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.

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.

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.

Calcium and colorectal epithelial cell proliferation: a preliminary randomized, double-blinded, placebo-controlled clinical trial.

BACKGROUND: Colonic epithelial cell proliferation is increased in patients at high risk for colon cancer. Calcium administration has ameliorated the proliferative changes in rodents, and findings in small, uncontrolled clinical trials have suggested similar effects in humans. PURPOSE: This preliminary, double-blind, randomized clinical trial was designed 1) to investigate whether supplemental calcium will reduce colonic epithelial cell proliferation in patients with sporadic adenomas who consume a high-fat, Western-style diet; 2) to determine the sample size (number of scorable crypts per person) needed to achieve adequate statistical power; and 3) to evaluate the feasibility of full-scale clinical trials. METHODS: Twenty-one sporadic adenoma patients were treated daily with placebo or 1200 mg of supplemental calcium. To determine colonic epithelial cell proliferation, we used tritiated thymidine labeling of colon crypt epithelial cells in rectal biopsy specimens and calculated the percentage of labeled cells (labeling index [LI]). Two pathology technician "readers" independently scored each specimen, and inter-reader reliability was determined. Subjects remained on their usual diet during the study, and intake of calories, calcium, total fat, and vitamin D did not differ substantially among them. We calculated curves for statistical power to determine the number of scorable crypts needed per person for detection of a statistically significant difference (P < .05) of 1.0% in mean LI. RESULTS: The pooled baseline LI was 4.7%. In the calcium-treated group, the LI increased 0.6% (proportional increase, 12.8%); in the placebo-treated group, it decreased 0.5% (proportional decrease, 10.6%). The difference between change in the mean LI from baseline to 8 weeks' follow-up in the placebo group versus the calcium group was not statistically significant. The intraclass correlation coefficient for inter-reader reliability for the baseline LI was .66. Analyses indicated scoring eight crypts sufficient for estimates of the LI adequate for between-group comparisons, a level achieved in 81% of biopsy specimens. CONCLUSIONS: Calcium carbonate supplements delivering 1200 mg elemental calcium daily may not decrease colonic epithelial cell proliferation over an 8-week period in sporadic adenoma patients. In future trials measuring the LI, consideration should be given to ensuring adequate numbers of scorable crypts and to the impact of inadequate biopsy procedures, labeling failure, reader reliability, and participant withdrawal. Our findings support the feasibility of a full-scale clinical trial to further study the relationships among dietary calcium, colonic epithelial cell proliferation, and colorectal cancer.

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.

Effect of flax seed ingestion on the menstrual cycle.

Lignans are a group of phytochemicals shown to have weakly estrogenic and antiestrogenic properties. Two specific lignans, enterodiol and enterolactone, are absorbed after formation in the intestinal tract from plant precursors particularly abundant in fiber-rich food and are excreted in the urine. We evaluated the effect of the ingestion of flax seed powder, known to produce high concentrations of urinary lignans, on the menstrual cycle in 18 normally cycling women, using a balanced randomized cross-over design. Each subject consumed her usual omnivorous, low fiber (control) diet for 3 cycles and her usual diet supplemented with flax seed for another 3 cycles. The second and third flax cycles were compared to the second and third control cycles. Three anovulatory cycles occurred during the 36 control cycles, compared to none during the 36 flax seed cycles. Compared to the ovulatory control cycles, the ovulatory flax cycles were consistently associated with longer luteal phase (LP) lengths (mean +/- SEM, 12.6 +/- 0.4 vs. 11.4 +/- 0.4 days; P = 0.002). There were no significant differences between flax and control cycles for concentrations of either estradiol or estrone during the early follicular phase, midfollicular phase, or LP. Although flax seed ingestion had no significant effect on LP progesterone concentrations, the LP progesterone/estradiol ratios were significantly higher during the flax cycles. Midfollicular phase testosterone concentrations were slightly higher during flax cycles. Flax seed ingestion had no effect on early follicular phase concentrations of DHEA-S, PRL, or sex hormone-binding globulin. Our data suggest a significant specific role for lignans in the relationship between diet and sex steroid action, and possibly between diet and the risk of breast and other hormonally dependent cancers.

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.

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.

Urinary lignan and isoflavonoid excretion in premenopausal women consuming flaxseed powder.

Lignans and isoflavonoid phytoestrogens, produced from plant precursors by colonic bacteria, may protect against certain cancers. We examined the effects of flaxseed consumption on urinary lignans and isoflavonoids. Eighteen women consumed their usual omnivorous diets for three menstrual cycles and their usual diets supplemented with flaxseed powder (10 g/d) for three cycles in a randomized crossover design. Three-day urine samples from follicular and luteal phases were analyzed for lignans and isoflavonoids by isotope-dilution gas chromatography--mass spectrometry. Excretion of the lignans enterodiol and enterolactone increased with flaxseed from 1.09 +/- 1.08 and 3.16 +/- 1.47 to 19.48 +/- 1.10 and 27.79 +/- 1.50 mumol/d, respectively (P < 0.0002). Enterodiol and enterolactone excretion varied among subjects in response to flaxseed (3- to 285-fold increase). There were no differences in excretion of isoflavonoids (daidzein, genistein, equol, and O-desmethylangolensin) or the lignan matairesinol with flaxseed. Excretion was not altered by phase of menstrual cycle or duration of flaxseed consumption.

Effect of the menstrual cycle on energy and nutrient intake.

Midfollicular and midluteal dietary intakes of 18 women were evaluated between four and six ovulatory menstrual cycles. Phase lengths were established by basal body temperatures and urinary luteinizing hormone excretion. Midfollicular and midluteal diet records were collected 6-8 d after menstrual onset and 6-8 d after ovulation, respectively. Significant increases in energy [0.66 MJ (159 kcal), P = 0.003], protein (6.1 g, P = 0.02), carbohydrate (15.3 g, P = 0.04), and fat (8.6 g, P = 0.002) intakes were observed in midluteal phase when compared with midfollicular phase. Intakes of vitamin D, riboflavin, potassium, phosphorus, and magnesium also were significantly higher during midluteal phase (P < 0.05). These results support the regulation of food intake by menstrual cycle hormones and suggest that it is essential to consider phase of menstrual cycle in studies of nutrient intake performed in premenopausal women.

Urinary isoflavonoid excretion in humans is dose dependent at low to moderate levels of soy-protein consumption.

Soybeans contain isoflavones, which have been associated with many health benefits, including decreased cancer risk. The purpose of our study was to measure urinary isoflavonoid excretion in response to daily consumption of soy that contained 0-36 mg isoflavones--a lower range than used in previous studies--and to compare urinary isoflavonoid excretion between equol excreters and nonexcreters. Fourteen men and women aged 20-40 y participated in the study. Half of the subjects were identified previously as equol excreters and the other half as equol nonexcreters. This randomized, double-blind, crossover study consisted of four 9-d diet treatment periods. During each treatment period participants consumed a low-photoestrogen controlled diet and a beverage containing 0, 5, 10, or 20 g soy protein. Urine collected on the last 3 d of each treatment period was analyzed for isoflavonoid (equol, O-desmethylangolensin, genistein, and daidzein) and lignan (enterodiol and enterolactone) contents by using isotope-dilution gas chromatography-mass spectrometry. There was a highly linear dose response of urinary isoflavonoid excretion to soy consumption, which did not differ significantly between equol excreters and nonexcreters. There were no significant differences in lignan excretion between the two diet treatments. Our results indicate that urinary isoflavonoid excretion is dose dependent in humans at low to moderate levels of soy consumption.

Influence of soybean processing, habitual diet, and soy dose on urinary isoflavonoid excretion.

In an attempt to explain the wide individual variation seen in urinary isoflavonoid phytoestrogen excretion, we conducted a series of 3 human feeding studies: a large cross-sectional study of equol production in humans with a soy challenge, a comparison of phytoestrogen metabolism when subjects consumed fermented and unfermented soy products, and a dose-response study of urinary isoflavonoid excretion at the low end of soy consumption. All studies were conducted in young, healthy humans. Urinary isoflavonoids were measured by isotope-dilution gas chromatography-mass spectrometry. Similar to results from other studies, 35% of screened subjects (30 men and 30 women) excreted equol (>2000 nmol/d). In women, equol excretion was associated with higher intake of dietary fiber and carbohydrate. Fermentation of soy decreased the isoflavone content of the product fed but increased the urinary isoflavonoid recovery, suggesting that fermentation increases availability of isoflavones in soy. When soy-protein powder was fed at 0, 5, 10, and 20 g/d (0-36 mg isoflavones), there was a linear dose response of urinary isoflavonoid excretion to soy consumption that did not differ between subjects with high and low equol excretion. These results suggest that equol excretion may be related to the fermentable carbohydrate content of the diet; additional study is needed. Processing of soy affects isoflavone metabolism and must be considered in recommending exposure to isoflavones from soyfoods. Although optimal isoflavone exposure for disease protection has not been determined, urinary isoflavonoid excretion appears linear at low-to-moderate soy consumption.

Serum lipid and fecal bile acid changes with cereal, vegetable, and sugar-beet fiber feeding.

Thirty-four subjects consumed six controlled formula diets for 3 wk each, supplemented with 0 g added fiber, 10 and 30 g dietary fiber as wheat bran (WB), 10 and 30 g dietary fiber as mixed vegetable fiber (VF), and 30 g dietary fiber as sugar-beet fiber (SBF). Serum cholesterol changes for fiber free, 10 g WB, 30 g WB, 10 g VF, 30 g VF, and 30 g SBF (-0.13, -0.18, -0.05, -0.17, -0.24, and -0.70 mmol/L, respectively) were significant for 30 g VF and 30 g SBF. Reduction in total cholesterol with SBF was largely due to significant lowering of low-density-lipoprotein cholesterol. Total fecal bile acid concentrations were significantly higher with the fiber-free diet than with 30 g WB, VF, and SBF (P less than 0.001) and were also higher with 30 g SBF than with 30 g WB and 30 g VF (P less than 0.005). Daily fecal bile acid excretion was not different on 30 g SBF compared with 30 g WB and 30 g VF. Differences in cholesterol reduction across the diets could not be explained by differences in fecal bile acid excretion.

Fecal lignan and isoflavonoid excretion in premenopausal women consuming flaxseed powder.

Lignans and isoflavonoids are diphenolic compounds found in plant foods, particularly whole grains and legumes. They have been shown to have anticarcinogenic properties in animal and cell studies, and have been associated with reduced cancer risk in epidemiological studies. In order to perform further epidemiological and metabolic studies on these compounds, it is necessary to be able to monitor concentrations in biological samples. In this study, we examined the effects of consumption of flaxseed, a concentrated source of lignans, on fecal lignan excretion and evaluated the effect of high lignan consumption on fecal excretion of isoflavonoids. Thirteen women were studied for two diet periods of three menstrual cycles each in a cross-over design. During the control period, they consumed their usual diets; during the treatment period they consumed their usual diets supplemented with 10 g/day ground flaxseed. Feces were collected on days 7-11 of the last menstrual cycle in each diet period. Five-day fecal composites were analyzed for lignans and isoflavonoids by isotope dilution gas chromatography-mass spectrometry. Fecal excretion of the lignans enterodiol, enterolactone, and matairesinol increased significantly with flax consumption, from 80.0 +/- 80.0 (SD) to 2560 +/- 3100; 640 +/- 480 to 10,300 +/- 7580; and 7.33 +/- 10.0 to 11.9 +/- 8.06 nmol/day, respectively. There were no differences in fecal excretion of the isoflavonoids, daidzein, equol, genistein, and O-demethylangolensin.

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.

Effects of cereal and vegetable fiber feeding on potential risk factors for colon cancer.

The effects of two doses of cereal fiber and vegetable fiber on mean transit time, stool weight, fecal pH and fecal bile acids were examined in 34 healthy volunteers. Subjects consumed five diets in random order for 23 days each, consisting of a fiber-free liquid diet and quick breads containing 0 g added dietary fiber, 10 g fiber as wheat bran (WB), 30 g fiber as WB, 10 g fiber as vegetable fiber (VF), and 30 g fiber as VF. Fecal wet and dry weights were 43% and 19% higher, respectively, on WB as compared to VF (P < 0.0001). Fecal pH was lower on WB than on VF (P < 0.0001) and decreased with increased fiber intake (P < 0.005). Transit time was 36% faster with WB than with VF (P < 0.0001). There was no VF dose effect on transit time, but transit time was 23% faster on 30 g WB than on 10 g WB (P = 0.04). Total bile acid concentrations decreased with increased fiber dose (P < 0.0001) but were not significantly different between WB and VF. Daily total bile acid excretion was 14% lower on VF compared to WB (P = 0.01). There was no VF dose effect on total bile acid excretion, but excretion was 13% lower on 30 g WB than on 10 g WB (P = 0.04). These findings are consistent with the capacity of fiber to alter potential risk factors for colon cancer but do not explain differences in epidemiological data between vegetable and cereal intake.

Urinary isoflavonoid and lignan excretion on a Western diet: relation to soy, vegetable, and fruit intake.

Dietary isoflavone and lignan phytoestrogens are potential chemopreventive agents. This has led to a need to monitor exposure to these compounds in human populations and to determine which components of a mixed diet contribute to the exposure. Typically, urinary isoflavonoid excretion is associated with soy consumption and that of lignans is associated with whole grains. However, other plant foods are known to contain phytoestrogen precursors. The purpose of this study was to examine the association between urinary isoflavonoid and lignan excretion and intakes of vegetables and fruits (V&F). Isoflavonoids (genistein, daidzein, O-desmethylangolensin, and equol) and lignans (enterolactone, enterodiol, and matairesinol) were measured in urine collected for 3 days from 49 male and 49 female volunteers (age, 18-37 years) reporting a wide range of habitual V&F intakes. Dietary intakes were assessed using 5-day diet records and a food frequency questionnaire. V&F groupings (total V&F, total V, total F, soyfoods, and V&F grouped by botanical families) were used to assess the relationship between V&F intake and urinary isoflavonoid and lignan excretion. Pearson correlations were performed. Intake of soyfoods was correlated significantly with urinary genistein (r = 0.40; P = 0.0001), O-desmethylangolensin (r = 0.37; P = 0.0002), daidzein (r = 034; P = 0.0007), and the sum of isoflavonoids (r = 0.39; P = 0.0001). There was no association between equol excretion and soy intake or between the isoflavonoids and any other V&F groupings. In addition, isoflavonoid excretion was correlated positively with intake of high-fat and processed meats, particularly among men who did not consume soy. This suggests that, even in the United States, on a Western diet, soyfoods are the primary contributors to isoflavone intake; however, additional "hidden sources" of soy may also contribute to exposure. In contrast, a variety of fiber-containing foods contributed to lignan excretion; the sum of the urinary lignans, enterodiol, enterolactone, and matairesinol, was associated with intake of total F (r = 0.27; P = 0.008), total V&F (r = 0.25; P = 0.01), soyfoods (r = 0.28; P = 0.006), and dietary fiber (r = 0.36; P = 0.0003). Overall, urinary phytoestrogens (isoflavonoids + lignans) were significantly higher in "high" compared with "low" V&F consumers. Compared with the "low" V&F group, the "high" group consumed diets that were, on average, higher in fiber and carbohydrate and soyfoods and lower in fat; thus, the urinary phytoestrogens may also be a useful marker of healthier dietary patterns.

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.

(Imidazolylphenyl)pyrrol-2-one inhibitors of cardiac cAMP phosphodiesterase.

Seven 3-alkyl-4-aryl-1,5-dihydro-2H-pyrrol-2-ones were prepared as potential inhibitors of cardiac cAMP phosphodiesterase (PDE). The design of these compounds made use of rolipram, a known inhibitor of the brain cAMP PDE isozyme, as a lead structure and was guided by a model which describes the features required for potent inhibition of the cardiac isozyme. Syntheses for the new compounds are described, together with the results of theoretical and crystallographic studies aimed toward ascertaining their three-dimensional structures. The activities of these compounds as inhibitors of the cardiac and brain cAMP PDE isozymes and their positive inotropic activity in ferret papillary muscle are also reported. Selected compounds were further examined in an in vivo hemodynamic model. One compound 1,5-dihydro-4-[4-(1H-imidazol-1- yl)phenyl]-3-methyl-2H-pyrrol-2-one, was identified as a potent and selective positive inotropic agent and inhibitor of cardiac cAMP PDE.

Heterocyclic analogues of benzamide antiarrhythmic agents.

A series of heterocyclic N-[(diethylamino)alkyl]arenamides related to acecainide was prepared and examined for antiarrhythmic activity. The compounds were synthesized from the corresponding known heterocyclic carboxylic acids or esters by using standard amide formation methods. The effects of the compounds on the electrophysiological properties of canine Purkinje fibers and ventricular muscle strips were determined. Most of the compounds showed effects consistent with weak class I activity. Two compounds, N-[2-(diethylamino)ethyl]-3,4,5-trimethyl-1H-pyrrole-2-carboxamide and N-[2-(diethylamino)ethyl]-1H-indole-2-carboxamide, displayed prolongation of the action potential duration and functional refractory period indicative of modest class III electrophysiological activity. Representative compounds were examined by using molecular modeling techniques. Compounds of differing activity classes displayed qualitatively different electrostatic potential maps.