CytochromeP450sinhumansOct.

31,2013
DavidNelson
Reading(optional)
NelsonD.R.CytochromeP450andtheindividualityofspecies.(1999)
Arch.Biochem.Biophys.369,110.
Nelsonetal.2004ComparisonofcytochromeP450(CYP)genesfromthemouseandhumangenomes,
includingnomenclaturerecommendationsforgenes,pseudogenes,andalternativesplicevariants
Pharmacogenetics14,118
Objectives:
ThislectureprovidesasurveyoftheimportanceofcytochromeP450sinhumans.Pleasedonotmemorize
thepathwaysorstructuresgiveninthenotesorinthelecture.DobeawareofthemajorcategoriesofP450
functioninhumanmetabolism,likesynthesisandeliminationofcholesterol,regulationofbloodhemostasis,
steroidandarachidonicacidmetabolism,drugmetabolism.Beparticularlyawareofdruginteractionsand
theimportantroleofCYP2D6andCYP3A4inthisprocess.
YouwillnotbeaskedhistoricalquestionsaboutP450discovery.
Youwillnotbeaskedwhatenzymecauseswhatdisease.
UnderstandthatP450sarefoundintwodifferentcompartmentsandthattheyhavetwodifferentelectron
transferchainsinthesecompartments.
UnderstandthatP450sareoftenphaseIdrugmetabolismenzymesandwhatthismeans.
BeawarethatrodentsandhumansarequitedifferentintheirP450content.ThesameP450familiesare
presentbutthenumberofgenesismuchhigherinthemouse.Whatistherelevancetodrugstudies?
UnderstandthatP450scanberegulatedorinducedbycertainhormonesorchemicals.
KnowthatthelevelsofindividualP450scanbemonitoredbynoninvasiveprocedures.
BeawareofthesignificanceofpolymorphismsinhumanP450sandtheireffectsondrugmetabolismand
druginteractions.

CytochromeP450Proteins:
Mutationscausedisease,cancersbyinduction(procarcinogenscarcinogens)
Metabolizedrugs,makescholesterol,steroids,lipids,bileacids,suchasprostacyclinsand
thromboxaneA2(metabolitesofarachidonicacid,omega6fattyacids)(structuralcomponentsand
signaling)
CYP450procarcinogencarcinogen,butcanactivateprodrugtoactivedrugtotreatcancer
Hemegrouppresent,membranebound,absorptionbandat450nm(reducedCOdifferencespectrum,
CObindstoFeheme,thiolateioninteractingwithhemeshiftsfrom420nmto450nm)
4Nligandsonhemering,5thligandthiolateanionandS(fromconservedcysteineathemebinding
regionofactivesite)
categorizedintofamilies(>40%identical)andsubfamilies(>55%identical)bysequencesimilarities
o pseudogenedefectivegene,nofunctionalprotein,relicsofgeneduplication
needsourceofelectrons,adding2etohemeFebreaksOObond
o edonatedbyproteinthatbindstoP450andpassesethroughprostheticgroup
electrontransferchain
o 2differentelectrontransferchains
dependsonlocationofenzymeincell
somefoundinmitochondrialinnermembraneandothersinER
bothmembraneboundproteins
o NADPHcytP450reductaseproteinthatdonateselectronstoP450

MembraneboundNterminaltailcrossesERonce,mostoncystolicside
2domainsthatcontainflavin
2efromNADPHFADFMNP450hemeFe

o Ferredoxinreductasedonateseinmitochondria

Inmitochondria,electrontransferchainlonger
Ironsulfurcluster,flavin
EfromNADPHferredoxinreductaseferredoxin(noflavin)P450
Importantforironsulfurclusters
o Cytb5
Smallmembraneboundhemecontainingprotein,getsefromNADH
Pharmaceuticalinteresttomodifyexistingdrugstomakeintopoorersubstratesforcytochrome
enzymessosubstrateslastlongerinbodybeforeelimination
o Cytp4503A4,causeofadversedrugreactions
P450Activities:
Catalyzemanyreactions,suchashydroxylation
o IncorporateoxygenatomintosubstrateandoneatomintoH2O
DrugMetabolism:
o Xenobioticmetabolism(eg.Lipophilicdrugs)
PhaseI:chemicalmodification,addfunctionalgroupsocanattachconjugate
Conjugatemorewatersolublesourineexcretion
o ManyP450saddhydroxylgroup,servesassiteforfurthermodification
RegulationofP450Enzymes
Generegulatorymechanisms,inducedbychemicalsignal
o Eg.SteroidbiosyntheticP450sinducedbyACTHadrenocorticotropichormone

ACTHcAMPcAMPdependentproteinkinasephosphorylateddiacylglcerol
kinasethetaincreasesproductionofphosphatidicacidincreaseingene
transcriptionforsteroidproducingP450s(eg.CYP17A1)
Peroxisomeproliferatorsclofibrate
o DrugsbindtoPPARnucleusheterodimerizeswithRXRandbindswithDNA
sequencesinregulatoryregionofgenesneededforperoxisomegeneration
Eg.CYP4A1fattyacidhydroxylase(inperoxisome)
EthanolCYP2Eenzymes(alsoinvolvedindrugmetabolism)
o Foundinalcoholics,stabilizesenzyme
PhenobarbitaltheratCYP2Benzymes4050fold(notsameinhumans),throughaphenobarbital
receptorcalledCAR
o dimerizeswithRXRbindstoaphenobarbitalresponseelementintheDNAactivatethe
gene
o Cyp2C8metabolizestaxol
o Cyp2C19omeprazole,ulcerdrug,polymorphic,differentinsequenceaffectsdrug
metabolism,Caucasians(poormetabolism3%),inasians(poormetabolismin28%)
Chip,polymorphismsincyp2D6(importantfordrugmetabolism,mostpolymorphic,
92alleles,lotsofvariation,10%missing2D6*5,codeinemetabolism)andcyp2C19
aromatichydrocarbons(cigarettesmoke)CYP1family
o Ah(arylhydrocarbon)receptorbindtoaromatichc+arntenternucleusandbindDNA
toactivatetranscription
o CYP1A2inducedbycigarettesmokingcancers(colon)(procarcinogencarcinogen)
o CYP1Bglaucoma,signalingmoleculethatcontrolspressureineyes
P450enzymesareinduciblerelatedtoP450'sroleindetoxificationofforeignchemicalsfoundin
plants
DrugMetabolism

Cyp3A4nopolymorphisms,sequencesidentical
o acetaminophen,codeine,cyclosporineA(immunosuppressant),diazepam,erythromycin,
lidocaine,lovastatin,taxol,warfarin
o eg.Druginteraction,morethandrugbindstosameactivesite,onecanhavemoreinteraction
sootherdrugsarehigherinblood
druginteractions:anychangeoftherapeuticeffectivenessortoxicitycausedby
concomitantuptakeoftwoormoredrugs
REASONWHYDRUGCOMPANIESDONOTWANTDRUGS
METABOLIZEDBYCYP34A
Cyp2D6metabolizesoxycodone,antiarrythmics,antidepressants,antipsychotics,betablockers,
analgesics
CYP19testosterone(fromCYP17)toestrogen,drugcompaniesinterestedbecauseinvolvedin
estrogenrelatedcancers,aromataseinhibitorsareimportantdrugclass
CYP26familyretinoicacid,boundariesinembryo,developingbrain,alsofoundineyes
CYP51familytargetforantifungaldrug(azole),triazoletargetcyp51infungiprevent
membranesynthesis,butcanalsointeractwithotherdrugs
Differencesinhumans,rats,andmouse
Cantusemiceasdrugmetabolismexperimentalorganisms,usebeagledogsinstead
NoninvasivemarkersformeasuringlevelsofP450enzymesinhumans
P450enzymescatalyzespecificreactionsthatcanbemonitoredbysamplingtheurine,bloodor
breathofpatientsgivenanoninvasivemarker.CaffeineisamarkerforCYP1A2.Itisdemethylated,andthe
rateatwhichitisdemethylatedisrelatedtotheamountofCYP1A2inaperson'sliver.Byadministering
caffeineandmeasuringtherateofdemethylation,itispossibletoestimatethelevelofCYP1A2inahuman.
Thiscanshowifapersonhasbeeninducedbyexposuretopolycyclicaromatichydrocarbons(PAHs).There

areavarietyofnoninvasivemarkersfordifferentP450s.AssaysofCYP1Aenzymesfromfishliverscan
alsobeusedtomonitorwaterpollutionlevels,sincecertaintypesofpollutantswillinducetheenzyme.This
isalsobeingdoneinsoilusingnematodeslikeC.elegans.

FunctionsofhumanP450sanddiseasescausedbydefectsinP450s
TheCYP1familyofP450scanhydroxylateestrogen(CYP1A2and1B1)andoxidize
uroporphyrinogentouroporphyrin(CYP1A2)inhememetabolism,buttheymayhaveadditional
undiscoveredendogenoussubstrates.Theseenzymesareinduciblebysomepolycyclichydrocarbons,some
ofwhicharefoundincigarettesmokeandcharredfood.Theseenzymesareofinterest,becauseinassays,
theycanactivatecompoundstocarcinogens.HighlevelsofCYP1A2havebeenlinkedtoanincreasedrisk
ofcoloncancer.Sincethe1A2enzymecanbeinducedbycigarettesmoking,thislinkssmokingwithcolon
cancer.TheCYP1A2crystalstructureisnowknown.
TheCYP1B1genehasbeenlinkedtoprimarycongenitalglaucoma(SeeHumanMolecularGenetics
6,6417,1997;AmJHumGenet.62,325331998;AmJHumGenet.62,573841998;JMedGenet.36,
29041999).Thenormalsubstrateinmammalsisnotknown,butitisspeculatedthatthisP450maybe
requiredtoeliminateasignalingmolecule.Defectsinthegenecouldleadtochronichighconcentrationsof
thesignalingmoleculethatleadtoglaucoma.Themoleculeaffectedmaybeasteroid.
AsyoucanseefromthetableofhumanP450s,the2familyisthelargestfamilyinhumans.28%of
humanP450sareinthisfamily.Manyoftheseproteinscanhydroxylatesteroids,andsomeofthemare
expressedinasexspecificmanner.Thiswouldbeexpectedforenzymesthatonlyactonsexspecific
steroids.Someofthesemayalsobedrugmetabolismenzymesthataredefensive,toprotectusfromtoxins
inourfood.Plantsespeciallymakemanytoxiccomponentsthatareprobablydefensivefortheplants.Since
weeatalmostanything,itisnecessarytohaveadetoxificationsystemcodedinourgenes.Thisideahas
beencalledplantanimalwarfareonthechemicallevel.
CYP2Bisinduciblebybarbituratesinrodents.ItwasoneofthefirstP450stobepurifiedfrom
mammals,butitsroleinhumansisnotunderstood.
CYP2C8isknowntocatalyzethe6alphahydroxylationoftaxol.Thisisadrugusedintreating
breastcancer.Thecrystalstructureofhuman2C8isnowknown.
CYP2C9isoneof12humanP450sthathasaknowncrystalstructure(seepage1foralist).The
CYP2C9structurewaspublishedinNature(Williamsetal.CrystalstructureofhumancytochromeP450
2C9withboundwarfarin.Nature.Jul24;424,4644682003.)CYP3A4inYanoetal.Thestructureof
humanmicrosomalcytochromeP4503A4determinedbyXraycrystallographyto2.05Aresolution.JBiol
Chem.Sep10,279,380914.2004Williamsetal.CrystalstructuresofhumancytochromeP4503A4bound
tometyraponeandprogesterone.Science.Jul30305,68362004.CYP2A6structure:NatStructMolBiol.
12,822823(2005).
CYP2C19metabolizesomeprazole,acommonulcermedication.Polymorphismsinthisgenecause
ahigherincidenceofpoormetabolizerphenotypesinAsians(23%)vscaucasians(35%).

DrugmetabolismdifferencescausedbypolymorphismsinP450s.
ApolymorphismisadifferenceinDNAsequencefoundat1%orhigherinapopulation.These
differencesinDNAsequencecanleadtodifferencesindrugmetabolism,sotheyareimportantfeaturesof
P450genesinhumans.CYP2C19hasapolymorphismthatchangestheenzyme'sabilitytometabolize
mephenytoin(amarkerdrug).InCaucasians,thepolymorphismforthepoormetabolizerphenotypeisonly
seenin3%ofthepopulation.However,itisseenin20%oftheasianpopulation.Becauseofthisdifference,
itisimportanttobeawareofaperson'sracewhendrugsaregiventhataremetabolizeddifferentlyby
differentpopulations.Somedrugsthathaveanarrowrangeofeffectivedosebeforetheybecometoxic
mightbeoverdosedinapoormetabolizer.Veryrecently,RochehasmarketedaCYP450DNAchiptodetect
majorknownpolymorphismsinhumanCYP2D6andCYP2C19.Forabout$400youcantestapersontosee
iftheyareapoormetabolizer,normalmetabolizerorultrametabolizer,foralargenumberofdrugs.Since
1A2,2C9,2C19,2D6and3A4areresponsibleforoxidizingmorethan90%ofcurrentlyuseddrugs(2C9
paperabove),thisisasignificantbeginningtocharacterizingriskofadversedrugreactions
inpeople.AcytochromeP450allelewebsiteisavailablefromSwedenathttp://www.imm.ki.se/CYPalleles/
CYP2D6isperhapsthebeststudiedP450withadrugmetabolismpolymorphism.Thisenzymeis
responsibleformorethan70differentdrugoxidations.Sincetheremaybenootherwaytoclearthesedrugs
fromthesystem,poormetabolizersmaybeatsevereriskforadversedrugreactions.Iheardastatisticata
meetingthatadversedrugreactionsarethenumber4causeofhospitalizationintheUS.Thereareatleast72
namedallelesidentifiedinCYP2D6.Thecrystalstructureisknown:JBiolChem.281,76147622(2006).
CYP2D6Substrates
Antiarrhythmics:Flecainide,Mexiletine,Propafenone
Antidepressants:Amitriptyline,Paroxetine,Venlafaxine,Fluoxetine(Prozac),Trazadone
Antipsychotics:Clorpromazine,Haloperidol,Thoridazine
BetaBlockers:Labetalol,Timolol,Propanolol,Pindolol,Metoprolol
Analgesics:Codeine,Fentanyl,Meperidine,Oxycodone,Propoxyphene
CYP2E1isinducedinalcoholics.Thereisapolymorphismassociatedwiththisgenethatismore
commoninChinesepeople.Themutationcorrelateswitha2foldincreasedriskofnasopharyngealcancer
linkedtosmoking.ThisisthesecondP450enzymethatmayberelatedtosmokinginducedcancer(see1A2
above).
TheCYP3Asubfamilyisoneofthemostimportantdrugmetabolizingfamiliesinhumans.CYP3A4
is"themostabundantlyexpressedP450inhumanliver".(Arch.Biochem.Biophys.369,11231999)The
colorofperfusedliverisduetothisprotein.CYP3A4isknowntometabolizemorethan120differentdrugs.
SomeofthesearewellknownandIgivealisthereofsomeoftherecognizableones.

CYP3A4Substrates
Acetominophen(Tylenol)
Codeine(narcotic)
CyclosporinA(animmunosuppresant),
Diazepam(Valium)
Erythromycin(antibiotic)
Lidocaine(anaesthetic),
Lovastatin(HMGCoAreductaseinhibitor,acholesterolloweringdrug),
Taxol(cancerdrug),
Warfarin(anticoagulant).
PoisoningbyacetominophenoverdoseiscausedbyCYP2E1intheliverandkidneythatconvert
acetominophenintoaverytoxicintermediatethatcanreactwithcellularmacromoleculestodamagecells
andeventuallykillthem.Thisintermediatenormallyreactswithglutathione,anaturalantioxidantincells.
Itisonlywhentheglutathioneisdepletedthatcelldeathcanoccur.That'swhyacetominophenoverdoses
don'thaveanyserioussymptomsuntil34dayslater.Thisproblemisworseinalcoholics,sincetheyhave
inducedCYP2E1thatmakesmoreofthetoxicintermediate.TheantidotetoacetaminophenoverdoseisN
acetylcysteine(NAC)torestoreglutathionelevels.Itismosteffectivewhengivenwithin8hoursof
ingestingacetaminophen.
TherearecommondrugsgivenforspecialpurposesthatinhibitP450enzymes.Theseinclude
erythromycin(anantibiotic),ketoconazole,anditraconazole(bothantifungalsthatinhibitthefungalCYP51
andunintentionallytheyalsoinhibitCYP3A4).Ifthesedrugsaregivenwithotherdrugsthatarenormally
metabolizedbyP450enzymes,thelifetimeoftheseotherdrugswillbeprolonged,andplasmalevelswillbe
increased,sincetheywon'tbeclearedasfast.Ifthesedrugsaffectheartrhythmsorothercriticalsystems,the
resultcanbefatal.Forexample,inhibitionofCYP3A4inapatienttakingwarfarincancausebleeding.
Thisiscalledadruginteraction.Druginteractionsareoneofthemajorcausesofdeathin
hospitalizedpatients.Theriskofanadversedruginteractionincreaseswiththenumberofdrugstaken,with
aprobabilityof40%when10drugsormorearetaken.Themostseriouscasesareduetodrugmetabolism
byP450enzymes.Acasereportofa63yearoldmanreceivingmedicationformajordepressionshowedhe
boardedaplaneinTorontotoflytoLondon.Onarrivalhewasunrousable.InhisCarryonbaghehad
Mefadazone(fordepression),Ketoconazole(forfungalinfection)andTriazolam(anantipsychoticalsoused
forinsomnia).AllthreeofthesedrugsbindtoCYP3A4.KetoconazoleinhibitsCYP3A4andprobably
causedtheothertwodrugstobecomeoverdosed.
Anotherexampleisterfenadine(anonsedatingantihistamine)withketoconazole.Studiesin1993
(Honig)showeda1572foldincreaseinterfenadineAUC(Areaunderthecurve)duetoinhibitionof
CYP3A4byketoconazole.Torsadesdepointes(TDP)isapotentiallyfatalventriculartachycardia.TDPisa
sideeffectthathasledtowithdrawalofseveraldrugsfromthemarketincludingterfenadine.Thisisacase
wherea72foldincreaseindrugdosemightharmorevenkillapatient.

Anotherfactorindrugdosageisinterferingsubstancesfromfood.Grapefruitjuicecontainsa
CYP3A4inhibitor(6',7'dihydroxybergamottin)thatcausesabouta12foldincreaseinsomedrug
concentrations.Andtheeffectlastsforseveraldays.Itisadvisabletodiscourageyourpatientsfrom
drinkinggrapefruitjuicewhileonmedicationmetabolizedbyCYP3A4.Ihavereadthatsomedrugsof
abusearebeingtakenwithgrapefruitjuicetoenhancetheireffect.
NowwewillleavethedrugmetabolizingenzymesbehindandtalkaboutP450sthatareveryspecific
intheirreactions,justtheoppositeofCYP3A4.Theseenzymestendtobeinfamilieswithoneortwo
membersandtheyhaveonlyonesubstrate.Mostoftheseenzymesusesteroidsorsteroidprecursorsastheir
substrates.
CYP5isthethromboxaneA2synthase.ThromboxaneA2isafattyacidinthearachidonicacid
cascade.Arachidonicacidcanbemetabolizedintwopathways,thelinearpathwaythatleadsto
leukotrienes,andthecyclicpathwaythatleadstoprostaglandinsandthromboxanes.Thefirstenzymes
leadingtocyclicproductsofarachidonicacidarecyclooxygenases1and2.Theseenzymesareinhibitedby
aspirinandnonsteroidalantiinflammatorydrugs(NSAIDS).Aspirinacetylatesaserineintheenzymethat
blocksthebindingofarachidonicacid.CurrentresearchshowsthatCOX2isinducibleandisfoundtobe
inducedininflammation.COX1isconstitutive.ThisdifferencesuggeststhatCOX2specificinhibitors
wouldblockinflammationwhilenotinterferingwiththebeneficialeffectsofCOX1,suchasmaintainingthe
stomachlining.Oneofthesedrugs,VIOXX,wasrecentlytakenoffthemarket.Afterthisstepthepathway
branches.TwoofthebranchesincludecytochromeP450reactions.OneleadstothromboxaneA2(CYP5)
andtheothertoprostacyclin(CYP8A1).ThromboxaneA2causesplateletaggregationandthatiswhy
aspirinpreventsplateletaggregation.ProstacyclinactsinoppositiontothromboxaneA2.Itisavasodilator
andaninhibitorofplateletaggregation.TheacetylationofCOX1andCOX2inplateletsiscriticalsincethe
plateletshavenonucleusandcannotresynthesizetheinhibitedenzymes.
CYP7Aisthefirstandratelimitingstepofbileacidsynthesis.Thispathwayistheonlymeansthe
bodyhasofeliminatingcholesterolinliver.Aswewillseelater,CYP51isakeyenzymeincholesterol
biosynthesis,soP450sareactiveatbothendsofcholesterolmetabolism.Inthesummerof2003,patients
werefoundwithdefectsinthisgene.Theyhadelevatedlevelsofcholesterol,decreasedlevelsofbileacids
andincreasedtriglyceridesasacompensationforthereducedbileacids.JohnKaneetal.JournalofClin.
Invest.July2002.
CYP7BanovelbraincytochromeP450,catalyzesthesynthesisofneurosteroids7alphahydroxy
dehydroepiandrosteroneand7alphahydroxypregnenoloneProc.Natl.Acad.Sci.USA94,49254930
(1997)
CYP8Aisprostacyclinsynthase(prostaglandinI2).Itispartofaregulatorycomponentof
hemostasisthatopposesCYP5thatmakesthromboxaneA2.Crystalstructure:J.Mol.Biol.364,266274
(2006).
CYP8Bisthe12alphahydroxylaseneededinbileacidbiosynthesis

CYP11A1isthesidechaincleavageenzymethatconvertscholesteroltopregnenolone.Thisisthe
firststepinsteroidbiosynthesis.Defectsinthisenzymeleadtoalackofglucocorticoids,feminizationand
hypertension.[mitochondrial]
CYP11B1isthe11betahydroxylaseenzymethatcanacton11deoxycortisoltomakecortisolorit
canhydroxylate11deoxycorticosteronetomakecorticosterone.[mitochondrial]Defectsinthisgenelead
tocongenitaladrenalhyperplasia.
CYP11B2isaldosteronesynthasethathydroxylatescoricosteroneatthe18position.[mitochondrial]
Defectsinthisgeneleadtocongenitalhypoaldosteronism.
CYP17isthe17alphahydroxylaseand1720lyase(twoenzymesinone).Amutationinthisgeneis
describedinNatureGenetics17,201205(1997)thatcausesthelossofthe1720lyaseactivitywithout
affectingthe17hydroxylaseactivity.Thisenzymeisrequiredforproductionoftestosteroneandestrogen.
Defectsinthisenzymeaffectproperdevelopmentatpuberty.
CYP19isaromatasethatmakesestrogenbyaromatizingtheAringofthesteroidnucleus.Lackof
thisenzymecausesalackofestrogenandfailureofwomentodevelopatpuberty.Aninterestingdefect
foundinamalewasanoveractiveCYP19enzymewithabout50timesnormalactivity.Thisboydeveloped
breastsatayoungage.Aromataseinhibitorsarenewestrogenpositivebreastcancerdrugs.
CYP20isanewP450thatmaybeinvolvedindevelopment.Ithasorthologsinseaurchin,seq
squirtsandspongessoitisanoldanimalspecificP450.Nothingisknownyet.Aboutitsfunction.
CYP21istheC21steroidhydroxylase.Defectsinthisgenecausecongentialadrenalhyperplasiadue
tolackofcortisolsynthesis.Sincecortisolisnotmade,theprecursor17hydroxyprogesteronebuildsupand
thiscausesexcessiveandrogen(testosterone)biosynthesisresultinginvirilization.
CYP24isa25hydroxyvitaminD(3)24hydroxylaseusedinthedegradationorinactivationof
vitaminDmetabolites.[mitochondrial]
CYP26A1isanalltransretinoicacidhydroxylase.Itdoesnotrecognize9cisor13cisretinoicacid.
CYP26A1hasbeenmutatedinzebrafishanditcausesadevelopmentaldefect.Thehumanandmouse
cDNAshavebeencloned,buttheeffectsofamutationinmammalsisnotyetdetermined.Retinoicacidis
knowntobeanimportantmoleculeinvertebratedevelopment.Itoperatesthroughseveralretinoicacid
receptors.Thehydroxylasedegradestheretinoicacidsignalandthusturnsoffadevelopmentalswitch.
Cyp26a1isexpressedintheanteriorhindbraindowntotherhabdomerer2/r3boundarytokeeptheretinoic
acidconcentrationlow.
CYP26B1isahumanP450thatmetabolizesretinoicacidanditsexpressionisinducedbyretinoic
acidduringdevelopmentinchickens(andprobablyallvertebrates).(SeeNelson,D.R.AsecondCYP26
P450inhumansandzebrafish:CYP26B1.ArchivesofBiochem.Biophys.371,3453471999andReijntjes
S,GaleE,MadenM.ExpressionoftheretinoicacidcatabolisingenzymeCYP26B1inthechickembryoand
itsregulationbyretinoicacid.GeneExprPatterns.Oct;vol.5,6216272003.

CYP26C1CYP26C1hydroxylatesalltransand9cisretinoicacidanditisinducedinrhabdomerer4
duringdevelopment.Itseemstobeinvolvedinshiftingthehoxb1expressionboundaryfromr2/r3tor4/r5.
Development132,26112622(2005).Retinoicacidisrequiredforhoxb1expressioninr4ofthedeveloping
hindbrain.Therefore,thetransientexpressionofofhoxb1inther4segmentfromembyronicdayE7.5to
E8.25isstoppedbytheactionofCYP26C1.
CYP27A1isasterol27hydroxylasethatcatalyzesthefirststepinsidechainoxidationofsterol
intermediatesinbileacidbiosynthesis.Thesterolstoragedisordercerebrotendinousxanthomatosis(CTX)is
characterizedbyabnormaldepositionofcholesterolandcholestanolintissuesliketheAchillestendonand
nervoustissues.ThisdiseaseiscausedbymutationsintheCYP27A1gene.Rememberthatformationof
bileacidsistheonlywaythebodycaneliminatecholesterol,soifthispathwaybecomesblocked,then
cholestrolcanbuildupandbecomeaproblem.Theendproductsofbileacidsynthesisarecholicacidand
chenodeoxycholicacid.Thesearethefeedbackinhibitorsthatshutdownthebiosynthesisofbileacids.This
diseasecanbetreatedbygivingcholicacidtoshutdownthebileacidpathway.CYP7AandCYP8Baretwo
otherenzymesinthisbileacidbiosynthesispathway.CYP27A1also25hydroxylatesvitaminD3.
CYP27B1isthe1alphahydroxylaseofvitaminD3thatconvertstheD3precursortotheactive
vitaminform.Thisgenewasclonedaftermucheffort,becausetheproductactstofeedbackinhibitmRNA
systhesis.ThepaperappearedinScience(Sept.19,1997).Becauseofthismechanism,itwasveryhardto
getenoughmRNAtoclonethiscDNA.Thetrickthatwasusedwastomakeaknockoutmousethatwas
missingthevitaminD3receptor.ThispreventedthefeedbackinhibitionandallowedabuildupofmRNA
forthegene.[mitochondrial]
CYP27C1isonlyknownfromgenomicDNAsequencing.Thefunctionisnotknown.
Thisgeneappearstobemissinginrodents,soitcannotbeessentialforvertebratedevelpoment.
CYP39isthe7hydroxylaseof24hydroxycholesterol.Itisexpressedintheliverandtheeyeandit
mayhaveaspecialroleintheeye.(MayberelatedtoCYP1B1functionthatisdefectiveinglaucoma)
CYP46isthebraincholesterol24hydroxylaseanditispartofthecerebralcholesterolelimination
pathway.DefectsinthispathwayareassociatedwithAlzheimersdisease.
CYP51isthelanosterol14alphademethylasethatiskeyinmakingcholesterolfromlanosterol.
Thisisthetargetofthetriazoleantifungaldrugslikeketoconazole.Thisenzymeisevolutionarilyconserved
inplants,fungi,animals,andbacteria.ItisfoundinMycobacteriumtuberculosis.ThisistheonlyP450to
besohighlyconservedanditmayhavebeentheancestortoalleukaryoticP450s.
Differencesinhumans,miceandrats.
NotallmammalshavethesameexactsetsofP450enzymes.Theydotendtohavetheveryspecific
oneswetalkedaboutformakingsteroidsandbileacids,buttheydonotalwayshavethesamexenobiotic
metabolizingP450s.The2Dsubfamilyisaninterestingexample.Inhumansthereisonlyoneactive2D
P450,the2D6enzyme.The2D6enzymeinhumansisalsotheenzymeresponsibleforthedebrisoquine

hydroxylasepolymorphismwetalkedaboutearlier.InmicethereareninedifferentfunctionalCyp2dP450
enzymes.HumanshaveoneCYP2J2whilemicehaveeightCyp2jP450s.Humanshave4CYP2Cs
whilemicehave15.Thishasimplicationsfordrugtestinginanimals.Onehastobeconcernedthatstudying
theeffectofadruginratsmaynotberelevanttohumans,sincethedrugmetabolizingsystemsaredifferent.
Beagledogsaresometimesusedindrugexperiments,becausetheirdrugmetabolismissupposedtobecloser
tohumansthanrodents.ForamoredetaileddiscussionseeNelson,D.R.CytochromeP450andthe
individualityofSpecies.ArchivesofBiochem.Biophys.369,Sept.1issue110,1999.Nelsonetal.2004
ComparisonofcytochromeP450(CYP)genesfromthemouseandhumangenomes,includingnomenclature
recommendationsforgenes,pseudogenes,andalternativesplicevariantsPharmacogenetics14,118
UseofaP450forgenetherapyincancer
ImentionedearlierthatCYP1A2canactivateprocarcinogenstocarcinogens.Theinductionofthis
enzymemaybeacancerrisk.TheactivationofaprodrugtoanactiveformbyaP450mediatedreactionhas
beenexploitedtofightcancer.AvectorwithaP450geneonit(andaP450reductasegene)canbeinjected
intocancertumors.SomeofthesecellstakeupthevectorandexpressTheP450anditsreductase.Thena
nontoxicprodrugisadministeredthatisconvertedbytheP450intoatoxiccompoundthatkillsthecells.
Sincethecancercellshavecellularconnections,thetoxingetssharedaroundandthetumordies.Fora
reviewonthisapproachtocancertherapyseeWaxmanDJ,ChenL,HechtJE,JounaidiYCytochromeP450
basedcancergenetherapy:recentadvancesandfutureprospects.DrugMetabRev31,503221999.