Urinary phytoestrogen excretion and prostate cancer risk: a nested case-control study in the Multiethnic Cohort.

BACKGROUND: Phytoestrogens are of special interest in prostate cancer research because populations in Asia with a high consumption of phytoestrogens have a lower incidence of the disease than comparable populations in Western countries. METHODS: This case-control study is nested within a large multiethnic cohort in Hawaii and California. Urine samples were analysed for daidzein, genistein, equol, and enterolactone among 249 incident prostate cancer cases and 404 controls matched on age, race/ethnicity, date/time of specimen collection, and fasting status. RESULTS: The median excretion of daidzein was 0.173 nmol mg(-1) creatinine in cases and 0.291 in controls (P=0.01), and the median excretion of genistein was 0.048 in cases and 0.078 in controls (P=0.05). An inverse association was seen for daidzein overall (odds ratio for the highest vs lowest quintile=0.55, 95% confidence interval=0.31-0.98, P(trend)=0.03) and seemed to apply to localized (P(trend)=0.08) as well as advanced or high-grade cancer (P(trend)=0.09). This association was consistent across the four ethnic groups examined. Although the relationship was weaker for genistein, the odds ratios and trends were similarly inverse. Urinary excretion of equol and enterolactone was not significantly related to prostate cancer risk. CONCLUSION: Our findings suggest that high intake of isoflavones, as reflected by urinary excretion of daidzein and genistein, may be protective against prostate cancer.

Effects of beta-carotene and alpha-tocopherol on bleomycin-induced chromosomal damage.

The number of bleomycin-induced chromosomal breaks in cultured peripheral blood lymphocytes has been proposed as a measure of the sensitivity of an individual to carcinogens. Although "mutagen sensitivity" (clastogenicity) may be a useful biomarker for the identification of individuals at high risk for DNA damage, there is some uncertainty whether the results of this assay can be modified by environmental factors, such as diet. We designed an intervention study to determine whether micronutrient supplementation with beta-carotene and alpha-tocopherol influenced the mutagenicity score among 22 healthy volunteers. This intervention study followed a double-blind, randomized, cross-over design. Chromatid breaks ranged from 0.30 to 2.30 per cell and were uncorrelated with plasma beta-carotene (r = -0.07; P = 0.50) and a-tocopherol (r = -0.01; P = 0.92) levels, after accounting for the time of the measurement. The average number of breaks per cell was similar (P for difference in means = 0.90) among subjects during periods of vitamin supplementation (mean = 0.87 breaks per cell) and placebo (mean = 0.86 breaks per cell), averaged over groups and after adjustment for baseline breaks. Substantial within-person variation may indicate some imprecision in the mutagen sensitivity assessment. Our results suggest that mutagen sensitivity is not affected by plasma levels of beta-carotene or alpha-tocopherol. Although mutagen sensitivity does not appear to be modified by changes in plasma levels of two common antioxidant vitamins, it may be useful for the identification of high-risk individuals for participation in large intervention studies with cancer outcomes.

Lifestyle and nutritional correlates of cytochrome CYP1A2 activity: inverse associations with plasma lutein and alpha-tocopherol.

Cytochrome CYP1A2, a liver enzyme responsible for the metabolic activation of a number of putative human carcinogens, exhibits wide inter-individual differences in activity. In order to characterize sources of variability in CYP1A2 activity, we phenotyped (with the caffeine test) 90 subjects of various ethnic backgrounds in Hawaii. Forty-three subjects were patients with in-situ colorectal cancer treated by polypectomy and 47 were healthy population controls. Subjects were also administered a detailed lifestyle questionnaire, including a quantitative food frequency questionnaire, and were assessed for plasma levels of carotenoids, tocopherols, retinol, ascorbic acid, cholesterol and triglycerides. In a stepwise multiple regression, 27% of the overall variation in CYP1A2 activity was explained by seven variables. Plasma lutein explained the largest portion of the variance (7%) and was negatively associated with CYP1A2 activity (p < 0.01), as were use of menopausal replacement estrogens (p = 0.04), plasma alpha-tocopherol (p = 0.05) and alcohol consumption (p = < 0.01). Acetaminophen use (p = 0.05), coffee consumption (p = 0.05) and plasma lycopene (p = 0.06) were positively associated with CYP1A2 activity. After adjustment for these variables, no association was found between CYP1A2 activity and sex, race, age, education, smoking, physical activity, weight, vitamin E supplements, the other plasma micronutrients measured, and dietary intakes of red meat, processed meat and cruciferous vegetables. Results were similar for colorectal cancer cases and controls. Almost two-thirds (73%) of the variability in CYP1A2 activity remained unexplained. This study confirms an enhancing effect of acetaminophen and coffee on CYP1A2 activity and suggests and inhibitory effect of estrogens, alcohol and food sources of lutein and alpha-tocopherol on this enzyme.

Correlations between mutagen sensitivity and plasma nutrient levels of healthy individuals.

Increased mutagen sensitivity and decreased intake of antioxidant-rich fruits and vegetables have been associated with an increased risk of upper aerodigestive tract cancers. The objective of this study was to investigate the intraindividual variation in mutagen sensitivity and its possible correlation with plasma nutrient levels in a group of 25 healthy individuals in Hawaii. Mutagen sensitivity, as assessed by bleomycin-induced chromosomal breaks in cultured peripheral blood lymphocytes and plasma nutrient levels were measured monthly for 11 months. The monthly numbers of chromosomal breaks/cell ranged from 0.04 to 0.80 and showed considerable intraindividual variation. Based on individual means, significant inverse correlations were found between mutagen sensitivity scores and the plasma levels of alpha-carotene (r = -0.64), total carotenoids (r = -0.41), and ascorbic acid (r = -0.40). There were also significant inverse associations between monthly mean plasma levels of alpha-carotene (r = -0.58), beta-carotene (r = -0.76) and total carotenoids (r = -0.72) and monthly mean chromosomal breaks. In contrast, there was a significant positive correlation between monthly mean plasma triglyceride level (r = 0.60) and monthly mean mutagen sensitivity. These results suggest that mutagen sensitivity as assessed by the bleomycin assay may be influenced by plasma levels of certain nutrients and could potentially be modified by dietary interventions or micronutrient supplementation.

Seasonal variations in plasma micronutrients and antioxidants.

Plasma samples were collected at monthly intervals for a period of 1 year from a group of healthy nonsmoking men and women (n = 21) living in Honolulu, HI. Analysis of plasma cholesterol and triglyceride levels showed marked seasonal variations, with higher mean levels in winter months and lower values in the summer. Cholesterol and triglycerides were highly and inversely correlated with plasma levels of the provitamin A carotenoids. Mean beta- and alpha-carotene levels were highest in late summer and fall. Plasma retinol levels were significantly lower in the summer and higher in the winter. Variations (either between individuals or seasonally) in plasma retinol were unrelated to plasma provitamin A carotenoid levels. Plasma levels of alpha-tocopherol, gamma-tocopherol, beta-cryptoxanthin, and lutein were also higher in the winter and lower in the summer. Significant seasonal correlations, both positive and negative, with environmental variables, such as temperature, solar UV radiation, and rainfall, are noted for many of these plasma micronutrients. The number of samples required to accurately characterize long-term plasma levels for an individual generally ranged from 1 to 4. However, plasma retinol levels exhibited the highest ratio of intra- to interindividual variability, suggesting the need for multiple sampling (> 8 samples) for this micronutrient. Some of this variability for retinol was associated with seasonal changes. Assessment by a diet history of food and supplement intake of micronutrients and phytochemicals for 1 year showed good agreement with 1-year mean plasma levels for most carotenoids, vitamin C, and alpha-tocopherol. Retinol, gamma-tocopherol, cholesterol, and triglyceride levels in plasma were unrelated to estimates of dietary intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of micronutrients and antioxidants on lipid peroxidation in human plasma and in cell culture.

Plasma levels of triglycerides, retinol, cholesterol, lipid-phase antioxidants (alpha-, gamma-tocopherols, beta-carotene, alpha-carotene, lycopene, beta-cryptoxanthin and lutein/zeaxanthin), and thiobarbituric acid-reactive substances (TBA-RS), as an indicator of lipid peroxidation, were repeatedly determined in nine individuals over a 3-month period. Levels of TBA-RS were positively correlated with plasma triglycerides and gamma-tocopherol, and negatively correlated with plasma carotenoids. These results were consistent with in vitro cell culture studies which showed increased TBA-RS for cells supplemented with linolenic acid and decreased levels when treated with beta-carotene. We conclude that TBA-RS measurements in plasma accurately reflect the level of peroxidizable substrate as modified by the presence of a variety of dietary antioxidants, particularly carotenoids. Although the inter- and intra-individual variabilities for TBA-RS are comparable with the micronutrients and antioxidants measured in this study, high interassay variability and the strong association with the more commonly measured plasma triglycerides suggest the TBA-RS assay to be of limited use in epidemiologic studies. However, this assay does appear to be useful in cell culture studies where experimental conditions can be better controlled. Low ratios of inter- to intra-individual variability in some of the plasma micronutrient and lipid-phase antioxidants measured suggest that multiple samples may be required to characterize individuals in studies evaluating the relation between these plasma constituents and disease incidence.