Ignatius Hapsoro Wirandoko

Dipresentasikan pada Seminar Nasional “Healthy Diet for Healthy Life,How to Eat Healthy Diet that Your Body and Soul Agree”

Program Studi Ilmu Gizi Fak Kedokteran Univ. DiponegoroSemarang, 08 Maret 2009

Nutrigenomics:Molecular nutrition of genetic

variation linked to diet

Nutrigenomics Definition

Analyzing the effects of diet on the activity of on individual’s genes and health and the effect of an individuals genes on metabolism of dietary chemicals

Diet = nutritional scienceActivity of genes = molecular biologyIndividual = genetics/genomicsHealth = physiology

A systems biology science : Multi - disciplinary

Nutrient is independent variable

Gene expression is independent variable

Gene Expression

Nutrient

Effects of individual genetic variation in response to nutrient

Nutrigenetics Definition

Any two individuals share 99% of their DNA sequence

Most common form of variation Single nucleotide polymorphism (SNP) Changes in single base pair Occur ~ 1 in every 1000bp of human genome

(~ 3 million in human genome)

SNPs may alter regulation of gene expression, mRNA processing (splicing, half-life etc) and protein activities

Ancestral diet

Modern diet

Molekul mechanisms of genetic variation Linked

diet

Selection pressures leading to metabolic programming, i.e., SNPs tailor man to enviroment

Human diseases resulting from incompatibility between genetic/metabolic programming and modren diet

Dietary Nutrients

Micronutrients Macronutrients

Other food components

Transduction of signal via sensory mechanisms

Metabolism

NUTRIGENOMIC ASPECTS OF CELLULAR FUNCTION

NUTRIGENOMICS

Genomics Transcriptomics Proteomics Metabolomics

Genomics, transcriptomics, proteomics, metabolomics as analytical tools in molecular nutrition

DNA mRNA MetabolitesProtein

Sequencing and Genotyping

Pattens ofGene expression

Synthesis and Structure of Proteins

Profile and FuctionOf metabolites

Examples of Nutrient Interatcions with Genotype That Have Implications for Human Health

Gene SNP/Isoform NutrientMTHFRAPOEAPOA 1GPX4HFE

C677TE2+ , E3+ , E4-75 (G/A)3‘ – UTRC282Y, H63D, S65C

Folate, alcohol- 3 PUFAPUFASeleniumIron

Genetic variation (SNP) may contribute to disease differentials

Several alterations will be “diet responsive” and can be rendered harmless

Challenge Defining the right diet for the right population Tailoring dietary recommendation based on genetic when

appropriate

Nutrigenetics

SusceptibilitySNP1SNP2

PoorNutritionIn utero

FoodComponent I

Time

Smoking

ProtectiveSNP1

GoodNutritionIn utero

FoodComponent 2

Physicalactivity

Healthpendulum

Health Disease

THE HEALTH PENDULUM

Fatty acid

sC

ho

lesterolP

rotein

&

amin

o acid

Carb

oh

yd

rates

i.e

., glu

cos

eV

itamin

AB

ioflavo

no

ids

Vitam

in E

Xen

ob

iotics

Zin

cIro

nC

alcium

Vitam

in D

•Sterol regulatory element biding protein•Hepatocyte nuclear factor•Carbohydrate response element biding protein•Peroxisome proliferator activated receptor•Liver X receptor

•Modifies gene expression via signal transduction pathways•Pregnane X receptor

•Liver X receptor•Farnesoid X receptor•Pregnane X receptor

•Calcineurin/nuclear factor of activated T cells

•CCAAT/enhancer-biding protein

•Iron regulatory protein 1 and 2

•Sterol regulatory element binding protein•Upstream stimulatory factor•Carbohydrate response element binding protein

•Metal responsive transcription factor

•RAR•RXR

•Constituvenly active receptor•Pregnane X receptor

•Estrogen receptors•Nuclear factor xB

•VDR

Trancription factor Nutrient ligand

Tran

sciptio

n facto

rs and

their

Co

mp

on

ent S

NP

s con

tribu

te to

Th

e mo

saic of n

utrig

eno

mic effects

Th

at mo

dify p

hen

otyp

e, and

C

on

tribu

te to h

um

an in

divid

uality

GENETIC BUFFERING UNDERPINS NUTRIGENOMIC RELATIONSHIPS

PHENOTYPIC STABILITY

A more robust cellular integrity

A lessrobust cellular integrity

PHENOTYPIC INSTABILITY

•Health•Reproductive efficiency•Enhanced competitiveness

•Desease•Reproductive inefficiency•Reduced competitiveness

Natural selection acts to promote a robust phenotype in the face of nutrient variability. Genetic buffering confers stability and is achieved via interactions between gene loci, nutrient and genes, biologically active nutrients and the metabolome, and nutrients with nutrients. Other buffering mechanisms include gene duplication, a complex regulatory mesh of epistatic gene interactions, and protein-protein interactions that lead to molecular stability

Stochastric variables in the external enviroment:i.e.,avaviability of food nutrient, and influence of mutagenic processes, are subject to genetic buffering as a mechanism to impprove phenotypic stability

The Balances between phenotypic outcomes with respect to nutrition and genetic buffering

Important micronutrient–gene interactions, with particular reference to the effect ofcertain vitamins and minerals on the genomic machinery and/or gene product.

Some Important Micronutrient–Gene Interactions

Dietary Component

BackgroundInformation

Effect on Genomic Machineryand/or Gene Product

Retinoic acid(vitamin A)

RXR forms homodimers andheterodimers with vitamin D,PPAR, thyroid hormone, andCOUP receptors

Binds either RXR or RAR nuclear retionoid receptor and enhances transcription, although in absence ofretinoic acid, heterodimers repress gene expression

Ascorbic acid(vitamin C)

Oxidative DNA damage in vitaminC depletion (formation of 8-hydroxyguanine)

Enhances transcription of procollagen and translation of lysyloxidase

PyridoxalPhosphate(vitamin B6)

Modulates responsiveness ofsteroid hormone receptor

Attenuates transcription

Riboflavin(vitamin B2)

Flavin cofactor for 5,10MTHFR May interact with cellular folate to influence elaboration of DNA (1-C unit from folate donated to thymine)

Folic acid Provides 1-C unit for purine, pyrimidine, and methyl groups May modulate both expression of DNA via CpG methylation pattern and elaboration of DNA via provision of thymine. If 1-C shortage, uracil ismisincorporated and DNA becomes unstable

Vitamin D Vitamin D receptor forms a heterodimer with RXR Enhances transcription of calcium binding proteins

Vitamin K Growth arrest specific gene 6 product contains γ -carboxyglutamate residues

Regulates apoptosis, but it does not interact directly with genomic machinery

α-Tocopherol(vitamin E)

Antioxidant properties. Ameliorates damage to DNA from excess iron. Induces two signaltransduction pathways that act at several genes, but also acts independent of these two pathways

Protects genomic machinery from freeradical damage. Alters activity of protein kinase C and phospotidylinositol 3-kinase. This in turn regulates the expression of several genes . Also actson genes independent of these kinases

Calcium Critical for intracellular signaling Increased transcription of c-fos, c-jun,c-myc

Iron During deficiency, iron-regulatory protein binds mRNA and promotes synthesis of transferring receptor protein while ferritinproduction is repressed. The net effect is to increase iron utilization

Enhances transcription of metallothionein and translation of ferritin

Magnesium Required for nucleic acid polymerase enzyme activity Maintains fidelity of the DNA blueprint

Potassium Influences transcription of aldosterone synthase

Selenium Selenocysteine residue in glutathione peroxidase provides antioxidant properties

Helps prevent free radical damage to genome

Zinc Structural motif of zinc finger transcription factors Augments transcription factor binding

TRANSCIPTOMICS

APPLICATIONS TECHNIQUES

Screening and development of new antioxidants

Assessing potential effects of antioxidants

Defining biomarkers of oxidative stress

Evaluating the bioavailability of antioxidants

Studying redox sensitive signal transduction pathways

Differential display

cDNA arrays and Gene chips

Serial Analysis of Gene Expression

RT-PCR

Northern blotting

Analytical techniques and potential applications of transcriptomics in the fileds of free-radical research

• DNA micro arrays

• Protein chipsLarge scale genomics and proteomic investigations monitoring of the expression of thousands of

genes in response to diets

how nutrients modify;- cancer risk- chronic disease- aging

most human disease are largely avoidable by lifesyle changes

Nutrigenomics at the - forefront of preventive medicine- special emphasis on the gene regulatory activity of

- antioxidants- phytochemicals- micronutrients

Leading edge Laboratory Tools;

2 mol glutathione (GSH)

NADP+

Glutathione reductase

NADPH

Radical generatedLipid peroxides

1 mol reduced glutathione (GSSG)

Glutathione peroxidase enzyme protein with a selenocysteine residu at the catalytic site

+H3N ─ CH

CH2 ─ │

│C = 0│0

SeH

Free radikal

Mechanism of selenium as on evolutionary pressure on gametogenesis

5, 10-Methylenetetrahydrofolate

5-Methylenetetrahydrofolate

Equlibrium in favor of 677C allele

Equlibrium in favor of 677T allele

C667T-MTHFR one carbon flux B2

S-Adenosylhomocysteine Homocysteine

S-Adenosylmethionine

methionine

Genomic methyiations

B12

Methyionine synthase

Methyionine biosynthesisPertubations may increase homocysteineAnd hence vascular disease. They may alsoInfluence DNA methylationPatterns and gene expressionHomocysteine is alsoConsidernet to be embryotoxic

dUMPThymidylate synhase

dTMPNucleotide biosynthesis and the elaboration of DNA

Pertubations may influence embryogenesis; inadequate folate due to a poor diet and 677-MTHFR might lead to uracil misincorparation in DNA, genomic instability, and loss of the developing embryo. It may also promote cancer

Contemporary selection pressure from periconceptional folate supplements

Schematic of vitamin A and gene regulation

Micronutrients that act directly or indirectly as antioxidants or influence DNA expression

Vitamin A

Vitamin E

Folicacid

Vitamin D

Zn,Se,FeMg, Cu

Vitamin B2

Vitamin B3

Vitamin B6

Vitamin C

Vitamin B12

Nuclear DNA Damage

Threat and management of deleterious radicals generated by cellular respiration

Freeradicals

+O2

Mitochhondrial DNA Damage

Superoxidedismutase

Catalase

H2O2

H2O and

O2

Superoxide radical

ATP energy

O2 +

Glu

co

se

Membrane Damage

Antioxidants evolutions & Human Health

Homocyteine : genetic and nutritional factors

MTHFR - Homocyteine

Oxidative stress Reduce NO

Reduce tetrahydro biopterin

Low methylation

Homosisience

Metionin(Borto & Yang,2000)

MTHFR:C677C (normal)

C677T (akt rendah)

Metioninsintase

5 metilTHF

5,10 metilen THF

various mechanisms involved in the deleterious actions of homocysteineupon cellular processes.

Homocystein and modern society

Cellular genomic and nongenomic effects of isoflavones. The effects differ according to thetype of tissue and the number of estrogen receptors within that tissue. The effect on reproductive tissueis of particular interest and may influence reproductive efficiency.

Causes of Metabolic Syndrome

Various Factors Cause Metabolic Stress

Food

Stress

Pollution

Second hand smoke Genetic

Inheritance

…Lack of Exercise

Oxidative Activities

Cholesterol

Toxine

Diabetes

BacteriaGerm

Lack of enzyme

Gene Enviroment

INSULIN RESISTANCE

Effect of cytokines TNF,

IL 1 and IL6

Raised blood lipids

Production ofOxidant molecules

Acute phaseprotein

Fever Glucose Synthesis

AppetiteLoss andlethargy

Plasma copper

Plasma ZnPlasma Iron

Increased urinaryNitrogen sulphur

And mineral losses

Loss of leanTissue andfat

Fat proliferates abnormally (OBESITY)

chytokines

chytokines

Chronic inflammation develops

How Does Abdominal Obesity CauseInsulin Resistance

A collection of metabolic risk factors that accelerate the onset of diabetes, heart disease, stroke and certain cancers.

Metabolic SyndromeHealth Destroyer

Proinflammatory Cytokines Released

Glucose Uptake Decreases

Blood Glucose Levels Increase

Hyperglycermia

Hyperinsulinemia

Pancreas Increases Insulin Production

Triglycerides Released to Blood Stream

Cardiovascular Disease

Adipose tissue expands

O2 = dangeraous friend (a free radical)

evolutionas the terminal electron acceptor for respiration biradical ;

~

Others : - SUPEROXIDE ANION/ HYDROL RADICALS- oxidative- metabolism, and energy production- ionizing radiations

endowed with a higher chemical reactivityinvolued in - regulation of signal transduction

- gene expression, - activation of receptors,

- nuclear trancription factors,- oxidative damage to cell components

- antimicrobial and cytotoxic action of immune system cells neutrophils and macrophges in

aging &age related degenerative diseases

OXIDATIVE STRESS

Oxidative stress can lead to cell and tissue injury

Free radical generated by Nitric oxide synthase (NOS)

modulates physiological responses in the circulation

e.g.- vasodilatation (eNOS)

- signaling in the brain (nNOS) During inflamation : 1/3 isoenzyme is induced (iNOS)

everproduction of NO tissue damage

- + superoxida anion a strong oxidant : peroxynitrite Oxidation of

- lipid

- protein

- DNA by peroxynitrite tissue injury

NITRIC OXIDE (NO)

ROSNOS

redox regulation of cell functions

Oxidative stress as a major upstream component in

- the signaling cascade (in inflamation responses)

- stimulation of adhesion molecule, and

- chemo attractant production

H2O2 decomposes in the presence of transition metals to the highly reactive hydroxyl radical by 2 major reactive

- hydrogen abstraction and addition Oxidative damage to:

- lifoid- sugar- nucleic acid

H2O2 : an important signaling molecul

activate NFKB (transcription factor in inflammatory responses)

Low concentration :

- regulated cell signalling

- stimulates cellprofiferation

High concentration :

triggers apoptosis necrosis

Free radicals

Secondary ; most cases Causal

A Delicate balance : oxidands – antioxidants

proper balance healthy aging

Oxidative stress

1)Redox status the degree to which a cells components in the oxidized state

the reducing environment inside cells helps to prevent oxidative damage

maintained by (remove ROS)- oxidative metabolism- the action of antioxidant enzymes,

- superoxide dismutase- catalase- selenium dependent glutathione

reductase- glutathione hydroperoxidase- thioredoxin hydroperoxidase

- substances glutathione thioredoxin, vitamin E, C.

2) Depletion of antioxidants

Index of oxidative stress

- Thiol redox status- GSSG/ GSH ratio (Glutathione disulfide/ glutathione)- redox couples ratio

- NADPH/NADP- NADH/ NAD- Thioredoxin reduced/ thioredoxin oxidized- Dihydrolipoic acid/ lipoic acid- lactate/ pyruvate

Energy status of the cell(ratio ATP/ ADP + AMP)

Current hypotheses: How oxidants – antioxidants modulate ? lowering oxidative stress cell and tissue fuction can have a health benefit.Can be - over produced free radicals

- natural antioxidant system defenses weakened oxidative injury - heart disease

- cancer - neurodegenerative

disordersOxidation of human LDL : early step in the progression and

eventual development of atherosclerosisOxidative DNA damage

initiate carcinogenesisEnvironmental source of ROS oxidative stress disease

- UV radiation- Ozon- Cigarette smoke- others

FROM EPIDEMIOLOGICAL STUDIES : antioxidant status (vit C, E)

~ risk of several disease- Cataract- Cancer- Neurodegenerative disorder- Rheumatoid arthritis- DM

scientific evidenceClinical - prevention

- treatment

As - a primary cause - a secondary complication in many disorders

- inflamatory bowel disease- retinal ischemic- CVD and restenosis- AIDS- adult respiratory distress syndrome- stroke- Parkinson’s disease- Al zheimers disease

Major natural

antioxidant enzyme/ substances (in foods & beverage)

- vit E, A, C- flavonoids- polyphenols- caretenoids- lipoic acid- coenzyme Q10- carnitine- other micro nutrients

Trauma/infection/burn

Immune system activation

Pro-inflammatory cytokines

oxidants Antioxidantdefence

Tissuedamage

Pathogenkilling

FeedbackSystemsIL10, HeatShock proteins

Creation of a hostile enviroment

NutrientRelease fromHost tissues

Sulphuraminoacids

Antioxidantdefencesstrenghened

GlutathioneSynthesis

Appetite loss

T and B Cells

Glucose

Glutamine

Immunonutrition

Oxidants

Vit EReduced

Vit Eoxidised

Dehydroascorbicacid

Ascorbicacid

Methionine

Homocysteine

Cysteine

GlutathioneGSSG

GlutathioneGSH

Vit B6

Riboflavin

Glutathionereductase

Inflammatory stimuli LPS, Oxidants, stress

AP1 NFKB

CellProliferation

IL2

AcutePhaseprotein

IL1,IL6,IL8,TNF

GSHsynthesis

Adhesionmolecules

HIVreplication

Transciptionfactors

Antioxidants

Antiageing, Antiatherogenic, Anticarcinogenic,Immunomodulatory, Neuroprotective Effects

Preventions of OxidativeDamage towards Lipids

Proteins and DNA

Redox SignallingMolecules

Free Radical ScavengersMetal Chelators

Antioxidants as free-radical scavengers, metal chelators, and redox signaling molecules – both prevention of oxidative damage towards lipids, protein, and DNA as well as redox signaling contributes to their beneficial effects.

InhibitoryEffect of

Vitamin E onNitric oxide and

Cytokine production

Scavenger receptorexpression

Smooth muscleCell proliferation

LDL oxidation

Platelet adhesionAnd-aggregation

Cell adhesion protein expression

Molecular mechanisme for the anti-atherogenic activity of VE

Receptors

PhosphataseKinases

Gene Expression

Protein levels

Enzyme Activity

Oxidants Antioxidants

Transcription Factors

Cell receptors, cellular key enzymes, and transcription factors as molecular targets of oxidants and antioxidants

Rekayasa genetika pangan

KEBODOHAN (logos)

KESERAKAHAN (eros)

Kanker (Musibah) GLOBALISASI

KEARIFAN LOKAL

Pangan - GIZI (anugerah)

BIOTEKNOLOGI

NUTRIGENOMIC

Perilaku

GAYA HIDUP

KANKER LINGK- Kontaminan- Pestisida- Limbah

• Pola/kebiasaan makan

• Rokok, alkohol• Sedentary (obeis)

- Genotoksik/ pro kanker- Anti kanker

- Olah- Simpan- BTP- Plastik

GLOBALISASI

Pangan

Fenotipe Sehat

Fenotipe Sakit

Ekspresi gen/ fenomena epigenetik

RISETEKOLOGI

RISETEPIDEMIK

Uji in Vitro

Uji Hewan

UJIKLINIS

Fakta Epidemiologis

Kashmir : Ca. Oesofagus ~ pengolahan teh + garam

Skandinavia : Cancer lambung & colon ~ daging merah

Migran Jepang : kacang cycad

Mesir : Cancer hati ~ bijian disimpan

Kaukasus : Cancer payudara ~ lemak

Ceko-Polandia : Lemak >< kubis

China : teh hijau, bumbu/ rempah cara masak singkat

PANGAN KARCINOGENIC Geno Toksik~ Alamiah : • hidrazin

• safrole• estragole• psoralen

Buatan/ perilaku manusia :prose

s• Simpan : Aflatoksin, Patulin, Citrinin • olah : panas tinggi (goreng, bakar)

aditif pangan

residu minyak goreng& Lemak trans (peroksida lipid) pengasapan langsung garam/ pengasinan

– PAH– HAA– NOC• etanol

• sacharin• karamel• furyl furamid• pewarna azo • nitrat (III, V)

Energi (+ OR minimal) Alkohol berlebih ROS endogen

Asupan :

KONTAMINAN Lingkungan Pangan(Via: mata rantai pangan)

Antropogenic environtment pollutant

Mutagenik - Karsinogenik Polutan organik PCB (PCDD, PCDF, VOX, Pestisida)

Polutan anorganik

• Nitrat (III, V)• Benzo [a] pyrene• Pestisida: Khususnya organochlorin: DDT,Chlordane,lindane,DDE,Aldrin• Plastik-styrofoam kemasan (vynil-chlorida)• Benzene• Dioxin• Organohalogen votatil air PDAM• Logam berat; Pb, Ni, As, Cr

Reparasi SEL

RegulasiHormonal

Respons Radang

Metabolisme Karsinogen

DiferensiasiKematian SelTerprogram

Siklus SEL

KOMPONEN BIOAKTIFPANGAN

Cegah terjadi Hambat perjalanan keganasan Halangi kekambuhan

Gambar : Modulasi Komponen pangan pd Sel Kanker

HANAHAN & WEINBERG

Mandiri signal tumbuh

Insensitif signal hambat tumbuh

Hindar apoptosis

Replikasi tak terbatas

Angiogenesis

Invasi - metastosis

2001 : proyek genom manusia tuntaspenggunaan dalamriset gizi :- genomik

- transkriptomik- proteomik- metabolomik

nutrigenomik

era post genomik

Biomarker

Lokasi sel target

Tahapan Spesifik

Efek spesifik

Dapat dipantau adanya perubahan

risiko terhadap respon intervensi gizi

Dapat dipantau adanya perubahan

risiko terhadap respon intervensi gizi

MEKANISME MOLEKULER DIET ANTI KANKER

Aktivasi antioksidan• pembersihan radikal bebas• reduksi stres-oksidatif• pengurangan “nitrasi,nitrisasi)• pencegahan ikatan DNA

Hambat proliferasi sel induksi diferensi sel hambat ekspresi onkogen, induksi ekspresi gen penekan tumor induksi “henti siklus sel” dan kematian sel terprogram Induksi enzim & peningkatan detoksifikasi: (enzim fase III, GPX, SOD) Hambat enzim (COX-2, iNOS, Xanthine oksidase, enzim fox I)

• anti pembentukan p. darah baru• hambat adhesi sel (lengket) & invasi• regulasi metabolism H. steroid & estrogen• aktivasi anibakteri-virus

VARIASI DIIT & FAKTOR GENETIK

Respon terhadap intervensi diit

Diit bersifat individual (Personalisasi diit) ~ variasi ekspresi gen :

protein transport reseptor enzim katabolis

Penanda biologisperubahan fenotipe :

proteomic metabolomic

Mis: aktivitas dehydrogenese alkohol Kaukasus > Jepang

Regulasi pembelahan sel

• genistein (isoflavon), fitoestrogen kedele

Signal Antitumbuh

• flavonoid buah sayur• n.3. FA : EPA, DHA ikan• resveratrol anggur• Vit A, Vit D Apoptosis

• resveratrol anggur merah• lyeopere teh• carotene sayur• allyl sulfur bawang putih• caffeic acid, ester propolis• curcumin temu lawak,madu,

Angiogenesis

• Retinoid sayur buah • EGCG teh hijau• Curcumin •Vit D

• Katekin teh hijau• EGCG teh hijau• Resveratrol• n-3Fa, EPA, DHA

Replikasi tak terbatas

Invasi metatase

• Katekin• EGCG the hijau + hitam

DIIT BERBASIS TARGET MOLEKULER

ANTI Oksidan

Et, Vitamin C Caroten Se EGCG Quercetin Genestein Taxifolin

ANTI Radang

n-3, EPA DHA minyak ikan Vit A, Vit E Bromelein Curcumin Resveratrol Quescetin EGCG

Detoksifikasi

Regulasi

Enzim xenobiotik : Glukosinolat brocoli

Epigenik : - Folat- Vit B, 12, B2, B6, methionin- Zn, Se- Retinoid acid

KHEMOPREVENSI KANKER Mikronutrient : Vit A, D, E, C, folat, Se Komponen bioaktif :

Makronutriet : omega 3, spingolipid, CLA

Serat

Carotenoid :• Carotene (..)• Lutein• Lycopene

Fenolic : • Fenolic acid• Flavonoids• Stilbene• Tannin• Coumarin

Organosulfur : • Isotiosionat• Indole• Alyl sulfur : sulfida

- Flavonols (Quercetin)

- Flavones (Apigenin)

- Flavanols (Catechin)

- Flavanone (Naringetin)

- Anthocyanidine (Cyanidin)

- Isoflavonoid (Genistein)

PREVENSI (Lain) Intensif penggunaan fitokimia

• buah• sayuran• biji utuh• serat• produk (ikan, kedele)• susu rendah lemak

kontrol BB, cegah obesitas Olah raga/ latihan minimal 30 menit kurangi makan (goreng, bakar/grill, asap, asin) kurangi lemak jenuh, tak jenuh trans) maks 25% Stop rokok, minum alkohol minimal

KHEMOPREVENSI DIIT & TARGET MOLEKULER

Mekanisme Target Molekuler Khemoprev. Diit

Hambat tangkapanKarsinogen

As. Empedu Kalsium

Hambat aktivasi karsiongen Sitokrom P450s -PE ITC-Indol -3- carbinol-Isoflavon

- PG Synthase Hydroperoksidase Slipoxygenase- As. empedu

Curcumin

-Urosdial

Dexoksifikasi karsinogen GSH/ GST NAC bisulfida

Cegah ikat karsinogen-DNA Sitokran P450s Katekin

Luas + tingkatan Reparasi DNA

ADP riboxyl transferete

NAC, Protease, Inhibition

Modulasi hormonAktivitas fc tumbuh

- Reseptor estroge- Steroid 5 reductose- IGF.1- AP-1- PPARs

-Isoflavon-Katekin-Isoflavon,,Likopen-Retinoid

MEKANISME DIET (lanjutan)

Hambat aktivitas onkogen FP transferase Limonen, DHEA

Hambat metabolisme poliamin ODC induksi Retinoids, curcumin, katekin

Induksi diferensiasi terminal TGF- Retinoids, vit D nofloam

Restorasi respons imun TNK limfosil sel langerhons

Selenium katekin

Reduksi inflamasi NF.KB EGCG, resveratrol, curcumin

Hambat prod ekosanoid Cycloxygenne & lipoxygenne

Curcumin resveratrol EPA, DHA, Katekin

Akeselerasi komunikasi inter sel

Connexin 43 Lycopene retinoids

Induksi Apoptosis - TGF - Rosfarelisasi- Arachidonic Acid- Caspase

-Retinoid isoflavon vit D-Penillyl alcohol limonen,

DHEA-Retinoic acid-Retinoids

Induksi senesens Telomerase Vit D retinoids

Hambat angiogenesis FGF receptorTyronin kinaseTranmodulin

Isoflavon restinoid

Koreksi imbalansi metilasi DNA

Cp6 island metilasi Asam folat

Hmbt defradesia membran basal

Collagenase IV Proteese inhibisi

Hambat sintesa DNA G.6.P dehydrogenase DHEA

MEMERANGI KANKERAICR Piramida Pedoman Makan

• keberagaman sumber pangan + proporsi harian• Pembatasan asupan

- Energi- Lemak- Gula sederhana

• Lemak

- buah-sayur- karbohidart komplek- serat

• tinggi asupan

- n-3- FA

Keseimbangan Energi Positif- gagal regulasi homeostatis (proliferasi, voskularisasi)- ritme metabolisme stress oksidatif/ internal- efek biogenetik E-radang-kanker

Tenets of Nutrigenomics

1.Improper diets are risk factors for disease2.Dietary chemicals alter gene expression and/or

genome structure3.Influence of diet on health depends upon an

individual’s genetic make up4.Genes regulated by diet play a role in chronic

diseases5.“Personalized nutrition” – diets based upon

genotype, nutritional requirements and status – prevents and mitigates chronic disease