Chemoprevention of Cancer and DNA Damage by Dietary Factors

726 Pages·08.517 MB·English

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3.5 OtherThermalnDegradatioProducts 43
)
12 (Continued
13
ATPdepletion Extensivelyabsorbedandeliminatedafterinhalation Skinandmucousmembraneirritation
11
5
6(cid:2) 7 10
cientevidencein
(cid:1)
HCCinmaleandfemaleB6C3F1miceandmaleF344rats (cid:1)Hepatocarcinogeninrodents Sufanimalexperiments Inadequateevidenceinhumans Inadequateevidenceinhumans;limitedevi-denceinexperimentalanimalsHCCinmice(gavage)
DNA invitro
!
4
DepletionofATPdoublestrandbreaksinhepatocytesuspensionculture MostlynegativeinSalmonellatyphimurium SCEinCHOcellsandhumanlymphocytes CAinCHO,andV79cellsNoSCEorCAinmousebonemarrow
Othertoxiceffects 3
Carcinogenicity
-2-butene-1,4-dial
cis
9
:produc- 8 :solvent
Genotoxicity
Use Usening,in
1 (cid:1)
Reactivemetabolites
2
heattreatment Naturallyincertainwoodsandduringthecombustionofcoals;foundinengineexhausts,woodandtobaccosmokeProductionbydecarbonyla-tionoffurfural.tionoftetrahydrofuran,thiophene,andpyrrole componentofawiderangeoffruitsandvegetables Producedcommerciallybyacidhydrolysisofpentosanpolysaccharidesfromnon-foodresiduesoffoodcropsandwoodwastes.inpetroleumreproductionofphenolicresins
Sometoxiccompoundscontaminatingnaturalorhome-madefood. Occurrence Infoodthatundergoes 10-00-9 Furfuralisavolatile 8-01-1 OCH
1 O 9
S: S: O
A A
C C
Table3.1 Compound Furan Furfural
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42 3 InductionofDNADamageandCancerbyDietaryFactors
3.5
OtherThermalDegradationProducts
Overthelastyears,strongattemptshavebeenmadetoidentifythermaldegradation
productsotherthanHAsinhumanfoods.
alicypTlesmpexaareemidlaryac)(AAand.ansfurAAshaenbeundfoinecisp (cid:1) c
dsfooatlyingishonastghhitbuingryvaelslevnive(gasamgrromicg/kAA),uctodpr
chsuasscksnazelre(p,ksicstdltesat,cuibisandailcktcoksacsn154(1 (cid:1) 0),78s,ispcr
dltesa totapo srawst 66(7 (cid:1) 9),55 hncfre siefr 24(4 (cid:1) ),498 dan piscr deabr
08(4 (cid:1) 1)478].[1Itisdmeforgindurethginownbronctireardllaai(M)ontiacreyinlma
omfrtheinoamidacsineagaraspdanrsgasuchsuas,seucogl,sectofru,sectolaand
e.oscrsuketaInymaryvaydelwientwebe0.3and2 m kgg/ay/dbworymachreaneve
5 m gg/kay/dbwatethh99teilntrcepeinghhismernsuco].[19seTheearglyinarmal
ghhielslevforableobaprnmahugeninorccathwiacxiotogendemoof.ontiac
The primary effect is neurotoxicity and was detected after occupational expo-
sure.AAisalsotoxicforreproductionanddevelopmentinratsandmiceandwas
found to be a germ cell mutagen. During metabolism, the reactive metabolite
glycidamide is formed that is responsible for the genotoxicity and probably the
carcinogenicitytoseveralorgans.H,oweverepidemiologicalstudiesdidnotpoint
toanassociationbetweeneitheroccupationalordietaryexposureandanexcessof
cancerincidenceso;faronlyarecentstudyhasfoundanincreasedbreastcancer
risk(positiveforestrogenreceptors)inpostmenopausalwomenafteradjustment
for smoking [20]. The innovative approach in this investigation was exposure
monitoringbymeasuringhemoglobinadductsofAAandglycidamideandnotby
the usual assessment by food frequency questionnaires.
It is worth noting that mammary tissue was also a target organ in rodent
carcinogenicitystudies.TheauthorsoftheaforementionedstudysuggestthatAA
itselfmayhaveanongenotoxicmodeofactiontowhicharodentstudylendssupport
byshowingthatthecompounddosedependentlyinducesDNAsynthesisinthree
otherhormone-dependentorgans[21].
thealHkristsenssmseasofethalergenontiulapoparedsebaonangeeraavureosexp
to40. m kgg/,y/dabwchwhincaeeascrininghhirsmesuconto4 m kgg/.ay/dbwreThe
rspeaap to stexi a fsu (cid:1) tlyenci eivectotpr inrgma of eurosexp E)(MO of 020 for
tycixitouronein eragavers.mesucon,erwevHothe EMO foricennogrcicasskri is
ytelmaoxiprap 300 and is eddernsico to be tno fsu (cid:1) tlyenci ve.ctiotepr A armilsi
ionusclconishedacreifarkhmancbeedoserlowcon (cid:1) ncedemitli)MDL(Bforrnceca
isedivderandedviddiby antyintacerunrctofa of 030ngiviarrat aleabertolyilda
eakint of 1 m kgg/ ,ay/dbw chwhi is in the engra of eragave ontimpnsucose/do
s.elleve,orrefTheralvesersthoauandestirithoauvehaddemenomrecginlorexprthefur
ressumeatoizenimmiemidlaryacionatrmfoinodfoandtoeducreanhume.urosexp
Amultitudeofothercompoundsareformedduringfoodprocessing.Someare
generatedduringtheaillardMreaction,andtheirhealtheffectsarestillunknown.
AselectionofafewrepresentativesisgiveninableT3.1,whichprovidesinformation
on the main endpoints of toxic effects. As can be seen, most compounds have
a functional aldehyde group with the exception of furan that, ,however can be
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3.4 PolycycliccAromatiHydrocarbons 41
Scheme3.4 Metabolicactivationofbenzo( a )pyrene.AFB1
isattackedintheliverbyseveralcytochromeP-450,isoforms
themajorroleistakenbyCYP3A4resultinginformationofan
epoxideattheolefinicbondin8,9position.Thisistheeultimat
reactivecarcinogenthat,afteradductingDNAbases,transforms
intoastableadductbytheopeningofthepyrrolringofthe
guaninebase.
ThedevelopmentofbiomarkersofPAHexposurehassubstantiallycontributed
to the improvement of the risk assessment. The relation of environmental air
pollutiontoPAHswiththeassociatedbiomarkershasbeenevaluatedinarecent
metastudy [14]. The urinary metabolite 1-hydroxypyrene and, to a lesser extent,
PAH (cid:133) DNA adducts in peripheral lymphocytes correlated well at the group level
with exposure to B( a )P, even at low PAH exposures. Albumin or hemoglobin
adductsdidnotwellcorrelatewithenvironmentalexposuredata,anobservation
thathasbeenmadeearlierinoccupationalsettings[15].
ThedietaryexposureofhumanstoPAHscanbereducedbyuseoflow-tempera-
ture cooking and/or prevention of direct contact of meats with the (cid:2) ames during
barbequing. It has also been shown that compounds that induce GST activities
protectfromDNAdamageand.cancerAlreadyinthe1970sand1980s,attenbergW
and coworkers identi (cid:1) ed a number of protective dietary constituents such as
breakdownproductsofglucosinolates,constituentsofalliumvegetables,andcoffee
diterpenoids that protect against PAH-induced cancer formation in rats and
mice[16],tonameonlya.few,RecentlywereportedtheinductionofsGSTinhuman
lymphocytesbydifferentdietaryfactors(e.g.,bycoffeeconsumptionandgallicacid)
andfoundthattheinductionoftheseenzymesledtoprotectionagainstinduction
of DNA damage by B[ a ]P-7,8-dihydrodiol-9,10-epoxide, the ultimate metabolite of
B( a )P[17].
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3.5 OtherThermalnDegradatioProducts 45
35
Teratogenicinexperimentalanimals Decreasedspermmotilityandimpairedfertilityinratsandothermammals CNSlesionsat>25mg/kg lularcarcinoma;
33
broblasts
(cid:1)
:cytotoxic
Esophagealtumors:as-sociatedwithgeneticallydetermined,highmeta-boliclevelsofacetalde-hydeafterdrinkingalcohol(IARC) Inhalationandcarcinogenictonasalmucosaofrats Oralchronicstudyinrats:progressivenephropathy,dose-dependenttubularhyperplasiaandadenomaHyperplasticandneo-plasticlesionsintestes,mammarygland,andpancreasMalignanttransforma-tionofmouseinvitro
31
30 32
invitro
DNAadductsofacetaldehydeinlymphocytesofalcoholabusers GenotoxicinhumanlymphocytesGenotoxicinanimalmodels Mutagenicinbacterialassays,butnegativeinthepresenceofexogenousmetabolicactivation Alsoinmammaliancells Noevidenceofgenotoxicityinvivo
Othertoxiceffects
Carcinogenicity
Genotoxicity (cid:1)sh Referencesmaybeobtainedfromtheauthors.
Reactivemetabolites 1(cid:133)37
Highestlevelsinchemicallyhydrolyzedvege-tableproteins Mostlikelyinbreadandbiscuitsandincookedmeator Averagedailyintake2lgperperson
) H2 H
C O
2
(ContinuedTable3.1 CompoundOccurrence Monochloro-36,37propanediol CAS:96-24- Cl CHCH2 OH Abbreviations:ATP,adenosinetriphosphate;CA,chromosomeaberrations;CHO,Chinesehamsterovary;CNS,centralnervoussystem;HCC,hepatocelSCE,sisterchromatidexchange.
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44 3 InductionofDNADamageandCancerbyDietaryFactors
:
50 34
LD
27
46mg/kginrats
Strongirritantrespiratorytract;cardiovascularsystemtoxicity7(cid:133) Neurotoxiceffectsduringembryonicdevelopment
24 25
(cid:133)
17
26
inchemical
"
18
HMFpromotesgrowthofcolonicmicroadenomas Incolondose-dependentinductionofaberrantcryptfoci Initiationofraturinarybladdercarcinogenesis 2-yearstudyinratsnoneoplasticresponseAvailabledatainadequateforevaluationofhumancarcinogenicity Tumorsofbronchiandoralcavityworkersexposedtovari-ousaldehydes
21
toxicity andin
!! 22
15
S.typhimurium16 Drosophila S.typhimurium 23 29
Escherichiacoli
SMFinteractswithDNA,RNA,andproteinsstructuraldamageandmutagenicityCMFisofhighermutagenicpotencyinthanSMF Genotoxicin Mutagenicinandxerodermapigmentosum(cid:1)broblasts Cross-linkswithDNAingastricmucosaandcolonicmucosacells
Othertoxiceffects
Carcinogenicity
5-Sulfooxymethylfurfural(SMF) 5-Chloromethylfurfural(CMF)isformedfromHMFbyallylicchlorination Mothercompounditself:acrolein Mothercompounditself:acetaldehyde
20
Genotoxicity
28
Reactivemetabolites 14 ;produced
19
ProductofMaillardreaction aminoacids,vegetableoils,andanimalfatsduringheat-ingoffoods;intobaccosmokecommercially Usedtoproduceacrylicacid(startingmaterialforacrylatepolymers),toproduceDL-methionine,andasaherbicideandslimicide Metaboliteofsugarsandethanol;hasbeendetectedinplantextracts,tobaccosmoke,engineexhaust,ambientandindoorair,andinwater
) O H O H
C C O H
(Continued Occurrence 7-47-0 O Formedfromcarbohydrates, 07-02-8 CH 5-07-0 C
Table3.1 Compound 5-Hydroxy-methyl--furfural(HMF) CAS:6 OH CH2 Acrolein CAS:1 HC2 AcetaldehydeCAS:7 HC3
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46 3 InductionofDNADamageandCancerbyDietaryFactors
zedlydrohy to a .ydedehaldiThetyliabiilavaandyvittiacre of eth eyddehalsoupgr
rspeaaptoatectdiethictoxo)en(gs.ectefferthAnoctduproedrmfogrinductimesdo
gkincooesssoceprandsoalingdurmesodfooginturacnufmais,2--1neopaoprorchl3-
.oldi sThi undpocom dowesh an trenpaap yancrepscdi entwebe eth tycioxiotgen
ltssure inrovit tthaeweriveitposdanethtycioxiotgenltssure inoviv tthaewer.vetigane
seThe (cid:1) singndymabedinelaexpbythectfatthatheinmacoliabmetuteroinsalmmma
isethontimaforoftectalarolo-chtabeandclioxa,idaclewhinymaarictebazeoliabmet
oldianerop-p1,2o-orchl3-lyariimprvia,dolyciglethrttelaingbeaalricteba.enagmut
3.6
Mycotoxins
Mycotoxinsareachemicallyheterogeneousgroupofmetabolitesofmouldsthatare
mostlyformedinplantfoodsduringcultivationandstorage.
A (cid:2) inoxatB FB(A )isblyobaprethstmottenpocxiotogengeninorccain.anshum
1 1
It is dmefor by lusgilerAsp flusav and A. sicusitrapa and undfo lyantmindopre in
dsfoo chsu as edsseoil g.,(e.,tsanupes),anybesolseacer ,.g.(e e,izma e),ric esicsp
,.g.(eiilch),perpepandetretsnu,.g.(e,dsmonalio)achstpiinsrientcouthwiathoand
idhumte.macliBAF iseddersiconto ,untcoac in ontidiad to alvirs,ionectinffor
1
theghhieencalevprofrlalluoceathepmainorccaC)(HCinsrientcouofalntrcearicAf
and na.Chi The llyuractrust tedlare a (cid:2) nsoxiat G FG(A , AFG ) are ceddupro by
1 2
A.suticsirapa ,hicwhshaaedmitli.onutiribstdiMAF isndfouinlk.mieTh-inorcca
1
yiticgenofntreffedia (cid:2) insoxatshaenbetedluaevabyRCIA2,[2].23reTheisfsu (cid:1) entci
eencidevofyiticgeninorccaof BAF , G , dan M tos,anhumedmitlicedenevifor
1 1 1
AFB ,andteuadeqinacedenevirfoAFG ,chwhilaleducinyrilmaprirvelis.mortu
2 2
AFB anderothlyralcturustedatrelinstoxearedvattiacelyatminedoprintherveliby
1
2P1ACYand4,3Arewhe1A2CYPisvetiacthwighhiaf (cid:1) tyniatwloAFB ra-ntnceco
1
s.ontiInsethes,onctireaanteimaultvetieac-rADNe,itboltame -exo AFB ,dexiepo,9--8
1
isedrmfotthasndbito,onethitaglumruse,minbualdan.DNATheingndbitoN7-
eninguaisdniepaomaccbyontilacaerintointethADNle.ecumoloxiDet (cid:1) onticaofthe
vetiacreesitboltamesuroccyinlmabysTGSehem(Sc).3.5
ThegenotoxiceffectsofAFB arewelldocumentedinexperiments invitro with
1
bacterialandmammalianindicatorcellsandalsoinlaboratoryrodents.AFB isa
1
potentlivercarcinogeninrats,whileonlylowormoderateeffectswereseeninmouse
strainsthathavehigherGSTactivities.Inhumans,AFB exposurecausesaspeci (cid:1) c
1
(cid:1) ngerprintmutation(i.e.,G ! Ttransversion)incodon249ofthetumorsuppressor
genep53.Onthebasisofthisobservation,itwaspossibletoanalyzeDNAfromHCC
anddrawconclusionsiftheyareduetoexposuretoAFB .Indeed,suchmutations
1
werefoundinDNAfromlivertumorscollectedinAfricaandChinabutnotintissues
from HCC patients from Europe [24]. Exposure monitoring of AFB has been
1
conductedbyalbuminadductmeasurementsandbythea (cid:2) atoxin-speci (cid:1) curinary
adductAFB (cid:133) N7-guanine.
1
OchratoxinAA)(OTisformedby enicilliumPochraceus andisfoundparticularly
inbeans,coffee,grain,andporkproducts.ItisbelievedtobethecauseofBalkan
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3.8 FoodAdditivesands/HerbicidePesticideResidues 49
isseen,forexample,withbreakdownproductsofglucosinolatesfromcruciferous
vegetablesandalliumcompounds.AsyntheticandpotentGSTinducerisoltipraz,
andintermittentresultsofhumaninterventiontrialsinhighAFB exposureareas
1
inChinawerepromising[35].
3.7
CarcinogensinPlantFoods
Plant-derivedfoodsaregenerallyregardedashealthyandsafe.Therefore,cycasinand
ptaquiloside werethe only examplesof plant-derived carcinogens for many years.
ycasinCisfoundinthe (cid:2) owerofcycadpalmsthatwasusedtoproducecakesand
biscuits,whileptaquilosideisfoundinbrackenfernsproutsconsumedasvegetables
inpartsofRussiaandChina.
In the early 1990s, B. Ames published a number of papers [36, 37] in which
examplesofplant-derivedcarcinogenswerelistedtowhichhumansareexposed
via the diet; they comprise constituents of mushrooms such as gyromitrin [38]
and agaritin [39], alkylbenzenes (e.g., safrol, eugenol, methyleugenol) that are
found in different spices suchas nutmeg andbasil, caffeicacidthatis found in
numerous vegetables and in coffee [40], and capsaicin the pungent principal of
chilis. Ames emphasized that some of these compounds are equally potent in
regardto-DNdaAmagingandcarcinogenicpropertiesassyntheticchemicalsand
that humans may be exposed to them even at much higher concentrations.
RecentevaluationofthecurrentstateofknowledgebyEhrlich etal. [41]showed
that the evidence for carcinogenic effects of the different plant-derived com-
pounds is restricted in many cases to animal experiments that do not meet the
current criteria of long-term carcinogenicity studies. In many of the trials only
extremely high doses were tested, and it is unclear if the results obtained with
rodentsarerelevantforhumans.orFexample,itwasclaimedthatcoffeecontains
about 20 different chemicals that were shown to cause tumor formation in
rodents[42],butnoevidenceoftheirpotentialcarcinogeniceffectswasfoundin
coffee drinkers in numerous epidemiologic studies (see Chapter 32). The weak
positiverelationshipbetweencoffeedrinkingandtheoccurrenceofbladderand
urinary tract cancer resided possibly on bias or confounding factors [43] and
could in no way be con (cid:1) rmed for renal cancer in a large prospective study [44].
Some of the coffee constituents are even suggested to be protective [45], and
coffeeasawholeshouldberegardedasapotentialeffectmodi (cid:1) erofcarcinogenic
exposures.
3.8
FoodAdditivesandPesticides/HerbicideResidues
umerousNinvestigationshavebeencarriedoutinwhichthegenotoxicandcarcino-
genicpropertiesoffoodadditiveshavebeenstudied.Theresultsaresummarizedin
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48 3 InductionofDNADamageandCancerbyDietaryFactors
p53geneofupperurothelialcancersassociatedwiththisdiseaseprovidedevidenceof
long-termexposuretoaristolochicacid;(3)therenalpathophysiologyandhistopa-
thology observed in endemic nephropathy most closely resemble those of aristo-
lochicacidnephropathy[28].
Anumberofothermycotoxinsmayalsocausehuman;cancertypicalexamplesare
fumonisins (e.g., fumonisin B ), trichothecenes (nivalenol, deoxynivalenol), -zear
1
alenon,andothercompoundssuchaspatulinandcitrinin.Thesetoxinsarefound
more frequently and at higher concentrations in human foods than a (cid:2) atoxins.
Resultsof invitro mutagenicitytestsindicatethatsomeofthesemycotoxinscause
DNA damage in mammalian/human cells at higher dose levels than AFB , but
1
results from animal studies are scarce and no (cid:1) rm conclusions concerning their
potentialmutagenicandcarcinogenicriskscanbedrawningeneral.
InthecaseoffumonisinB ,ithasbeenshown,,howeverthatitcausesinduction
1
of liver cancer in rats after administration of relatively high doses [29], and it is
notable that it has been postulated that the increased incidence of esophageal
cancer in countries with high contamination levels of fusarium-infected foods
(e.g., South Africa and China) may be due to exposure to these toxins [30].
The mechanism of carcinogenic action is possibly caused by both, genotoxic and
nongenotoxic mechanisms [31]. Although fumonisin B is not a bacterial muta-
1
gen[32],itcauses(oxidative)DNAdamageinmammaliancellsandinratkidneyand
is a clastogenic agent (induction of micronuclei and chromosomal aberrations in
mammaliancells)[33].Thenongenotoxicmechanismsincludecomplexalterations
of cellular signaling pathways by disruption of lipid metabolism and changes in
polyunsaturated fatty acids and phospholipid pools that eventually lead to an
imbalanceofboth,apoptosisandproliferationrates[31].
inulatPiscedduproyarlculrtipaby P.sumanexp ,atuifrgenthopatthaesuscapleap
t.ro It is tno ayarlulicrtpattenpo n,xito tbu alverseesudist veha nowsh ttha it is
c,oxiotgendanusneoutabcsuonticapliapin srat led to ethontimaforofs.marcosa
ughhoAltintulparspeaaptnotobeangrostinoxnotgeand,gennorcicaeurosexptosthi
noxicotmyymauteibntrcotoanhumicgeninorccak.rise,forereTha WHO-comre
ontidamensmitliintulpaineplapceuijatamumximaionratentnccoof50 m l.g/
Themycotoxincitrininwasoriginallyisolatedfrom P.citrinum buthasalsobeen
foundtobeproducedbysomeotherfungionhumanfoods,inparticulargrainand
cheese.Citrininwasnephrotoxicinallspeciestested,andsinceitcausesnephropathy
inlivestock,ithasbeensuspectedasoneofthecausalagentsofBEN.Itwasfound
tlycenretthaninitrcidditnouceindonstitamuin llanelmoSa tertesnsraisttbuedducin
leinucromic thwi arilsim cytenpo as A,OT hugthoal the mnishamec is ghouthr
yoiduplane].[26
Someotherfoodcomponentsmayprotectfromthesefungaltoxins:Inanumberof
invitro experimentsandalsoinafewanimalstudies,itwasdemonstratedthatlactic
acidbacteriabinda (cid:2) atoxinsaswellasothermycotoxinsA,(OTcitrinin,zearalenon)
andithasbeenreportedthatconsumptionoffermentedfoodsmayprotecthumans
againsttheirtoxiceffects.AlsochlorophyllsareapparentlyabletodetoxifyAFB by
1
direct binding, and another mode of protection is the upregulation ofsGSTthat
inactivates-reactiveDNAmetabolitesofAFB [34].uchSmechanismofdetoxi (cid:1) cation
1
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3.6 Mycotoxins 47
Scheme3.5 MetabolicactivationofaflatoxinB .AFB isattacked
1 1
intheliverbyseveralcytochromeP-450;isoformsthemajorroleis
takenbyCYP3A4resultinginanepoxideattheolefinicbondin8,9
position.Thisistheultimatereactivecarcinogenthat,after
adductingDNAbases,transformsintoastableadductbythe
openingofthepyrrolringoftheguaninebase.
endemicnephropathy(BEN),achronicrenaltubulointerstitialdiseaseofpreviously
unknowncausethatoftenisaccompaniedbyupperurinarytracturothelialcancer
thatwasfoundinruralareasofBosnia,ulgaria,Broatia,CRomania,andSerbia.The
disease was (cid:1) rst described in the 1950s but appears to be decreasing since the
1990s[25].AOTismutagenicincertain invitro testswithmammalian-andhuman-
derivedcellsbutnotinbacteria,anditisstillamatterofdebateifitcausesDNA
adductformationinhumans[26].AOTiscarcinogenicinmouseandratliversand
kidneys,andtwoofitsmetabolitesareimmunosuppressiveandmaycontributeto
canceretiology[27].Recentadvancesintheunderstandingofendemicnephropathy
nowfavorthecausativeroleofaristolochicacidovertheubiquitousmycotoxinknown
asochratoxinA.Speci (cid:1) ,cally(1)aristolactam (cid:133) DNAadductshavebeenfoundinrenal
tissuesandurothelialcancersofaffectedpatients;(2)a(cid:1)signature(cid:2)mutationinthe