Andersons pediatric cardiology 2109

and*3,themostinvestigatedCYP2C9alleles,resultindecreasedactivity,
althoughthedegreeofchangeissubstrate-specific.Comparatively,the
CYP2C9*3alleleresultsinagreaterdecreaseinenzymaticactivity(~70%to
90%).19ThemostcommonapplicationofCYP2C9polymorphismisrelatedto
warfarinpharmacogenetics,whereitaccountsfor~15%to20%ofthevariation
indoserequirements.26Furtherdetailsofwarfarinpharmacogenomicsare
detailedfurtheron,underPracticalApplications.

CYP2C19
Despitecomprisingonly1%to4%ofthetotalhepaticCYPcontent,19CYP2C19
isthesecondmostimportantDMEintheCYP2Csubfamily,estimatedto
contributeto~7%metabolismofallclinicallyuseddrugs.20Itisalmost
exclusivelyexpressedintheliverandcomprisesonly2%ofCYPexpressionat
theintestinaltract.25ExpressionofCYP2C19occursinthefetus(~10%to20%
ofadultlevels),anditundergoesconsiderablechangeduringgestationor
immediatelypostpartum.22IncontrasttoCYP2C9,frombirthto5monthsofage
therewasanincreasingtrendofCYP2C19expression,approaching50%to75%
ofadultlevels.Thereisvariabilityinthiswithinthisagegroup,butless
comparedwithCYP2C9.Conversely,frominfancy(>5months)through
puberty,a21-foldrangeofenzymeexpressionwasobservedbyKoukouritakiet
al.22Postpubertalexpressionwasequivalenttoadultlevels,whichisincontrast
totheaforementionedfindingsbyTreluyeretal.23forCYP2C9.
CYP2C19,alsolocatedonchromosome10q23.33,ishighlypolymorphic,
havingover35reportedallelicvariants
(Twoallelicvariants,CYP2C19*2
and*3resultinnofunctionalactivity,andCYP2C19*17producesincreased
enzymaticactivity.27ThevariantallelicfrequencyofCYP2C19*2fluctuates
withindifferentpopulationgroups,beingnearly15%inwhitesandblacksand
30%inAsians.27SimilartoCYP2D6,CYP2C19iscategorizedintophenotype
groups:ultrarapid,extensive,intermediate,andpoormetabolizers.Theultrarapid
metabolizers,accountingforbetween5%and30%ofpatients,carrytwo

increased-activityalleles(e.g.,*17/*17)oronefunctionalallelewithone
increased-activityallele(e.g.,*1/*17).Extensivemetabolizers,accounting
between35%and50%ofpatients,carrytwofunctionalalleles(e.g.,*1/*1).
Intermediatemetabolizers,accountingfor18%and45%ofpatients,carryone


functionalplusonedecreased-functionallele(e.g.,*1/*2,*1/*3).Poor
metabolizers,accountingforthe2%to15%ofpatients,carrytwodecreasedfunctionalleles(e.g.,*2/*2,*2/*3,*3/*3).Interpretationofthepotentialriskfor
adverseeventsandevaluationoftheefficacyprofilesmustbeperformedinthe
contextofthesubstrateinvolved,comparabletothedescriptionsprovided
previouslyforCYP2D6.Forinstance,protonpumpinhibitors(e.g.,omeprazole,
pantoprazole)aresubstratesforCYP2C19,resultingindeactivationofthe
compound.ThereforeapoormetabolizerofCYP2C19wouldhaveincreased
AUC(e.g.,systemicexposure)ofthedrugandthusanincreasedriskofadverse
events.Conversely,CYP2C19isresponsiblefortheactivationofthe
antithromboticagentclopidogrel.ThuspoormetabolizersofCYP2C19would
havedecreasedAUCandanincreasedriskoftreatmentfailure.Clopidogrelis
discussedinfurtherdetailunderPracticalApplications.

CYP3A4/5/7
CYP3AisqualitativelyandquantitativelythemostimportantsubfamilyofCYP
enzymes,comprisinganaverageof30%to35%ofthetotalhepaticCYP
content12,19andcontributingtothemetabolismof30%to45%ofalldrugs.19,28
TheCYP3AsubfamilyiscomposedoffourCYPenzymes(3A4,3A5,3A7,
3A43).CYP3A43isminimallyexpressedanddoesnotparticipateindrug
metabolism.CYP3A7isthedominantCYP3Aenzymeexpressedinfetallife,
decliningsteadilyoverthefirstyear.1Conversely,CYP3A4isminimally
expressedinfetallife(~10%to20%ofadultlevels),increasesto30%to60%of
adultlevelsafter1weekofage,andapproachestheadultlevelat1year.1
CYP3A5expressionishighlyvariable,doesnothaveanage-dependent

expressionpattern,andismorehighlyexpressedinblackthaninwhiteand
Hispanicpopulations.29Inadults,increasedclearanceofCYP3A4substrates
occursinfemalescomparedwithmales.30However,thereisapaucityofdata
relatedtotheinfluenceofgenderonCYP3A4-mediatedclearanceinchildren.
Asmentionedearlier,intheCYP2C9category,CYP3Acomprises~80%of
thetotalCYPcontentintheenterocyte25andshouldbeconsideredinthe
evaluationofpresystemicclearanceofCYP3Asubstrates.Ofnote,thetotalCYP
contentintheliverandintestinaltractcanbesignificantlyincreasedinblacks
secondarytoahigherallelicfrequencyofthefunctionalCYP3A5*1,which
increasesCYP3A5contentrelativetononexpressers.31
CYP3A,locatedonchromosome7q22.1,hasan85%similarsequenceidentity


amongthethreemajorenzymes(CYP3A4,CYP3A5,CYP3A7),making
substratespecificityandtheimpactofindividualisozymepolymorphism
difficulttointerpret.Currentlyover40allelicvariantsarereported
(),yettheyarelesswelldescribedcomparedwith
CYP2D6.TheCYP3A4*22allele,intron6C>Tvariant,isassociatedwith
decreasedCYP3A4expressionbothinvitroandinvivo.32,33Infact,carriersof
thevariantTalleletakingastatinmetabolizedbyaCYP3A4-mediatedpathway
(e.g.,atorvastatin,lovastatin,simvastatin)requiresignificantlylowerstatin
dosingcomparedwiththosecarryingthereferencegenotype(CC)32secondary
todecreaseclearanceoftheparentdrugandactivemetabolite.33Additionally,in
thestudybyKleinetal.,variationintheperoxisomeproliferatoractivated
receptoralpha(PPARα)influencedCYP3A4phenotypeandaccountedfor10%
ofthevariabilityinatorvastatinhydroxylaseactivity.CYP3A5*3,themost
commonCYP3A5allelicvariant,leadstodecreaseenzymeexpressionwhilethe
presenceofaCYP3A5*1gain-of-functionmutation,leadingtoanincreasein
liverandintestinaltractCYP3A5content.31Thelattergenotypeisfoundin
~60%ofblacksand~30%ofwhites.31

Udp-GlucuronosylTransferases
UGTsaremostimportantphase2metabolizingsuperfamilyofenzymes
responsiblefortheconjugationofxenobiotics,developingamorepolar
compoundforelimination.UGTsaccountfor~35%ofphase2enzymatic
metabolismofalldrugs.20UGTsaresubdividedintotwogenefamilies,UGT1
(UGT1A1,1A3,1A4,1A5,1A6,1A7,1A8,1A9,1A10)locatedonchromosome
2q37andUGT2(2A1,2B4,2B7,2B10,2B11,2B15,2B17)locatedon
chromosome4q13-13.2.TheontogenicprofilesoftheUGTsareless
characterizedcomparedwithCYPs.UGT1A1isabsentinthefetus,increasing
immediatelyafterbirthandapproachingadultlevelsat3to6months.34
UGT1A6ispresentatlowlevels(1%to10%)duringfetallife,slowlyincreases
afterbirth,andapproaches50%ofadultlevelsafterbirth.Incontrastto
UGT1A1,completematurationofUGT1A6occursnearpuberty.34UGT2B7is
detectableinthefetus(~10%to20%ofadultlevels),withadultlevelsachieved
at2to3monthsofage.34HundredsofUGTpolymorphismsarereported
(www.pharmacogenomics.pha.ulaval.ca/cms/ugt_alleles/);however,the
importanceofthesegeneticvariantsrequiresfurtherelucidation.