5 Nutritional Genomics and Proteomics EpigenomicCH3-DNAGenomic Post-translationalDNAmRNAProteinsEnzymes, structural,Transport,signaling caused by phosphorylation, glycosylation, etc.BioactiveFoodComponents
6 Influence of Caffeine on Bone Mass May Depend on Genes 6< 300 mgCaffeine> 300 mgD Spine Bone Mass Density (%)-6BACKGROUND: The role of caffeine as a risk factor for bone loss is controversial. OBJECTIVE: Our goals were 1) to compare in both a cross-sectional study and a 3-y longitudinal study the bone mineral density (BMD) of postmenopausal women consuming high or low amounts of caffeine and 2) to study the interaction between caffeine intake, vitamin D receptor (VDR)polymorphism, and BMD in the longitudinal study. DESIGN: The results are derived from cross-sectional measurements of BMD in 489 elderly women (aged y) and from longitudinal measurements made in 96 of these women who were treatedwith a placebo for 3 y. Changes in BMD were adjusted for confounding factors and were compared between groups with eitherlow (< or =300 mg/d) or high (>300 mg/d) caffeine intakes and between the VDR genotype subgroups of the low- andhigh-caffeine groups. RESULTS: Women with high caffeine intakes had significantly higher rates of bone loss at the spine than did those with low intakes ( /- 0.97% compared with /- 1.08%; P = 0.038). When the data were analyzed according to VDR genotype and caffeine intake, women with the tt genotype had significantly (P = 0.054) higher rates of boneloss at the spine ( /- 2.62%) than did women with the TT genotype ( /- 1.42%) when their caffeine intake was>300 mg/d. CONCLUSIONS: Intakes of caffeine in amounts >300 mg/d ( approximately 514 g, or 18 oz, brewed coffee) accelerate bone loss at the spine in elderly postmenopausal women. Furthermore, women with the tt genetic variant of VDRappear to be at a greater risk for this deleterious effect of caffeine on bone.-12TT Tt ttTT Tt ttVitamin D Receptor GenotypeRapuri et al. Am J Clin Nutr 2001 Nov;74(5):
7 Diet-Gene Interactions in Colon Cancer p21+/+ AIN-76A Diet100p21+/- AIN-76A Diet9080p21+/+ Western Diet70p21-/- AIN-76A Diet60p21+/- Western DietPercent survival5040p21-/- Western Diet3020104812162024283236WeeksYang et al, Cancer Res. 61, 565, 2001
9 Selenium & Skin Cancer Prevention Trial Phase III trial with 1,312 skin cancer subjectsSe (200 mg) as Brewers Yeast vs. Placebo, follow-up 6.4 yrsSelenium Placebo RR 97% CISkin CancerSquamous cellBasal cellCancer (- Skin)LungProstateColorectalBreastAll Sites (- Skin)Clark et al. JAMA 276: 1957, 1996.
10 Prostate Cancer Prevention Selenium and Vitamin E Cancer Prevention Trail (SELECT) ($175M)32,000 men, age >55 (> 50 for Black Men)Selenium 200 ug/dVitamin E 400 mg/dSeleniumVitamin EPlacebo7 + Years TreatmentEndpoint Prostate Cancer Incidence
11 Early Biomarkers Needed Ideal Qualities:Readily accessibleEasily & reliably assayedDifferentially expressedDirectly associated with disease progressionModulablePredictive
13 Diet May Influence Genetic & Epigenetic Events Associated with Several Cancer Processes DNA RepairCarcinogenMetabolismHormonal RegulationBioactiveFoodComponentsCell CycleDifferentiationApoptosisU54 RFA Review Nov
14 Numerous Dietary Components Can Alter Genetic and Epigenetic Events Essential Nutrients- Ca, Zn, Se, Folate, C, ENon-EssentialPhytochemicals- Carotenoids, Flavonoids, Indoles, Isothiocyanates, Allyl SulfurZoochemicals - Conjugated linoleic acid, n-3 fatty acidsFungochemicals - Several compounds in mushroomsBacteriochemical - Those formed from food fermentations and those resulting from intestinal flora
15 Gene Expression in Human Cultured Colon Cells ButyrateCurcuminRed - increasedGreen - decreasedBlack - unchanged.Mariadason et al, Cancer Res . 60, 4561, 2000
16 How Should We Consume Bioactive Food Components? MARKET STAGE BROCCOLI3-DAY SPROUTS3 gramsFREEZE-DRIEDSPROUT EXTRACT150 grams150 mgAll preparations contain the same quantity of detoxification enzyme inducer activity, (Glutathione S-transferase and Quinone Reductase)
17 S S OLTIPRAZ Isothiocyanates (OLTIPRAZ) Cytoplasm Nucleus ARE nrf2 HSSHkeap-1keap-1nrf2Cytoplasmnrf2nrf2smallNucleusmafAREGene expression“antioxidant responsive element”
18 isothiocyanates (nutrient) have similar mechanism of action Effect of Nrf2 genotype on induction of GST and NQO1 activities by oltipraz in mouse liver (Ramos-Gomez et al. Proc Natl Acad Sci U S A 2001;98:3410)Oltipraz (drug)andisothiocyanates (nutrient) have similar mechanism of action
20 Tea and Cancer Prevention SkinLiverCamellia SinensisColonOralEsophagusProstateMammaryStomachLungYang CS. Personal Communication
21 Types of Bioactive Compounds May Vary with New Varieties Tomato Varieties
22 Recent Epidemiologic Studies of Lycopene and Cancer Risk Cancer Type of Study ReferenceBreast Cohort Dorgan et al Can Cau Cont 9: 89-97, 1998Colon Case-control Franceschi et al Int J Cancer 72:56-61, 1997Lung Case-control Agudo et al Eur J Cancer 33: , 1997Prostate Cohort Giovannucci et al J Natl. Cancer Inst. 87: ,
23 Prospective cohort study with 41,837 women age 55 to 69, examined 127 food items. “The strongest association in the present study was that for garlic consumption, with an approximate 50% lesser risk associated with high consumption.” Steinmetz et al. Amer. J. Epidemiology 139:1, 1994Recent meta-analysis of Data from 11 trials concluded The random-effects relative risk (RR) estimate for raw and cooked garlic and colorectal cancer was 0.69 and for stomach was 0.53.Fleischauer, et al. Amer JClin Nutr 72, 1047, 2000.
24 Effects of Microwave Heating of Garlic on Total DMBA-Induced DNA Adducts 100030 secondsa60 secondsa750(nmol Adducts/mol DNA)DNA Adducts500bb250ControlPeel/CrushedMicrowave/ Peel/CrushedSong and Milner J Nutr 1999;129:657-61
25 How Much of A Given Food is Needed Indole 3-carbinol changes site of hydroxylation of estradiol (>2 and <16 OH). Causes depression in tumor growth and apoptosis.(Telang, et al. PSEBM 216: 246: 1997).
26 Wang, Kim and MilnerAACR 2002 Top 20 down-regulated genes from 3 microarray analysis from MCF-7 cells (T: with, C: without 100µM indole-3-carbinol)Name T/C (Ave) p valueALOX5AP--arachidonate 5-lipoxygenase-aBMP7--bone morphogenetic proteinERCC6--excision repair cross-complemenESR1--estrogen receptorEXTL3--exostoses (multiple)-likeGATA3--GATA-binding proteinHMG2--high-mobility group (nonhistoneHomo sapiens cDNA FLJ14201 fis, cloneHomo sapiens clone mRNA sequenceKIAA0165--extra spindle poles, S. cereKRT7--keratinLAP18--leukemia-associated phosphoprotNRCAM--neuronal cell adhesion moleculeSFRP5--secreted frizzled-related proteTCF3--transcription factorUGDH--UDP-glucose dehydrogenaseUnknownUnknownUnknownZXDA--zinc finger, X-linked, duplicateWang, Kim and MilnerAACR 2002
27 Indole 3-Carbinol and Tamoxifen Interactions in Attached MCF-7 Cells 100-I3C (mM)80-5060-Integrated Density/Area(pixel value/mm2)10040-20-0-0.51mM TamoxifenCover et al. Cancer Research 59:1244, 1999.
28 Soy Intake and Cancer Concerns 17 of 26 animal studies reveal soy or soybean isoflavones reduce tumor tumor development19 or 21 human epidemiological studies provide evidence of protection against cancer, especially rectal and stomach cancers (1 study reported increase)ConcernsGrowth enhancement of human mammary tumors transplanted into mice that were fed soy or isoflavonids (Hsieh, et al. Cancer Res. 58:3833, 1998).13
29 Soymilk Intake & Prostate Cancer Risk 1.00.90.8Relative Risk0.3*<11>1Daily Intake (servings)Cancer Causes Control 9: 553, 1998
30 More is Not Always Better: Energy Intakes and Expenditures Are Linked to Health!
31 Caloric Restriction in Yeast causes silencing of genes and extended life span (Guarente and Kenyon Nature 2000; 408:255
33 Is it Possible that Bioactive Compounds might be beneficial in some circumstances and detrimental in other?
34 Some Women Appear Susceptible to Flavonoids Several flavonoids found to cause change in MLL gene on chromosome band 11q23Associated with increased risk of infant leukemia linked to MLL geneSome cancer patients treated with drugs that modify topoisomerase develop leukemia involving MLL gene.Ross (2000) Proc. Natl Acad. Sci. 97:Strick et al. (2000) Proc. Natl Acad. Sci. 97:
35 Antioxidant reduces efficacy of cisplatin Vitamin E Inhibits Cisplatin-Induced Apoptosis in MCF-7 Breast Cancer Cells.6 -Antioxidant reduces efficacy of cisplatin4 -% Apoptosis +**2 -*0 -ControlECPCP+ESalganik, et al. Carcinogenesis 21: 909, 2000.