Genetic ancestry in relation to the metabolic response to a US versus traditional Mexican diet: a randomized crossover feeding trial among women of Mexican descent.

BACKGROUND/OBJECTIVES: Certain populations with a large proportion of indigenous American (IA) genetic ancestry may be evolutionarily adapted to traditional diets high in legumes and complex carbohydrates, and may have a detrimental metabolic response to US diets high in refined carbohydrates and added sugars. We tested whether IA ancestry modified the metabolic response to a US versus traditional Mexican diet in a controlled dietary intervention. SUBJECTS/METHODS: First and second generation Mexican immigrant women (n=53) completed a randomized crossover feeding trial testing the effects of a US versus traditional Mexican diet. The metabolic response to the diets was measured by fasting serum concentrations of glucose, insulin, insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3), adiponectin, C-reactive protein, interleukin-6 and computed homeostasis model assessment for insulin resistance (HOMAIR). Blood collected at baseline was used for genotyping, and estimation of African, European and IA ancestries with the use of 214 ancestry informative markers. RESULTS: The genetic ancestral background was 56% IA, 38% European and 6% African. Women in the highest IA ancestry tertile (>62%) were shorter in height, less educated and less acculturated to the US lifestyle, and tended to have higher waist-to-hip ratio compared with women in the middle and lowest IA ancestry tertiles, respectively. Compared with the US diet, the traditional Mexican diet tended to reduce glucose, insulin, IGF-1, IGFBP-3 and HOMAIR among women in the middle IA ancestry group (IA ancestry ⩽45-62%), whereas having no effect on biomarkers related to inflammation. CONCLUSIONS: We observed modest interactions between IA ancestry and the metabolic response to a US versus traditional Mexican diet among Mexican immigrant women.

Obesity prevalence in relation to gut microbial environments capable of producing equol or O-desmethylangolensin from the isoflavone daidzein.

BACKGROUND/OBJECTIVES: Studies have observed associations between the gut microbiome and obesity. O-desmethylangolensin (ODMA) and equol are gut bacterial metabolites of daidzein, a compound found in high amounts in soy foods. Approximately 80-95% and 25-60% of individuals harbor gut microbial communities capable of producing ODMA or equol, respectively. Given that other phenotypes of gut bacterial metabolism of dietary compounds have been associated with obesity, we hypothesized that daidzein-metabolizing phenotypes would be associated with obesity. The objective of this study was to compare the prevalence of ODMA-producer and equol-producer phenotypes in obese, overweight and normal-weight individuals. SUBJECTS/METHODS: Adults aged 18-95 years (n=297) provided a first-void urine sample after a 3-day soy challenge, and urinary ODMA and equol concentrations were used to classify individuals as producers or non-producers. Body mass index was calculated from self-reported weight and height. RESULTS: There were 60 ODMA non-producers and 173 equol non-producers. Obese individuals were 2.8 times more likely to be ODMA non-producers (odds ratio (OR)=2.8, 95% confidence interval (CI): 1.2, 6.2) compared with normal-weight individuals, when adjusted for age, race (white vs non-white), and gender and menopausal status (male, premenopausal female and postmenopausal female). Obesity was not associated with equol-producer phenotype (OR=1.1, 95% CI: 0.5, 2.2). Stronger associations with obesity were observed in the ODMA non-producers who were also equol producers than in the equol non-producers. CONCLUSIONS: Results from this analysis suggest that the ODMA-producer phenotype, but not equol-producer phenotype, is associated with obesity in adults. These results support further work to replicate these findings and evaluate the mechanisms of the observed associations.

Self-reported menopausal symptoms in a racially diverse population and soy food consumption.

OBJECTIVES: Evaluate the association of self-reported vasomotor symptom (VMS) frequency with race/ethnicity among a diverse midlife US population and explore menopause symptom differences by dietary soy isoflavone (genistein+daidzein) consumption. STUDY DESIGN: Cross-sectional population-based study of peri- and postmenopausal women, ages 45-58. OUTCOMES: Recent VMS frequency, VMS ever; recent symptom bother (hot flashes, night sweats, headache and joint-ache). RESULTS: Of 18,500 potentially eligible women, 9325 returned questionnaires (50.4% response); 3691 were excluded (premenopausal, missing data, taking hormones). Of 5634 remaining women, 82.1% reported hot flashes ever, 73.1% reported night sweats ever; 48.8% and 38.6% reported recent hot flashes or night sweats, respectively. Compared with White women, Chinese, Japanese, Vietnamese, other Asian (each p<0.001) and Filipino (p<0.01) women less commonly reported ever having hot flashes; Asian women less commonly reported recent VMS bother (p<0.001). Black women more commonly reported hot flashes ever (p<0.05) and recent VMS bother (p<0.05). Compared with non-Hispanic White women, Hispanic women were less likely to report hot flashes (p<0.05) or night sweats (p<0.001) ever. Women were classified by isoflavone consumption: (1) none (n=1819), (2) 0.01-4.30 mg/day (n=1931), (3) 4.31-24.99 mg/day (n=1347) and (4) ≥ 25 mg/day (n=537). There were no group differences in recent VMS number/day: (1) 7.0 (95% CI 6.5, 7.5); (2) 6.4 (95% CI 6.0, 7.1); (3) 7.0 (95% CI 6.3, 8.2); and (4) 6.8 (95% CI 6.1, 7.7). CONCLUSIONS: Menopausal symptoms, independent of isoflavone intake, varied considerably by race/ethnicity and were least common among Asian races.

Use of glucosamine and chondroitin supplements and risk of colorectal cancer.

PURPOSE: Glucosamine and chondroitin are non-vitamin, non-mineral supplements which have anti-inflammatory properties. These supplements are typically used for joint pain and osteoarthritis and are commonly taken as either glucosamine alone or glucosamine plus chondroitin. An exploratory analysis conducted within the VITamins And Lifestyle (VITAL) study observed any use of glucosamine and chondroitin to be associated with reduced risk of colorectal cancer (CRC) after 5 years of follow-up. METHODS: With two additional years of follow-up, we have studied these associations in greater depth, including associations by frequency/duration of use and by formulation, and have evaluated whether observed associations are modified by factors associated with inflammation. Participants include 75,137 western Washington residents aged 50-76 who completed the mailed VITAL questionnaire between 2000 and 2002. Use of glucosamine and chondroitin was ascertained by questions about supplement use during the 10-year period prior to baseline, and participants were followed for CRC through 2008 (n = 557). Cox regression was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). RESULTS: Persons reporting use of glucosamine + chondroitin on 4+ days/week for 3+ years had a non-statistically significant 45 % lower CRC risk than non-users (HR: 0.55; 95 % CI 0.30-1.01; p-trend: 0.16). This association varied by body mass index (p-interaction: 0.006), with inverse association observed among the overweight/obese (p-trend: 0.02), but not among the underweight/normal weight. Use of glucosamine alone was not significantly associated with CRC risk. CONCLUSIONS: There is great need to identify safe and effective cancer preventive strategies, suggesting that glucosamine and chondroitin may merit further attention as a potential chemopreventive agent.

Glycemic load effect on fasting and post-prandial serum glucose, insulin, IGF-1 and IGFBP-3 in a randomized, controlled feeding study.

BACKGROUND/OBJECTIVES: The effect of a low glycemic load (GL) diet on insulin-like growth factor-1 (IGF-1) concentration is still unknown but may contribute to lower chronic disease risk. We aimed to assess the impact of GL on concentrations of IGF-1 and IGF-binding protein-3 (IGFBP-3). SUBJECTS/METHODS: We conducted a randomized, controlled crossover feeding trial in 84 overweight obese and normal weight healthy individuals using two 28-day weight-maintaining high- and low-GL diets. Measures were fasting and post-prandial concentrations of insulin, glucose, IGF-1 and IGFBP-3. In all 80 participants completed the study and 20 participants completed post-prandial testing by consuming a test breakfast at the end of each feeding period. We used paired t-tests for diet component and linear mixed models for biomarker analyses. RESULTS: The 28-day low-GL diet led to 4% lower fasting concentrations of IGF-1 (10.6 ng/ml, P=0.04) and a 4% lower ratio of IGF-1/IGFBP-3 (0.24, P=0.01) compared with the high-GL diet. The low-GL test breakfast led to 43% and 27% lower mean post-prandial glucose and insulin responses, respectively; mean incremental areas under the curve for glucose and insulin, respectively, were 64.3±21.8 (mmol/l/240 min; P<0.01) and 2253±539 (µU/ml/240 min; P<0.01) lower following the low- compared with the high-GL test meal. There was no effect of GL on mean homeostasis model assessment for insulin resistance or on mean integrated post-prandial concentrations of glucose-adjusted insulin, IGF-1 or IGFBP-3. We did not observe modification of the dietary effect by adiposity. CONCLUSIONS: Low-GL diets resulted in 43% and 27% lower post-prandial responses of glucose and insulin, respectively, and modestly lower fasting IGF-1 concentrations. Further intervention studies are needed to weigh the impact of dietary GL on risk for chronic disease.

Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis.

BACKGROUND Hormonal effects of soy and isoflavones have been investigated in numerous trials with equivocal findings. We aimed to systematically assess the effects of soy and isoflavones on circulating estrogen and other hormones in pre- and post-menopausal women. METHODS The Cochrane Library, MEDLINE and EMBASE (plus reviews and experts) were searched to December 2007. Inclusion of randomized or residential crossover trials of soy or isoflavones for 4 or more weeks on estrogens, SHBG, FSH, LH, progesterone and thyroid hormones in women was assessed independently in duplicate. Six percent of papers assessed were included. Data concerning participants, interventions, outcomes, potential effect modifiers and trial quality characteristics were extracted independently in duplicate. RESULTS Forty-seven studies (11 of pre-, 35 of post- and 1 of perimenopausal women) were included. In premenopausal women, meta-analysis suggested that soy or isoflavone consumption did not affect primary outcomes estradiol, estrone or SHBG concentrations, but significantly reduced secondary outcomes FSH and LH [by approximately 20% using standardized mean difference (SMD), P = 0.01 and 0.05, respectively]. Menstrual cycle length was increased by 1.05 days (95% CI 0.13, 1.97, 10 studies). In post-menopausal women, there were no statistically significant effects on estradiol, estrone, SHBG, FSH or LH, although there was a small statistically non-significant increase in total estradiol with soy or isoflavones ( approximately 14%, SMD, P = 0.07, 21 studies). CONCLUSIONS Isoflavone-rich soy products decrease FSH and LH in premenopausal women and may increase estradiol in post-menopausal women. The clinical implications of these modest hormonal changes remain to be determined.

Soy protein and bone mineral density in older men and women: a randomized trial.

OBJECTIVE: Test the hypothesis that soy isoflavone supplementation preserves bone mineral density (BMD) in men and women. METHODS: We conducted a controlled, parallel-arm, double-blinded trial with 145 participants, 50-80 years, with random assignment to soy beverage daily for 12 months. Active treatment (+ISO) received soy protein containing 83 mg isoflavones (45.6 mg genistein, 31.7 mg daidzein), aglycone units; the comparison group (-ISO) received soy protein containing 3mg isoflavones. We measured BMD using dual-energy X-ray absorptiometry at the total hip and posterior-anterior spine (L1-L4) at baseline in 22 women and 123 men, and at 12 months in 13 women and 98 men. We used linear mixed models to test for an isoflavone effect on percentage BMD change from baseline in spine and hip. RESULTS: Among all participants, mean percent change in spine BMD (+/-S.E.) was 0.16+/-0.44 in -ISO (P=0.10) at 12 months. Treatment effects on spine BMD were significantly greater in women than men (P=0.01). At 12 months, in women, mean percent change was 0.58+/-0.70 in +ISO and -1.84+/-0.86 in -ISO (P=0.05); among men it was 1.32+/-0.53 in +ISO and 0.31+/-0.48 in -ISO (P=0.16). By comparison, percent change in hip BMD was similar in the treatment groups, and was not different between men and women. Mean percent change in hip BMD from baseline to 12 months was 0.54+/-0.38 in +ISO and -0.13+/-0.36 in -ISO (P=0.20) among all participants. CONCLUSIONS: Soy protein containing isoflavones showed a modest benefit in preserving spine, but not hip BMD in older women.

Familial correlations, segregation analysis, and nongenetic correlates of soy isoflavone-metabolizing phenotypes.

Particular intestinal bacteria metabolize the soy isoflavone daidzein to equol and O-desmethylangolensin (O-DMA), metabolites that can be identified in urine. Individuals that harbor bacteria capable of producing equol or O-DMA are known as equol producers (approximately 30%-50% of the population) and O-DMA producers (approximately 80%-90% of the population), respectively. The equol-producer phenotype has been associated with sex hormone-related outcomes in several studies. However, the bacteria responsible for these phenotypes have not yet been identified and factors that influence the manifestation of these phenotypes are not well understood. To evaluate familial clustering of and nongenetic factors associated with these phenotypes, 410 individuals from 112 families participated in phenotyping (3-day soy challenge and Day 4 spot urine collection). In segregation analyses of the equol-producer phenotype, the Mendelian dominant model provided the most parsimonious fit to the data, suggesting that the pattern of inheritance of the equol-producer phenotype is consistent with an autosomal dominant trait. This phenotype was positively associated with education (p trend = 0.01), but not with sex, smoking, or several dietary factors. Results of the segregation analyses of the O-DMA-producer phenotype were inconclusive; no other models provided a more parsimonious fit to the data than the general model. This phenotype was inversely associated with age in a nonlinear model (p = 0.01), positively associated with age- and sex-adjusted height (odds ratio [OR] 10-cm increase = 0.38, 95% confidence interval [CI] = 0.15, 0.95) and body mass index (kg/m(2)) (OR = 0.91, 95% CI = 0.85, 0.96), but not with sex, education, smoking, or several dietary factors. These results suggest the equol-producer phenotype may be under some degree of genetic control and that there are likely other environmental factors not evaluated in the present analysis that contribute to both of these phenotypes. These results provide a foundation for further work to refine our understanding of heritable and environmental determinants of daidzein-metabolizing phenotypes.

Indirect calorimetry protocol development for measuring resting metabolic rate as a component of total energy expenditure in free-living postmenopausal women.

An objective measure of energy intake is needed in epidemiologic studies to evaluate random and systematic error associated with dietary self-report tools. Total energy expenditure in weight-stable humans is accepted as a measure of energy intake, but doubly labeled water remains cost prohibitive for large studies. Our purpose was to develop a practical indirect calorimetry (IC) protocol for estimating resting metabolic rate (RMR) in free-living, postmenopausal women. We conducted duplicate IC measures 1 wk apart using a canopy system on 102 women ages 50-79 y from the Seattle area. We compared RMR for 0-5, 5-10, 5-15, 5-20, 5-25, 5-30, and 0- to 30-min IC segments and segments meeting stability criteria. The mean RMR for the first 5 min was significantly higher than other time segments (P = 0.001). Correlation coefficients between duplicate measures were high (r = 0.90). Use of defined stability criteria produced RMR measures that were 10-30 kcal (42-126 kJ) higher than the 5- to 10-min RMR measures and 40-60% of subjects did not achieve these stability criteria. For protocols including IC to assess RMR as a component of total energy expenditure in free-living, postmenopausal women, a single 10-min canopy study, excluding the first 5 min of data, produces reliable results with minimal subject burden.

CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk.

Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) has a protective effect on the incidence of colon neoplasia. However, polymorphisms in NSAID-metabolizing enzymes may alter this effect. NSAIDs, particularly aspirin, are glucuronidated by UGT1A6 and some classes of NSAIDs are also metabolized by cytochrome P450 (CYP) 2C9. Both of these enzymes have slow-metabolizing, variant forms. We tested the hypothesis that the slow alleles of these enzymes can modify the inverse association between NSAIDs and colon neoplasia in the Minnesota Cancer Prevention Research Unit (CPRU) adenomatous polyp case-control study. CYP2C9 and UGT1A6 genotypes were determined for 474 adenoma cases and 563 controls. NSAID use was inversely associated with adenoma risk [odds ratio (OR), 0.63; 95% confidence interval (CI), 0.44-0.90 for aspirin; and OR, 0.50; 95% CI, 0.31-0.82 for nonaspirin NSAID]. However, this association was absent in aspirin users who carried the CYP2C9 variant alleles (OR, 0.88; 95% CI, 0.51-1.53) or who were homozygous wild-type UGT1A6 (OR, 0.86; 95% CI, 0.50-1.50). Carriers of both of these alleles who use aspirin were also not at reduced risk of adenomatous polyps (OR, 1.59; 95% CI, 0.68-3.73). The variants of these enzymes did not influence the association between nonaspirin NSAIDs and adenoma risk. These data indicate that the effectiveness of chemopreventive drugs can be modulated by the genotype of metabolizing enzymes.

Wheat bran and soy protein feeding do not alter urinary excretion of the isoflavan equol in premenopausal women.

The capacity to convert the soy isoflavone daidzein to equol in vivo is presumably determined by an individual's intestinal microfloral populations; however, diet may also influence this conversion. The objectives of the present study were to determine whether a 1-mo supplementation of dietary fiber as wheat bran increases urinary equol excretion in equol excreters and stimulates equol production in nonexcreters and whether longer-term soy isoflavone intake increases equol production or alters overall urinary isoflavone excretion. First, we screened 74 women, ages 20-40 y, and determined their equol-excreter status. In these women, health and lifestyle patterns and habitual dietary intake did not differ according to equol-excreter status. Next, 26 of the women (13 equol excreters and 13 nonexcreters) were assigned (blocked on equol-excreter status) to either longer-term (1 mo) or short-term (4 d) soy protein supplementation. Within each soy treatment group, women participated in two 1-mo intervention periods (the exact length was determined by each woman's menstrual cycle) during which they consumed their usual diets supplemented daily with either 0 or 16 g dietary fiber in a randomized crossover design. A 1-mo washout period separated the two diet periods. Among the 19 women who completed both periods, fiber supplementation did not increase equol production in equol excreters or nonexcreters. In addition, isoflavonoid excretion did not differ by fiber dose or length of soy intervention. These results suggest that a daily 16 g-fiber dose as wheat bran and the addition of soy protein do not alter significantly the capacity of colonic microflora to produce equol.

Dietary soy isoflavone intake in older Japanese American women.

OBJECTIVE: In a sample of older Japanese American women, we aimed to: (1) describe the most commonly consumed soy foods, (2) estimate dietary soy isoflavone intake, (3) describe characteristics associated with dietary soy isoflavone intake, and (4) compare our estimates with previously published estimates in other Japanese samples. DESIGN: A 14-item soy food-frequency questionnaire was administered to older Japanese American women and responses were converted to quantitative estimates of soy isoflavones (genistein plus daidzein). Multiple regression was used to examine characteristics associated with dietary soy isoflavone intake, including self-reported lifestyle and cultural factors and dietary intake of various foods ascertained from a semi-quantitative food-frequency questionnaire. To compare our estimates with other samples, a review of the literature was conducted. SETTING/SUBJECTS: Data are from 274 women aged 65+ years, recruited from a longitudinal cohort study of Japanese Americans in King County, Washington State. RESULTS: The soy foods most commonly consumed were tofu (soybean curd), miso (fermented soybean paste) and aburaage (fried thin soybean curd). The mean intake of dietary soy isoflavones was 10.2 (standard deviation (SD), 12.4) mg day(-1), approximately a quarter to a half that of previously published estimates in Japanese samples. Dietary soy isoflavone intake was positively associated with speaking Japanese, the consumption of traditional Japanese dishes (kamaboko, manju and mochi), low-fat/non-fat milk and yellow/red vegetables, vitamin E supplement use, and walking several blocks each day. Dietary soy isoflavone intake was negatively associated with the consumption of butter. CONCLUSIONS: The estimated dietary soy isoflavone intake in Japanese American women living in King County, Washington State was about a quarter to a half that of women living in Japan. Dietary soy isoflavone intake was associated with speaking Japanese and healthy lifestyle and dietary habits.

Potential mechanisms of diet therapy for fibrocystic breast conditions show inadequate evidence of effectiveness.

Fibrocystic breast conditions, formerly referred to as fibrocystic breast disease, affect about half of all women and typically present as any combination of breast nodularity, swelling, and pain. We reviewed the literature to evaluate evidence supporting nutrition interventions commonly recommended for fibrocystic breast conditions by health care providers. Randomized, controlled studies of the effectiveness of caffeine restriction fail to support any benefit in fibrocystic breast conditions. Similarly, evidence supporting evening primrose oil, vitamin E, or pyridoxine as treatments for the discomforts of fibrocystic breast conditions is insufficient to draw conclusions about effectiveness. Dietary alterations that influence the intermediate markers for fibrocystic breast conditions include low-fat (15% to 20% energy), high-fiber (30 g/day), and soy isoflavone regimens. However, our findings provide no solid evidence for secondary prevention or treatment of fibrocystic breast conditions through a dietary approach. Health care providers should limit recommendations to proven diet therapies supported by randomized, placebo-controlled trials, given the instability inherent in fibrocystic breast conditions and the near 20% placebo effect associated with intervention. Because excessive estrogen or altered sensitivity to estrogen is the dominant theory of etiology, interventions that may modulate endogenous steroid hormones warrant further investigation as potential treatments for symptomatic fibrocystic breast conditions.

Modulation of human glutathione S-transferases by botanically defined vegetable diets.

Glutathione S-transferases (GSTs) conjugate activated xenobiotics with glutathione; thus, GST induction may improve detoxification and excretion of potentially harmful compounds. Using a randomized cross-over design, we tested the hypothesis that, in humans, serum GST-alpha concentration (GST-alpha) and GST activity increase with vegetable consumption and that this effect is GSTM1 genotype dependent. Twenty-one men (10 GSTM1-null and 11 GSTM1+) and 22 women (15 GSTM1-null and 7 GSTM1+), nonsmokers, 20-40 years of age and not on medications, ate four 6-day controlled diets: basal (vegetable-free), and basal supplemented with three botanically defined groups of vegetables (i.e., brassica, allium, and apiaceous). Fasting blood samples, collected on the last 2 days of each feeding period, were analyzed for GST-alpha, serum GST activity [against 1-chloro-2,4-dinitrobenzene (CDNB) and 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl)] and peripheral-lymphocyte GST-mu activity (against trans-stilbene oxide). The brassica, but not allium or apiaceous, vegetable diets (relative to the basal diet) increased GST-alpha by 26% (P = 0.005) and GST (NBD-Cl) activity by 7% (P = 0.02) in the GSTM1-null individuals, particularly the women. Apiaceous vegetable supplementation decreased GST-alpha in the GSTM1+ men (P = 0.03). Among the GSTM1+ women, both brassica and the allium diets increased GST-mu activity by 18% (P = 0.02) and 26% (P = 0.001), respectively. The vegetable diets had no effect on GST (CDNB) activity, irrespective of GSTM1 genotype or sex. These results demonstrate that GSTM1 genotype has a significant effect on GST responses to diet and that brassica vegetables are most effective at inducing GST-alpha, whereas both brassica and allium vegetables induce GST-mu. GST responses were more pronounced in women than men, but it is not clear from this study whether this is a dose-per-body-weight or a sex-specific effect.

Nutrition, genetics, and risks of cancer.

Dietary patterns, nutrients, and other constituents of food are major components of the environmental influences that contribute to risk for cancer, and the study of interactions between nutritional and genetic factors is a new and important area or research. This review describes the concepts and principles underlying this area of study and types of relationships between nutritional and genetic factors, and it provides examples of specific diet-gene interactions that are of current interest, with an emphasis on implications for cancer prevention and public health. Polymorphisms exist in the genes for the activating and conjugating metabolizing enzymes, and the induction of metabolizing enzyme activity by nutritional factors may result in either the activation of a carcinogen or the detoxification of a reactive intermediate metabolite. The relationship between the methylenetetrahydrofolate reductase gene and dietary folate is an example of a diet-gene interaction that involves a polymorphism in a vitamin metabolism gene, and the presence of the variant appears to influence both risk for cancer and folate requirements. Diet-gene interactions likely contribute considerably to the observed inter-individual variations in cancer risk in response to exposures to the nutritional factors that have the potential to promote or protect against cancer. Insights into mechanisms by which nutritional factors affect the process of carcinogenesis are provided by knowledge of the targeted gene function and enzyme activity. Increased knowledge in this area will allow a more refined approach to reducing risk for cancer, with diet interventions targeted toward individuals and subgroups that are genetically susceptible and responsive to the effects of nutritional factors.

Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets.

Induction or inhibition of biotransformation enzymes, enzymes that activate or detoxify numerous xenobiotics, is one mechanism by which vegetables may alter cancer risk. Using a randomized crossover design, we examined the effect of various vegetable diets on cytochrome P450 (CYP) 1A2, N-acetyltransferase 2 (NAT2) and xanthine oxidase activity in humans. Men and women, non-smokers, on no medication and 20-40 years of age ate four 6-day controlled diets: basal (vegetable-free) and basal with three botanically defined vegetable groups. Enzyme activities were determined by measuring urinary caffeine metabolite ratios after a 200 mg caffeine dose on the last day of each feeding period. Mean CYP1A2 activity for 19 men and 17 women (least squares means adjusted for sex, GSTM1 genotype, urine volume and feeding period) with basal, brassica, allium and apiaceous vegetable diets differed significantly (P

Prevalence of polymorphisms in the human UDP-glucuronosyltransferase 2B family: UGT2B4(D458E), UGT2B7(H268Y), and UGT2B15(D85Y).

UDP-glucuronosyltransferases (UGTs) of the UGT2B family conjugate steroid hormones as well as bile acids and xenobiotics. UGT2Bs are expressed in numerous human tissues, such as skin, breast, prostate, adipose, and intestine and are hypothesized to modulate steroid metabolism and excretion. Polymorphisms have been identified that may modify substrate specificities or enzyme activities of UGT2B family isozymes. We determined the prevalence of the UGT2B4(D458E), UGT2B7(H268Y), and UGT2B15(D85Y) polymorphisms in a sample of 233 individuals. The allele frequencies were significantly different (P < 0.02) between individuals of Caucasian and Asian descent for all three polymorphisms. In Asians (n = 32), the frequencies of the UGT2B4(D458), UGT2B7(H268), and UGT2B15(D85) alleles were 1.00, 0.73, and 0.64, respectively, whereas, in Caucasians (n = 202), the frequencies of UGT2B4(D458), UGT2B7(H268), and UGT2B15(D85) were 0.75, 0.46, and 0.45, respectively. The distribution of the UGT2B4(D458E), UGT2B7(H268Y), and UGT2B15(D85Y) genotypes also differed by ethnic group (P < 0.0001, P = 0.002, and P = 0.02, respectively). All Asians were homozygous for UGT2B4(D458) and had a greater than 2-fold higher prevalence of the UGT2B7(H268) and UGT2B15(D85) homozygous genotypes compared with Caucasians: 56.2% versus 21.8%, and 46.9% versus 22.3%, respectively. Concomitantly, only 9.4% of Asians were UGT2B7(Y268) homozygous and 18.7% were UGT2B15(Y85) homozygous compared with 29.2% and 32.2%, respectively, of Caucasians. The data suggest that there may be large differences in UGT2B polymorphisms between Asians and Caucasians. This warrants evaluation both in larger, multiethnic cohorts and in relation to known ecological differences in risk of sex hormone-dependent cancers.

Health effects of vegetables and fruit: assessing mechanisms of action in human experimental studies.

Epidemiologic data support the association between high intake of vegetables and fruits and low risk of chronic disease. There are several biologically plausible reasons why consumption of vegetables and fruit might slow or prevent the onset of chronic diseases. Vegetables and fruit are rich sources of a variety of nutrients, including vitamins, trace minerals, and dietary fiber, and many other classes of biologically active compounds. These phytochemicals can have complementary and overlapping mechanisms of action, including modulation of detoxification enzymes, stimulation of the immune system, reduction of platelet aggregation, modulation of cholesterol synthesis and hormone metabolism, reduction of blood pressure, and antioxidant, antibacterial, and antiviral effects. Although these effects have been examined primarily in animal and cell-culture models, experimental dietary studies in humans have also shown the capacity of vegetables and fruit and their constituents to modulate some of these potential disease-preventive mechanisms. The human studies have relied on intermediate endpoints related to disease risk. Design methodologies used include multiple-arm trials, randomized crossover studies, and more compromised designs such as nonrandomized crossovers and pre- and posttreatment analyses. Length of treatment ranged from a single dose to years depending on the mechanism of interest. Stringency of dietary control varied from addition of supplements to a habitual diet to provision of all food for the duration of a treatment. Rigorously conducted experimental dietary studies in humans are an important link between population- and laboratory-based research.

UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations.

Polymorphisms that alter UDP-glucuronosyltransferase (UGT) activities have been identified. Mutations in the promoter of the UGT1A1 gene (UGT1A1*28), resulting in 5, 7 or 8, instead of 6 thymine-adenine (TA) repeats, alter bilirubin conjugation. Two missense mutations on one allele of UGT1A6 (UGT1A6*2) result in T181A and R184S amino acid substitutions and reduced activity against phenolics, such as 4-nitrophenol, 4-hydroxycoumarin and butylated hydroxy anisole. We determined the frequency of these polymorphisms in 245 healthy men and women, aged 20-40 years and examined the relationship between TA repeat number and serum bilirubin concentrations in a subset of 24 Asians and 169 Caucasians. The frequencies of the UGT1A1*28 genotypes were 0.537, 0.348, 0.098, 0.008 and 0.008 for promoter TA repeats 6/6, 6/7, 7/7, 5/6 and 6/8, respectively. Both allele and genotype frequencies varied by race (P < 0.02), with 11% of the Caucasians and none of the Asians having the 7/7 genotype. Within both ethnic groups, serum bilirubin increased with increased numbers of UGT1A1 promoter TA repeats (P = 0.0001). However, a strong ethnic group-by-UGT1A1 genotype interaction suggests that additional ethnic differences in bilirubin metabolism contribute to observed bilirubin concentrations. Genotype frequencies for UGT1A6*2 were 0.478, 0.392, 0.029, 0.090, 0.012 for wild-type (wt)/wt, wt/T181A + R184S, wt/R184S, T181A + R184S/T181A + R184S and T181A + R184S/R184S, respectively. The co-occurrence of polymorphisms in UGT1A1 and UGT1A6 differed from that expected (P < 0.0001): individuals homozygous wild-type for UGT1A1 and UGT1A6 were observed at twice the expected frequency; individuals homozygous variant for both genes were ten-fold more frequent and individuals homozygous wild-type for one gene and homozygous variant for the other were ten-fold less frequent than expected. Overall, 8% were homozygous variant for both UGT1 polymorphisms and 43% had at least one variant allele for both UGT1A1*28 and UGT1A6*2. These highly prevalent polymorphisms, which result in modified expression and activity of UGTs, may influence susceptibility to cancers associated with altered metabolism of endogenous and xenobiotic compounds.