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Acetaminophen (APAP) glucuronidation is thought to occur mainly by UDP-glucuronosyltransferases (UGT) in the UGT1A family. Interindividual variation in APAP glucuronidation is attributed in part to polymorphisms in UGT1As. However, evidence suggests that UGT2B15 may also be important. We evaluated, in a controlled feeding trial, whether APAP conjugation differed by UGT1A6 and UGT2B15 genotypes and whether supplementation of known dietary inducers of UGT (crucifers, soy, and citrus) modulated APAP glucuronidation compared with a diet devoid of fruits and vegetables (F&V). Healthy adults (n = 66) received 1000 mg of APAP orally on days 7 and 14 of each 2-week feeding period and collected saliva and urine over 12 h. Urinary recovery of the percentage of the APAP dose as free APAP was higher (P = 0.02), and the percentage as APAP glucuronide (APAPG) was lower (P = 0.004) in women. The percentage of APAP was higher among UGT1A6*1/*1 genotypes, relative to *1/*2 and *2/*2 genotypes (P = 0.045). For UGT2B15, the percentage of APAPG decreased (P < 0.0001) and that of APAP sulfate increased (P = 0.002) in an allelic dose-dependent manner across genotypes from *1/*1 to *2/*2. There was a significant diet × UGT2B15 genotype interaction for the APAPG ratio (APAPG/total metabolites × 100) (P = 0.03), with *1/*1 genotypes having an approximately 2-fold higher F&V to basal diet difference in response compared with *1/*2 and *2/*2 genotypes. Salivary APAP maximum concentration (C(max)) was significantly higher in women (P = 0.0003), with F&V (P = 0.003), and among UGT1A6*2/*2 and UGT2B15*1/*2 genotypes (P = 0.02 and 0.002, respectively). APAP half-life was longer in UGT2B15*2/*2 genotypes with F&V (P = 0.009). APAP glucuronidation was significantly influenced by the UGT2B15*2 polymorphism, supporting a role in vivo for UGT2B15 in APAP glucuronidation, whereas the contribution of UGT1A6*2 was modest. Selected F&V known to affect UGT activity led to greater glucuronidation and less sulfation.

Although there is evidence from studies of prostate cancer cell lines and rodent models that several supplements may have anti-inflammatory, anti-oxidant, or other anti-cancer properties, few epidemiologic studies have examined the association between non-vitamin, non-mineral, “specialty” supplement use and prostate cancer risk. Participants, 50–76 years, were 35,239 male members of the VITamins And Lifestyle (VITAL) cohort who were residents of western Washington State, and who completed an extensive baseline questionnaire in 2000–2002. Participants responded about their frequency (days/week) and duration (years) of specialty supplement uses. 1,602 incident invasive prostate cancers were obtained from the Surveillance, Epidemiology, and End Results registry. Multivariate-adjusted hazards ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazards models. Any use of grapeseed supplements was associated with a 41% (HR 0.59, 95% CI: 0.40–0.86) reduced risk of total prostate cancer. There were no associations for use of chondroitin, co-enzyme Q10, fish oil, garlic, ginkgo biloba, ginseng, glucosamine, or saw palmetto. Grapeseed may be a potential chemopreventive agent, however as current evidence is limited, it should not yet be promoted for prevention of prostate cancer.

Background/Aims: Interindividual variation in aspirin (ASA) metabolism is attributed to concomitant use of drugs or alcohol, urine pH, ethnicity, sex, and genetic variants in UDP-glucuronosyltransferases (UGT). Little is known about the effects of diet. Methods: We evaluated cross-sectionally whether urinary excretion of ASA and its metabolites [salicylic acid (SA), salicyluric acid (SUA) phenolic glucuronide (SUAPG), salicylic acid acyl glucuronide (SAAG) and salicylic acid phenolic glucuronide (SAPG)] differed by UGT1A6 genotype and dietary factors shown to induce UGT. Following oral treatment with 650 mg ASA, urine was collected over 8 h in 264 men and 264 women (21–45 years old). Results: There were statistically significant differences in metabolites excreted between sexes and ethnicities. Men excreted more SUA; women more ASA (p = 0.03), SA, SAAG and SAPG (p ≤ 0.001 for all). Compared to Caucasians, Asians excreted more ASA, SA and SAAG, and less SUA and SUAPG (p ≤ 0.03 for all); African-Americans excreted more SAAG and SAPG and less SUA (p ≤ 0.04). There was no effect of UGT1A6 genotypes. Increased ASA and decreased SUAPG excretion was observed with increased servings of vegetables (p = 0.008), specifically crucifers (p = 0.05). Conclusion: Diet may influence the pharmacokinetics of ASA, but effects may be through modulation of glycine conjugation rather than glucuronidation.

Chemoprevention by isothiocyanates from cruciferous vegetables occurs partly through up-regulation of phase II conjugating enzymes, such as UDP-glucuronosyltransferases (UGT). UGT1A1 glucuronidates bilirubin, estrogens, and several dietary carcinogens. The UGT1A1*28 polymorphism reduces transcription compared with the wild-type, resulting in decreased enzyme activity. Isothiocyanates are metabolized by glutathione S-transferases (GST); variants may alter isothiocyanate clearance such that response to crucifers may vary by genotype. We evaluated, in a randomized, controlled, crossover feeding trial in humans (n = 70), three test diets (single- and double-“dose” cruciferous and cruciferous plus apiaceous) compared with a fruit and vegetable–free basal diet. We measured serum bilirubin concentrations on days 0, 7, 11, and 14 of each 2-week feeding period to monitor UGT1A1 activity and determined effects of UGT1A1*28 and GSTM1/GSTT1-null variants on response. Aggregate bilirubin response to all vegetable-containing diets was statistically significantly lower compared with the basal diet (P < 0.03 for all). Within each UGT1A1 genotype, lower bilirubin concentrations were seen in *1/*1 in both single- and double-dose cruciferous diets compared with basal (P < 0.03 for both); *1/*28 in double-dose cruciferous and cruciferous plus apiaceous compared with basal, and cruciferous plus apiaceous compared with single-dose cruciferous (P < 0.02 for all); and *28/*28 in all vegetable-containing diets compared with basal (P < 0.02 for all). Evaluation of the effects of diet stratified by GST genotype revealed some statistically significant genotypic differences; however, the magnitude was similar and not statistically significant between genotypes. These results may have implications for altering carcinogen metabolism through dietary intervention, particularly among UGT1A1*28/*28 individuals.

The present paper describes the evaluation of a nutrition service and research model for human immunodeficiency virus (HIV)-positive clients within a community based HIV acquired immune deficiency syndrome (AIDS) medical clinic. This program was designed to develop an effective, practical, replicable model for the delivery of nutrition services in the ambulatory HIV care setting. The objectives of evaluating the model were to define the ways that nutrition services in HIV/AIDS impacted clients, the clinic, and referral sources, and to continually refine the model by determining what services provide greatest benefit to clients, especially in view of the changing landscape of HIV therapy. Four evaluation activities completed during the study period of 5 years are described. These included a focus group and semistructured interview with clients, a semistructured interview with workers from the local network of service referral agencies and a client satisfaction survey at study "close-out." These evaluation processes confirmed or prompted programmatic modifications that improved access, confidentiality, and the relevance of specific components for clients. Providers/stakeholder's concerns were addressed through more frequent communication about clients' specific nutrition issues, clearer and easier referral and cooperation in recruiting patients. Also, the evaluation activities provided a platform for the communication of general and specific information about the program and for outreach. Although clients' and workers' priorities differed in some details of program implementation, there was strong agreement on the value of addressing nutrition concerns in HIV. Favorable feedback about the program gave impetus to continue nutrition services in the clinic after the project period ended and supports its application in other sites and settings.

Higher consumption of cruciferous vegetables is associated with lower risk of several cancers. Isothiocyanates (ITC), the bioactive compounds derived from glucosinolates in cruciferous vegetables, are thought to exert chemoprotective effects through modulation of several pathways critical to carcinogenesis. Urinary ITC excretion is used in epidemiologic studies as a measure of cruciferous vegetable intake; however, considerable inter-individual variation in ITC excretion is observed. Several factors may influence glucosinolate metabolism and excretion, including gut microbial hydrolysis and genetic variation in human enzymes. Thus, intake is not necessarily equivalent to ITC exposure. In a randomized cross-over trial, we evaluated total urinary ITC excretion in healthy participants (n=12 men; n=13 women) in response to 100 μmol glucosinolate intake from three acute feedings of cooked cruciferous vegetables– watercress (67 g), broccoli (125 g), and cabbage (250 g). The vegetables were fed alongside a standardized frozen pasta meal (227 g). GSTM1 genotyping (present or null) was conducted on buccal cell DNA. Total urinary ITC excretion (dithiocarbamates plus glutathione-derived conjugates) was assayed by HPLC from 24 h urine collections adjusted for completeness by creatinine. Linear mixed models were used to assess the effects of dietary exposure and urinary ITC excretion. Mean urinary ITC excretion was 7.21 (95% CI: 5.81, 8.94); 8.35 (95% CI: 6.73, 10.35); and 10.08 (95% CI: 8.20, 12.41) μmol/24 h for watercress, cabbage and broccoli, respectively. As a group, participants excreted significantly more ITC after consumption of broccoli compared to watercress (P=0.01). Intra- and inter-individual variances across all 3 vegetables were 0.29 and 0.07, respectively, and the intra-class correlation (ICC) was 0.20 when evaluating the three dietary measures as replicates of 100 μmol glucosinolate intakes. There were no main effects of GSTM1 genotype (n=9 positive; n=16 null) or ethnicity (n=14 Caucasians; n=9 Asians). Urinary ITC excretion profiles significantly differed between broccoli and watercress, as well as within and between individuals (ICCs below 0.45 indicate poor correlation between repeated measures). This suggests that ITC bioavailability within individuals differs by type of crucifer consumed. ITC are involved in the modulation of several pathways involved in carcinogenesis, therefore an individual's actual exposure to ITC may affect their ultimate risk of cancer. Citation Format: Sandi L. Navarro, Hannah Frenkel, Wendy K. Thomas, Karen Makar, C.Y. Wang, Johanna W. Lampe. Urinary isothiocyanate excretion profiles in response to acute feeding of various cruciferous vegetables in humans. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A101.

Biomarkers of low-grade systemic inflammation are used to study the associations of inflammation with chronic diseases, including cancers. However, little is known about the reliability (i.e., intraindividual variability) of most of these measures. Fasting (12-hour) serum samples, which were collected at the end of ≥3 week washout periods in a 4-diet crossover feeding trial, were used to measure the inflammatory markers hsCRP, IL-6, TNF-α, IL-8 and sTNFRI and II. Participants included 32 men and 31 women (5 men and 2 women were missing from analyses of IL-8, TNF-α, and sTNFR I and II), aged 20-40, who were free of factors known to influence inflammation, e.g., chronic disease, medication use, heavy alcohol use, smoking and obesity (body mass index >30 kg/m2). Intraclass correlations (ICC) were estimated using random effects analysis of variance, across all 4 time points (∼5 weeks apart). For TNF-α and sTNFRI & II, the ICCs were very high (ICC= 0.92, 95% CI: 0.89 - 0.96; 0.92, 95% CI: 0.88 - 0.95; and 0.90, 95% CI: 0.85 - 0.94, respectively). The ICCs for IL-8 and hsCRP were 0.73 (95% CI: 0.63-0.83 and 0.68 (95% CI: 0.58-0.78), respectively. The ICC for IL-6 was considerably lower, (ICC = 0.48, 95% CI: 0.36-0.62). With the exception of IL-6, reliability of all inflammatory markers in our panel over 4 time points was high, suggesting that a single measure accurately captures the variability within an individual and is a good measure for use in epidemiologic studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5486. doi:1538-7445.AM2012-5486

Although there is evidence from studies of prostate cancer cell lines and rodent models that several supplements may have anti-inflammatory, anti-oxidant, or other anti-cancer properties, few epidemiologic studies have examined the association between non-vitamin, non-mineral, specialty supplement use and prostate cancer risk. Participants, 50-76 years, were 35,239 male members of the VITamins And Lifestyle (VITAL) cohort who were residents of western Washington State, and who completed an extensive baseline questionnaire in 2000-2002. Participants responded about their frequency (days/week) and duration (years) of specialty supplement uses. 1,602 incident invasive prostate cancers were obtained from the Surveillance, Epidemiology, and End Results registry. Multivariate-adjusted hazards ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazards models. Any use of grapeseed supplements was associated with a 41% (HR 0.59, 95% CI: 0.40-0.86) reduced risk of total prostate cancer. Although not statistically different, the association was somewhat stronger for low-grade (HR 0.58, 95% CI: 0.33-1.03) than high-grade tumors (HR 0.82, 95% CI: 0.34-2.00). There were no associations for use of chondroitin, co-enzyme Q10, fish oil, garlic, ginkgo biloba, ginseng, glucosamine, or saw palmetto. Grapeseed may be a potential chemopreventive agent, however as current evidence is limited, it should not yet be promoted for prevention of prostate cancer. This work is supported by NCI grants R25-CA94880, R01-CA142545, and K05-CA154337 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1915. doi:10.1158/1538-7445.AM2011-1915

Isothiocyanates (ITC) in cruciferous vegetables modulate several signaling pathways involved in carcinogenesis, including nuclear factor kappa-B (NF-κB), a transcription factor and central mediator in the generation of inflammation. Glutathione S-transferase (GST)M1 & GSTT1 metabolize ITC; genotypic differences in biologic response to cruciferous vegetable intake, and variation in ITC pharmacokinetics have been reported. Previously, we found reduced serum IL-6 and CRP concentrations in response to cruciferous (broccoli family) and apiaceous (carrot family) vegetable feeding compared to a basal diet in a randomized, crossover trial. Reductions were most marked among individuals with a GSTM1-null genotype. Here, we extend our panel of biomarkers in this intervention to include serum interleukin (IL)-8, tumor necrosis factor-alpha (TNF-α), and soluble TNF receptors I & II (sTNFRI & II). We tested whether supplementation of cruciferous or apiaceous vegetables alters serum concentrations of these markers, and whether this response is GSTM1/GSTT1 genotype-dependent. Men (n=26) and women (n=30), 20-40 y, ate four 14-day controlled diets – basal (fruit &vegetable-free), basal + two doses of crucifers (single & double “dose”), and single-dose cruciferous + apiaceous vegetables – fed per kg body weight. Fasting bloods from days 0 & 14 of each period were analyzed for serum inflammatory markers (IL-8 & TNF-a using the High Sensitivity Human Cytokine Panel, sTNFRs using the Human Soluble Cytokine Receptor Panel, Millipore). In this healthy population, we observed no overall reduction in any of the current biomarkers in response to vegetable supplementation. However, similarly to what we observed with IL-6 and CRP, both sTNFRI & II were lower at day 14 on the double-dose cruciferous vegetable diet among GSTM1-null individuals (P=0.006 & 0.007, respectively). NF-kB is one regulator of these inflammatory markers; but overlap with other pro-inflammatory pathways that may be differently regulated by diet, e.g., STAT3, may preclude observation of an effect. Such diet interventions may be more effective in populations with higher circulating inflammation biomarkers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3682. doi:10.1158/1538-7445.AM2011-3682

Isothiocyanates (ITC), derived from glucosinolates, are thought to be responsible for the chemoprotective actions conferred by higher cruciferous vegetable intake. Evidence suggests that isothiocyanates exert their effects through a variety of distinct but interconnected signaling pathways important for inhibiting carcinogenesis, including those involved in detoxification, inflammation, apoptosis, and cell cycle and epigenetic regulation, among others. This article provides an update on the latest research on isothiocyanates and these mechanisms, and points out remaining gaps in our understanding of these events. Given the variety of ITC produced from glucosinolates, and the diverse pathways on which these compounds act, a systems biology approach, in vivo, may help to better characterize their integrated role in cancer prevention. In addition, the effects of dose, duration of exposure, and specificity of different ITC should be considered.

Regular use of aspirin is associated with lower colon cancer risk. High inter-individual variation in aspirin metabolism has been attributed to several factors, including sex, concomitant use of other drugs or alcohol, urine pH, ethnicity, and variants in metabolizing enzymes involved in glucuronidation of aspirin metabolites [i.e., UDP glucuronosyltransferases (UGT)]. However, little is known about the impact of other exposures, including dietary factors. Dietary constituents of citrus fruits, cruciferous vegetables and soy have been shown to induce UGT. Higher intakes may alter UGT activity and affect the ratio of aspirin metabolites excreted. We evaluated, cross-sectionally, whether urinary excretion of aspirin [ASA] and its metabolites (salicylic acid [SA], salicyluric acid [SUA], salicyluric phonolic glucuronide [SUPG], salicyl acyl and phenolic acid glucuronides [SAG/SPG]) differed by UGT1A6 genotype and dietary factors. Following an oral dose of 650 mg aspirin, healthy men (N=264) and women (N=264), 20–40 years, collected urine over an 8-h period. Participant exclusion criteria included medical history of gastrointestinal, hepatic or renal disorders, and exposure to non-dietary factors known to influence biotransformation enzymes, e.g., medications, excessive alcohol, and smoking. FFQ data were available for 481 participants. Multiple linear regression was used to determine whether there were differences in aspirin metabolism by UGT1A6 genotype, or daily intake of protein, total fruit or vegetable intake, and soy, citrus and cruciferous vegetable intake, adjusted for body mass index (BMI), age, sex, ethnicity, urine volume and pH, and energy intake. There were statistically significant differences in the ratios of metabolites excreted, (specific metabolite/sum of metabolites), between sexes and between ethnic groups. Men excreted more SUA (P Of the factors evaluated, ethnicity and sex were the greatest, albeit modest, contributors to variability in aspirin metabolism (R2=2−13%), whereas UGT1A6 had no effect. Our results also suggest that diet may influence aspirin metabolism, but the effects do not appear to be via glucuronidation. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B99.