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2 Interdisciplinary Graduate Program in Nutritional Sciences, Department of Epidemiology, University of Washington, Seattle, WA 98195 and 3 Fred Hutchinson Cancer Research Center, Seattle, WA 98109
* To whom correspondence should be addressed. E-mail: jlampe{at}fhcrc.org.
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ABSTRACT |
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 TOP ABSTRACT IntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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10 servings/d (doses adjusted for body weight) of crucifers, soy, and citrus for 2 wk compared with a fruit- and vegetable-free basal diet affected UGT1A1 activity as measured by serum bilirubin concentrations and whether effects were modulated by the UGT1A1*28 polymorphism. Healthy men (n = 32) and women (n = 31), aged 20–40 y, enrolled based on UGT1A1 genotype, completed the study. We measured bilirubin in blood collected at d 8 and d 15 of each feeding period. Overall, fruit and vegetables (F&V) did not affect serum bilirubin; however, among 7/7 individuals, d 8 total (P = 0.057) and indirect (unconjugated) (P = 0.051) bilirubin tended to be lower when individuals consumed the F&V diet (28.97 ± 2.36 µmol/L and 25.97 ± 2.15 µmol/L) compared with the basal diet (32.46 ± 2.63 µmol/L and 29.31 ± 2.43 µmol/L). We no longer detected this difference at d 15, by which time bilirubin had also decreased when participants consumed the basal diet. Additionally, intervention effects on bilirubin were restricted to women with 7/7 genotype (P = 0.002). These results suggest that serum bilirubin glucuronidation is modulated by dietary intervention, but factors such as UGT1A1 genotype and sex may affect the response to diet.
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Introduction |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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Polymorphisms in the upstream promoter region of UGT1A1, characterized by variation in the number of thymine-adenine (TA) repeats, modulate UGT1A1 transcriptional activity (8,9). Compared with the most common 6 TA repeats (UGT1A1*1), the presence of 7 (UGT1A1*28) or 8 TA repeats has been shown to decrease transcription (10,11) and is the genetic basis for mild unconjugated hyperbilirubinemia associated with reduced hepatic UGT conjugation of bilirubin (Gilbert syndrome) (3). In an observational study of Caucasians, we showed that individuals with the wild-type (wt) 6/6 genotype or heterozygous 6/7 genotype have approximately one-half the total serum bilirubin concentration of those with the homozygous 7/7 genotype (12). Raijmakers et al. (13) also demonstrated, using human liver samples, that, compared with the 6/6 genotype, median UGT1A1 activity is 63 and 48% for the 6/7 and 7/7 genotypes, respectively.
UGT1A1 is inducible by several dietary phytochemicals. Sulforaphane, the hydrolysis product of glucoraphanin in Brassica vegetables, has been shown to increase UGT1A1 mRNA and protein levels in HepG2, HT29, and Caco-2 cells (14–17). Soy isoflavones and flavonoids increase hepatic UGT activity in rodents (18–20). In a recent observational study, we reported a significant inverse association between serum bilirubin concentrations and interaction of UGT1A1*28 genotype with Cruciferae intake; only individuals with the 7/7 genotype had decreased bilirubin concentrations with increased intake of cruciferous vegetables (21). However, intervention studies of UGT activity modulation in humans by dietary components are limited (22,23) and the potential modifying effects of UGT polymorphisms have not been investigated.
Our objective was to determine, in a controlled, randomized crossover feeding trial, whether a defined fruit and vegetable (F&V) intervention affects serum bilirubin concentrations and whether there is a UGT1A1*28 genotype-by-diet response.
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Subjects and Methods |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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Feeding study design. The feeding study was conducted between April 2002 and May 2005. The recruitment strategy was to enroll at least 60 participants, maintaining the genotype ratios of 6/6, 6/7, and 7/7 of UGT1A1 and of wt/wt, wt/T181A+R184S, and T181A+R184S/T181A+R184S of UGT1A6 as 2:2:1; and the ratio of D/D, D/Y, and Y/Y of UGT2B15(D85Y) as 1:2:1, with equal numbers of men and women. Because of the substrate specificity of UGT1A1 for bilirubin, we focused only on the UGT1A1 genotype. (UGT1A6 and UGT2B15 genotypes are of interest in relation to other metabolic outcomes not discussed here.) Participants were requested not to take any type of medication, alcoholic beverages, or single-vitamin, multi-vitamin, mineral, and herbal supplements during each feeding period and to maintain their usual physical activity. Additional informed, signed consent was obtained from those who agreed to participate in the feeding trial. In all, we randomized 72 individuals. Of these, 5 withdrew from the study within the 1st 5 d on the initial diet, 2 withdrew after the initial feeding period, 1 withdrew during the 2nd diet, and 1 was noncompliant. As these individuals withdrew, we selected new recruits and randomly placed them into the appropriate treatment orders to maintain the blocks. A total of 63 participants completed the study; among them were 26 UGT1A1–6/6 (12 women and 14 men), 23 UGT1A1–6/7 (11 women and 12 men), and 14 UGT1A1–7/7 (8 women and 6 men). Upon completion of the study, each participant received $200.
Participants were randomized, blocked on sex and UGT1A1 genotype, using a crossover study design with each participant receiving 2 experimental diets (basal diet and basal diet supplemented with F&V) in assigned random order. Participants consumed each diet for 2 wk then resumed their habitual diets during a wash-out period of at least 2 wk between each diet period (Fig. 1). Within each diet period, we used a 2-d menu rotation to increase participant adherence.
Study diets.
Participants consumed 2 different diets: a basal diet devoid of F&V (Table 1) and the basal diet supplemented with cruciferous vegetables, soy foods, and citrus fruits, plant foods that increased UGT activity in animal and human studies (18,20,22,24). The amount of F&V provided to the participants was at levels equivalent to 10 servings/d, but we calculated doses on the basis of each participant's body weight (BW). First, we standardized the diet according to servings for a 55-kg individual, determining the g food/kg BW of each plant food item and then increased or decreased amounts for individuals who were heavier or lighter than 55 kg using 5-kg intervals (Table 2). The amounts of foods in the basal diet were also adjusted to accommodate the added F&V, such that both diets provided a similar percent energy from carbohydrate (56%), protein (16%), and fat (28%). All prepackaged foods were purchased in case lots and fresh foods were purchased from the same vendor. We determined the nutrient content of the diets using the Nutrition Data System for Research software version V 4.05_33 developed by the Nutrition Coordinating Center, University of Minnesota.
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Female participants were scheduled for the feeding periods according to time in their menstrual cycles, with the goal that sample collection for each feeding period occurred during the same phase of cycle. Women were also asked to keep menstrual cycle diaries.
Specimen collection. At d 8 and d 15 of each feeding period, a 10-h fasting morning blood was collected for serum. The serum, aliquotted and stored at –80°C, was used to measure total and direct (conjugated) bilirubin concentrations. On d 14 of each feeding period, participants collected urine for 24 h. All urine samples were refrigerated at 4°C until delivery in the morning (d 15). The total volume and pH value were recorded and the sample was aliquotted and stored at –80°C.
Determination of UGT1A1 genotypes. Genotyping of the UGT1A1 polymorphism was done as described previously (12), with the exception of using a fluorescently labeled forward primer (5'6FAM-GTCACGTGACACAGTCAAAC-3') and a tailed reverse primer (5'-GTTTCTTTTTGCTCCTGCCAGAGGTT-3') designed to reduce problems with A-additions to PCR fragments. Amplified fragments of 103, 105, 107, and 109 bp were analyzed using an ABI PRISM 3100 Genetic Analyzer and Genotyper 2.5 software (Applied Biosystems).
Determination of serum bilirubin measurement. Serum total and direct bilirubin were measured using a Cobas MIRA Plus centrifugal analyzer (Roche Diagnostic Systems) (12). Mean intra- and inter-assay CV were, respectively, 1.7 and 0.8% for total bilirubin and 6.3 and 7.5% for direct bilirubin. Indirect (unconjugated) bilirubin was calculated by difference.
Urinary isothiocyanates and isoflavones. Twenty-four-hour urine samples collected on d 14 were used to measure isoflavonoids and total isothiocyanates (ITC). The soy isoflavones, genistein and daidzein, and the daidzein metabolites, equol and O-desmethylangolensin, were measured by GC-MS in selected ion monitoring mode, as described previously (25). Intra- and inter-assay CV were <10% for all analytes.
The urinary total ITC assay, including the synthesis of phenethyl ITC-N-acetyl conjugate used for standard calibrations, was based on the method developed by Chung et al. (26), with each urine sample processed as duplicates. The HPLC set-up consisted of 1100 Agilent automated system (Agilent Technologies) equipped with Agilent diode array detector and C18 µBondapak analytical column (150 x 3.9 mm) and a guard column (Waters). The mobile phase was methanol:water (70:30, v:v) at 1.75 mL/min. At the beginning of each run, the mobile phase was held isocratic for 9 min then increased to 100% for 13 min with 7 min equilibration post time prior to the next injection. Total ITC was a single peak detected at 365 nm. The inter-batch CV at 10 µmol, 78 µmol, and 140 µmol were 9, 6, and 10%, respectively.
Statistical analysis. We stratified study participant characteristics, habitual bilirubin measures, and habitual F&V intake by UGT1A1 genotype and sex (Table 3). We performed tests for trends across UGT1A1 genotypes (men and women combined) by comparing means for each genotype and treating the variables as linear terms. P < 0.05 was considered significant.
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Results |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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Overall, in response to the controlled feeding periods, diet did not affect the 3 bilirubin measures. A strong genotype effect was detected for all 3 bilirubin measures (P < 0.001); participants with 7/7 genotype exhibited the highest bilirubin measures and 6/6 participants had the lowest. Sex affected total bilirubin (P = 0.014) and indirect bilirubin (P = 0.011), with men having higher concentrations than women. Total (P = 0.023) and indirect (P = 0.023) bilirubin measures differed between sampling day, with higher concentrations on d 8 than d 15. Diet order did not affect bilirubin concentrations.
Serum bilirubin measures stratified by UGT1A1 genotype, diet treatment, and day of sampling are presented in Table 4. Diet and day of sampling did not affect these variables in the 6/6 and 6/7 individuals. Among 7/7 individuals, however, the d 8 total (P = 0.057) and indirect bilirubin (P = 0.051) concentrations tended to be lower when participants consumed the F&V diet compared with the basal diet, but there was no difference on d 15. A weak UGT1A1 genotype and diet interaction was observed in d 8 total bilirubin (P = 0.059) and d 8 indirect bilirubin (P = 0.055). No significant interaction was observed in d 15 measures. The 7/7 individuals had decreases in total (P = 0.007), direct (P = 0.005), and indirect (P = 0.010) bilirubin concentrations from d 8 to d 15 of the basal diet. Total (P = 0.089) and indirect (P = 0.087) also tended to decrease when they consumed the F&V diet.
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Discussion |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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One possible reason for the modest effect of the F&V diet in the feeding study is our choice of foods for the intervention. Several lines of recent evidence suggest that different phytochemicals, even within the same plant food, might have opposite effects on UGT1A1. Pfeiffer et al. (27) recently reported that daidzein significantly stimulated the 3-glucuronidation of 17ß-estradiol, a pathway specific to UGT1A1 (5), in human liver microsomes, whereas genistein inhibited 3-glucuronidation. Furthermore, the fruit flavonoids, naringenin and quercetin, also have been reported to have opposite effects on UGT1A1; Galijatovic et al. (28) reported that 10 µmol quercetin significantly induced UGT1A1 activity in Caco-2 cells, whereas Williams et al. (29) reported that naringenin at the same concentration strongly inhibited 3-glucuronidation of 17ß-estradiol in human liver microsomes. Thus, the complex mixture of phytochemicals in the F&V diet may have reduced the potential for maximal increase in UGT1A1 activity.
When we compared data from different sampling days, we detected a significant decrease in bilirubin from d 8 to d 15 when participants consumed the basal diet, but not the F&V diet. Using the habitual bilirubin data from the observational study as a surrogate for baseline (d 0 of the feeding period), we found that, in the 7/7 individuals, total bilirubin concentration was 13% higher on d 8 of the basal diet compared with the habitual diet measure, a difference that was not observed when they consumed the F&V diet. The removal of F&V from individuals' habitual diets when they started the basal diet period may have contributed to the bilirubin increase. Li et al. (30) reported that incubation of rat hepatocytes with bilirubin (within the physiological range of serum bilirubin levels in rats) increased UGT1A1 mRNA expression, suggesting that bilirubin modulates its own metabolism. This may explain in part the reversion to baseline bilirubin concentrations from d 8 to d 15 of the basal diet.
Another possible explanation is that oxidative stress activates the nuclear factor erythroid 2-related factor 2-antioxidant response element pathway [review in (31)], which modulates the induction of UGT1A1 and several other phase II biotransformation enzymes. We hypothesize that, compared with the habitual diet (containing phytochemicals), removal of the F&V during the basal diet period may increase oxidative stress and activate the nuclear factor erythroid 2-related factor 2-antioxidant response element pathway, thus increasing UGT1A1 expression. Rezar et al. (32) reported that a diet devoid of F&V in pigs resulted in a significant increase in the rate of leukocyte DNA damage, a biomarker of oxidative stress. Similarly, in several human intervention studies, some, but not all, markers of oxidative stress were higher on low-F&V diets than F&V-supplemented diets (33–36).
To our knowledge, the extent to which the UGT1A1*28 polymorphism affects the enzyme's inducibility has not previously been studied in vivo. The interaction between UGT1A1 genotype and F&V diet in d 8 total bilirubin (P = 0.059) and d 8 indirect bilirubin (P = 0.055) in our study suggested that UGT1A1 inducibility differed by genotype, i.e. effects were observed in 7/7, but not in 6/6 and 6/7, individuals. Only 1 other study has examined enzyme inducibility by the UGT1A1*28 polymorphism. Ramirez et al. (37) incubated human hepatocytes with phenobarbital (a UGT1A1-inducer) and, using SN-38 as substrate, showed no difference in UGT1A1 inducibility in the hepatocytes from 6/6 and 6/7 donors. This is consistent with our observations. Unfortunately, the investigators did not have any samples from 7/7 donors. Structurally, an additional TA repeat in the UGT1A1 promoter region would change the distance to other transcription factors that may be binding further downstream in the promoter, and the 2-bp insertion can also change the alignment of transcription factors bound upstream or downstream of the TATA-box. However, the mechanism by which the extra TA repeat affects the capacity of phytochemicals and other agents to modulate UGT1A1 induction remains to be determined. We also cannot rule out the role of another UGT1A1 promoter polymorphism, UGT1A1*60 (-3279T > G), which is in linkage disequilibrium with UGT1A1*28 (38). UGT1A1*60 polymorphism has been shown to be associated with decreased UGT1A1 transcriptional activity and hyperbilirubinemia (39), and irinotecan toxicity (38). However, to date, there are no data on how this polymorphism affects gene expression.
The capacity of F&V to alter bilirubin glucuronidation also differed by sex in this study. Overall, men had higher serum bilirubin concentrations than women, which was reported previously in observational studies (12,40–42), but women responded more favorably to the F&V intervention. We formulated the feeding study diets such that F&V were dosed on the basis of BW to minimize confounding of sex by BW (43). Thus, the observed sex differences in response to diet are unlikely to be attributed to a dose/kg BW difference. Sex differences in biotransformation capacity in general have been documented (44) and estrogen is thought to be an important factor for the sex difference in liver gene expression (45). Oral contraceptive and postmenopausal estrogen use are associated with lower bilirubin concentration in women (46); however, evidence of the capacity of estrogens to modulate UGT1A1 induction by dietary factor is lacking and warrants further evaluation.
A primary strength of this study was the controlled feeding study design. In addition, we supplied F&V doses based on participants' BW, which allowed us to test effectively sex differences and avoid confounding by weight differences between men and women. Another strength of this study was the length of the treatment period. Most hepatic enzyme induction occurs rapidly in response to diet or drugs; 5 d is the typical period used for monitoring enzyme induction in drug tests (47) and other dietary studies showed that 3–10 d are sufficient to observe increased phase II enzyme activity (22,23,43,48,49). Our 14-d feeding period with sample collection midway and at the end of the period allowed us to investigate differences over time. Additional strengths included the strict selection criteria implemented to minimize factors (e.g. age; BMI; use of alcohol, tobacco, and medication; and chronic exposure to organic solvents) other than diet that could influence UGT activity. One limitation of our study was that, although this controlled feeding study is 1 of the largest to date to evaluate effects of diet on glucuronidation, we established the sample size to detect with 80% power a 15% difference in total bilirubin by diet. Based on post hoc calculations using the study data, we would need 32 individuals with the 7/7 genotype to have 80% power to detect the 10% difference observed in 7/7 participants. Another limitation was that we relied on serum bilirubin concentration as a surrogate marker for UGT1A1 activity. It is possible that the diet effect on UGT1A1 at the hepatic level is larger than what we can measure indirectly using circulating bilirubin.
UGT1A1 detoxifies several dietary carcinogens such as PhIP (50). In vitro and human studies showed that increased UGT1A1 activity by F&V constituent(s) increased the glucuronidation of PhIP metabolites (28,51). In a recent study using human liver samples, Girard et al. (6) reported that the UGT1A1*28 polymorphism influenced the glucuronidation of PhIP metabolites; the homozygous variant had poorer conjugation of these carcinogens. With some epidemiologic evidence also showing that the UGT1A1*28 polymorphism is associated with risk of certain cancers (11,52–56), more understanding of dietary effects on UGT1A1 activity modulation and genotype-by-diet interactions may be valuable in developing cancer prevention strategies.
In summary, supplementation of a F&V-free basal diet with cruciferous vegetables, soy foods, and citrus fruits resulted in lower serum bilirubin concentrations in individuals who were UGT1A1*28 homozygous variant (7/7). In addition, the intervention effects on bilirubin were restricted to women with the 7/7 genotype. These results suggest that serum bilirubin glucuronidation can be modulated by dietary intervention, but factors such as UGT1A1 genotype and sex may affect the degree of bilirubin conjugation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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4 Abbreviations used: BW, body weight; F&V, fruit and vegetable; ITC, isothiocyanate; PhIP, 2-amino-1-methyl-6-phenylimidaxo[4,5-b]pyridine; TA, thymine-adenine; UGT, UDP-glucuronosyltransferase; wt, wild-type.
Manuscript received 27 September 2006. Initial review completed 26 October 2006. Revision accepted 5 January 2007.
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LITERATURE CITED |
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