or unconjugated) bilirubin was calculated by difference (total bilirubin – direct bilirubin).
Statistical analysis. Serum bilirubin data were evaluated for normality of distribution; natural logarithmic transformations were performed prior to analysis for total serum bilirubin, direct bilirubin, and indirect bilirubin. Intake for each botanical group was divided into tertiles for analysis. One-way ANOVA was used to test for differences in intake of each botanical group by UGT1A1 genotype. To assess effects of intake of each botanical group (tertiles; predictor variable), multivariate linear regression models were used for each botanical group with serum total, direct, or indirect bilirubin as the dependent variable. The models were adjusted for UGT1A1 genotype (categorical), age (continuous), sex, BMI (continuous), and total fruit and vegetable intake (continuous). Because previous studies have shown that the greatest difference in UGT1A1 activity is between 7/7 and the presence of one or more 6 alleles (10,11), the 6/6 and 6/7 genotypes were combined for the analysis. Statistical analyses were performed using Stata 8.0 (Stata Corporation). P < 0.05 was considered significant.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Mean total and direct bilirubin concentrations stratified by UGT1A1 genotype and tertile of intake of each botanical group are given in Table 3. Again, using multivariate linear regression adjusting for UGT1A1 genotype, age, sex, BMI, and total fruit and vegetable intake, there was no significant association with any of the botanical groups independently. However, upon testing for interaction between UGT1A1 genotype and botanical group intake with the same regression model, there was a statistically significant inverse association between the UGT1A1 gene-Cruciferae interaction term and total bilirubin (P = 0.017). There was also a significant inverse association between the UGT1A1 gene-Cruciferae interaction term and direct (P = 0.003) and indirect bilirubin (P = 0.020, data not shown). A parsimonious multivariate model that included UGT1A1 genotype (6/6 and 6/7 grouped together), BMI, sex, age, total fruit and vegetable intake, Cruciferae intake, and UGT1A1 gene-Cruciferae interaction term explained 45%, 30%, and 47% (R2 values) of the variation in total serum bilirubin, direct bilirubin, and indirect bilirubin, respectively. There were no significant associations between serum bilirubin measures and UGT1A1 genotype interaction with Rutaceae, Liliaceae, or Leguminosae intake.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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One explanation for the observed gene-diet interaction in those with the 7/7 genotype is the possibility of greater ability to detect differences in serum bilirubin because the concentrations in these individuals are markedly higher than in those with 6/6 or 6/7 genotypes (9). Consequently, even higher Cruciferae intake may be needed to lower already low bilirubin concentrations in those with 6/6 or 6/7 genotypes. Constituents of cruciferous vegetables could influence UGT1A1 expression (and thus bilirubin levels) through several signaling pathways. A xenobiotic response element has been identified in the UGT1A1 sequence, which interacts with the complex of the aryl hydrocarbon receptor (AhR) and its ligand to stimulate transcription (31,32). Glucosinolates in cruciferous vegetables can be hydrolyzed, by the plant enzyme myrosinase, to indoles and isothiocyanates when the plant cells are damaged (e.g., chewed, cut); indoles have been shown to bind to the AhR (24). Sulforaphane, an isothiocyanate, has been shown to induce UGT1A1 by modulation of extracellular signal-regulated kinase in the mitogen-activated protein kinase pathway in Caco-2 cells (25). Additionally, the nuclear receptors, pregnane X receptor and constitutive androstane receptor, also influence UGT1A1 expression and thus activity (33–36), although interaction with crucifer-derived compounds has not been specifically tested. The ability of nuclear receptors to interact with a broad spectrum of compounds is widely acknowledged. Thus, constituents in the Cruciferae family could interact at various points in signal transduction pathways to trigger sufficient induction of the UGT1A1 gene (the effect being more pronounced with the 7/7 genotype, perhaps due to a different conformation of the promoter region) to result in more enzyme production, greater bilirubin conjugation and thus increased bilirubin clearance.
A primary strength of this study is the wide range of fruit and vegetable intake by participants based on a recruitment criterion of consuming either 2.5 or 4.5 servings/d. Mean intakes of Cruciferae and Leguminosae by participants in both genotype groups were at least double the U.S. average intakes of 0.2 servings/d and 0.22 servings/d, respectively (average U.S. intake of Rutaceae and Liliaceae not individually reported) (37). Additional strengths include homogeneity among participants with regard to factors other than diet that could possibly influence enzyme activity (for example, age, BMI, and alcohol, tobacco, and medication use). The main limitation to the study is the relatively small number of people with the 7/7 genotype. However, they represented 11% of the total number of participants, which is similar to the prevalence reported previously (4,28). The results suggest that further investigation is warranted in a larger study population or a group specifically recruited on the basis of their UGT1A1 genotype. Another limitation to this study includes the usual questions regarding the reliability of 3-d food records and how accurately they reflect what was actually consumed. However, because rapid change in biotransformation enzyme activity is possible with changes in the diet, 3-d food records would capture the most relevant information, namely that on the most recent intake of foods that influence UGT1A1 activity. Another possible limitation is that databases are not fully equipped to handle analysis based on phytochemical content of foods or botanical groupings may be too broad. For example, we evaluated the effect of exposure to all foods in the Leguminosae botanical family, whereas animal studies have examined the effect of soy specifically, and soy intake was only a small component of Leguminosae intake in this group of participants. Evaluations in populations with higher soy intakes may prove more informative. In addition, the lack of any effect by Rutaceae, Liliaceae, and Leguminosae could be due to intakes being less than necessary to achieve the effects seen in animal studies and controlled human trials; further investigation of these botanical groups in controlled feeding trials may be beneficial. Finally, extensive exclusion criteria could mean that the people studied were highly select and not representative of the general population; such extensive exclusion criteria, though, improved homogeneity on a variety of exposures and host factors and enabled a better opportunity to investigate the effects of diet alone.
Although little is known about the potential role of bilirubin in carcinogenesis, the results of this analysis may have implications for other UGT1A1 substrates and the effect of the 7/7 genotype on the handling of those substrates. For example, UGT1A1 has been shown to conjugate carcinogenic heterocyclic amines (38). Glucuronidation of the polycyclic aromatic hydrocarbon benzo[a]pyrene was significantly decreased in liver microsomes from subjects with the 7/7 genotype (11) and urinary mutagenicity measures in subjects fed fried meats were significantly higher in those with the 6/7 or 7/7 genotype (13). Thus, individuals with reduced UGT1A1 activity due to the 7-fold TA repeat could be at greater risk for cancer due to decreased conjugation of carcinogens, but our results imply that they may also have a greater opportunity to mitigate that risk through cruciferous vegetable consumption.
In conclusion, we found an interaction between UGT1A1 genotype and Cruciferae intake such that those with the 7/7 genotype showed reduced bilirubin levels with increasing intake of cruciferous vegetables, possibly reflecting an interaction of cruciferous phytochemicals with signaling pathways in ways that increase gene expression. Moreover, our results underscore the complexity of gene-environment interactions and the need for better understanding of the functional effects of various polymorphisms and their interactions with various dietary constituents.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported in part by National Cancer Institute grant R01 CA70913 and training grant CA80416 (Peterson), the Fred Hutchinson Cancer Research Center, the University of Washington NIEHS-sponsored Center for Ecogenetics and Environmental Health (NIEHS P30ES07033), the Clinical Research Center Facility at the University of Washington, and by the National Institutes of Health grant M01-RR-0037.
4 Abbreviations used: AhR, aryl hydrocarbon receptor; TA, thymine-adenine; UGT, UDP-glucuronosyltransferase.
Manuscript received 15 November 2004. Initial review completed 5 December 2004. Revision accepted 7 February 2005.
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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