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eeh Ran peAsFvabia[na NBrEaEs eset WS ITW OLSEN mie .- rs Srgag The mechanism underlying the hypolipemic effect of perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric acid Bente Haughom and @ystein Spydevold sae of Medco Biochem, Givers of Ol. Oto (Norway) (Rasives 12 une 1952) Keywords: Lind metabo: Tsar;Chaleur Hepatoon(eRa:t er) Te iCTnlhoeriabpiiinedcflamaunecedncdeoprnyoofpnatodhbueonucmpteeetd3scac0bexo0dsl%uoicmsbiamyloinPnFprOaintoSbsiAor.wtaahstFocrshretoseuldeipcesehdtor.lrfeolDslotiaresonrtooadclrtytwarraniosaaiiecimgnlecavcrneietedarso(oefldPmsFabnOlyeAbs)oeWtrihpusemtrpa,ferTirvhfroiaetursoocwroiocottchanonmehcpeosseuuenlnpdthstho,ronerifeCcahcIoavotlcemierpdisoir(oueaPnncntFdyOsgcSharAteees)erurlwaoicnalddss. iedivreoednsoof50p%aFlomyaOtPeFOwnSasAseal5oweTlaalncrtbeysidetadfoiantell. gTIrnoSuhpesap.aiTohrceyipebesrrfuoFomraor(eccdoarmapsoduanldlso{,hebnuconmaoptouclnhodfsiebreastseu,leoudsmeinmdseesldouomceendrsecdhsuoicltdeinoenroilTnhe a eedaiateed aaatrhcaosmemTohrne maseccthtaoinmietoosrfmef,S pnieSicrmpaoA aT:MinGr3-eCd1T osphrSooudsT futetcceeitdoluAntctaoatfseT tipwhoapsA rFroyeepdiounT lcpepedCatrR1etr0iCceSlAfeOfsTs e%)dcuCooerhfs a1lt0nehsgestseeefsdnuciaeonlemdpitornseyuenansitdhmsesesnimtnsayga,ornodauperslsetelaesarnttidefdpi3caa0trit,ophniibodeef hmolesierol together with enhanced oxdaion of fay acids n the fiver. In:tMraodnuyctihoynpolipemic drugs cause proliferation of per. fcrxoixsiomdeasionandin iruactrse(a1s-e3).theChaecmtiicvaitlylyo.f tthheesepedrrouxgissocmoanl- ifteuatced,2 nhieatdeernoagteeneaonuds lgornogu-pchianicnlusdoitnhgicolaocfeibtriactea,citdsb, Tltiadheansolb,eleonngs-ucghgaiensttehdiathaactidsthaendincMrEeaDseICiAn 201.Con oxidising system contributes to t1h6e[1f-a6]y the hy- DToclcihpaenmiicsmeffuencdterolfyitnhg.esereddruucgtsio(n7.5)ofThseerduommintraitaicynlg: SSinvcceeriraoilns. aOndthechrolmeesctheraonlisbmys twhheiscehdmraugysbies, ihmopwoervtearn,t SToyrnthtehseishoyfpoaltiepyemaiccidsefafnedctchionlcelsutdeer:olr(e9d-u1c2e)d rheedpuacteidc FCoOreromxon1d11e2n.cBl1ng:0ern,Spyd4e5v1ol7,OlIe,nrseoifnMetdieal Bochers. a POA, w i. n, VLDL rym denyepope rtes:Tr tedimouenit si, wTaitseoylogflyVceLroDlLredleegarsaedabtyiotnhe[6]l,iveirnc(r1e3a,s1e4d) uipntcarkeeasoefd arendduciendcrreealseeadseeoxcfrefattitoyn acoifdschboyleasdtieproolse itnitsosubeil(e15,a1n6d) feceTske(d1a7)et al. acid (PFOA) {a18n,d19]peorbfsleurovreodoctthaantepersfullupohroonoicctanacciicd (ttihPoeFnOdiiSneAd)r.aJtesufsfttihcaeitteanwtll.ey[r2ei0n]fdeurdceeptdohrettsehede ctpoheamrpotoxhiuesnpodemsralf(l0u-0oor2xo%icdaai-rn sbeorluimclaicpiiddslaelvteelrs hsehpoawtiincglitphiadtmtehteasbeolciosmmpaonudndrsedaulcseo bheylpoolnigpetomitcheeffgercto.upThoef ppeerroflxuiosroimnaaltepdrocloifmeproatuonrdsswiatrhe spaurbtjieccutlatrolyoridnitneraersytimnegtasbionlciec tmhoedyifoibcvaitoiuosnlsy. Tarhee neoft- efefcftePscetrsoofxofitshtoehmseaelccoomimpnpdououcunendrdssspmemaruysste., brtihnergefoarbeo,utbethdeuc h(y: pTeotlaibpoelmiiscm.effHeocwtevbeyr.afiftescteienmgsdliifkfeelryentthatssteopmseinimlpiopri-d 1pt3he7er1sfelsuicoeorpmospcoiounmnlpdisop.iudnTdmhesetmauabnokplehisyvsmiitopalovosegsiiccbaollemmcthhoaanrtatcwhtaeerirgreorefsfffotehcret TM I ------------------------------------------------------C--CC--OF--S---- Ce oitn elaispiiedrmettoabuonldiesrmstfaonldlowpsosasiptatetemrnecthhaatniwsomuldformatkhee TipiIdn rtehdeuctsieoanrcehffefcotr oaf ppeorsosxiilseomcaolmpmroolnifermaetcorhsa.nism Guuncdeerrsl.yiwneg hthaevehycpoomlpiapreemdicheefpfaetcitc offattpyeraocxiidsommeatlabion.. treilma,tecdho(lesttheersoel mseytnathbeosliisc apnrdoctehsesasciivnitihees loifveenrzoyfmaetss fed perfluorooctane sulphonic acid (PFOSA), perflvowoostsnoie seid (PFOAY and dafibrurs. Methods and Materials Ani`mMaalles Wistar rats were used, They were divided into ftiivbeitgurmou(pcso.ntrOonleratgsr)o.uTphwraese aotlhleorwegdronuoprsmawlerfeoogdivaedn ffouoodrowohcitcanhoiccontaaciindedor0.30%.0c2l%fibpreircflaucior,oo0c0ta2n%e pseurl.. psohaokniincgascitda,ndraersdpecftoiovdel(yi.nTpheelledtieftosrmw)erien pdrieetphayrleedthbeyr inrowuhpicwhastherecsoirmipcoeudnidnsfhoaodd ibneteankeditsosoltvheadt. cTohnesufmietdh btyhestehepaPirFeOdSfAeegdrionugp.expTehreimesnitosck. diet The was used for average body aweviegrhatgewdhaeilny tfhoeoedxcpoenrsiumemnpttsiosntapteerdrwatasin2t6h9e gdiafnedretnhte 2Sr2o7u5p,s wPeFrOeS;Ac:ont2r0ol0:523.7 3, clofibrate: 23.1 8, PFOA: . Mate[r2i*aClisMevalonic acid, [1-"Clpyruvic acid and [2(M1C-l#pCylraucveitcicaacciidd wwearseobftraoinmedNferwomEAngmlearnsdhaNmuc(lUeKa)r., Cfllovfoirooroactaenowiacs farcoidm Fwlauska p(uBucchhass,edSwitfzreorlmandA)l.driPcehr:. Csuhlepmhioenic(Satceiidnhweiams, fGreormmaFnlyu)oraoncdhemPer(lOllvdorGol-ooscstoapn,e UMKO),. UOStAh)e.r chemicals were fom Sigma (Si. Lows, PreTphareateifofnecotfsheopfatdoiceytiaersy treatment were studied in ahnepdatfoocryttehse isstouldayteodffdriormecratesffeecdtsthoef dtihcetscofomrpo1unwdeesk.. dhieepta.toIscoyliaetsiowneorfe hiespoaltaotceydiefsrowmasraptesrffeodrmtehde bsyanpedrafr.d s(2i1o)n, wwiitthh tchoellmaogdeinfaiscea,tiaocncsorddeisncgritboedBebryrSyegainedn F(r32i)e.nd sOtsriadtaetiinotno loifpipdaslmitate and contersion of labelled sub. ChrFisatitansaecnidetoxali.da2t3i]onwiwthas0.5memasMurpeadlmiatcactoerdai5ngsubt.o sraadtieo.actFiavierypraecciudrssoarnsd wecrhoelesetxetrroalctesdyntfhreosmi.zedt.he frcoaml SSutsoppepnesdiobnyattheer 9a0ddimtiinoninocfuba5ti%on.saTwhreaterdeacKtiOonHwaisn T<thheanolnomasnadpotnhiefimaibxlteureliwpaidss hewaetreed aetxt9r0acCtefdor w1ithh. pwietthroHlCeLu.mTehteheerx.trTachtes wseursepeenvsaipoonrawtaesd ttohednrynceisdsifaincdd htehxeanrea.dioTahcetivliepildipeixdtrraecstisdwueerweacshrdiosmsaotlovgedraipnhe1d00wi1th hexane, diethyl gel thindayer ether plates. acetic The acid spots (80:201:) on silica corresponding to achnodlewsetrereolthaenndifsaoltayteadcifdosrwmeeraesiudreenmiefnitedobfyrsadtiaonadcatridvs. i. lEinezsyme says and measurements of DNA, protein and ingPytrhueva"tCeOd,ehlyidbreorgateendaswehewnasheepsattiomcaytteeds bwyermeeaisnucru- bAacteetdatweitthhio5kimnaMse(w1a-s*"mCelpaysruurveadte3sdfeorsc3r0ibmeidn bayt J3o7neCs aacncdordLiinpgmatno E[a24s].omLaivnedr Zmaimcmriotso[m25e]s, awnedreHMpGre-pCaroeAd (r2e6d.uctCaDsePcwhaoslinmee:as1u.r2e-ddiaaolcgcloyrcdeirnogl to Drevon et al. _cholinephospho- transferase, EC 2.782 and lysolecithin acyltransferase Taste1 ody and cer Cinloafcihrapcrowusa.s wets and eer 5d conten in given a: 035% nw) 1nd PFOA eatnsdfPedFOdiSfAfear5s0d2s%fnorth7deeivts. Valu FishersPoles are gen = <005, 7 001.com ous, ar gen 3s meas 5.E. Ther wes four caenatons TT mw ome me wm seman Barmmw WnaaZoe wmTwamlLeses mssorore WTiileerns ma LLiLiossc: othnse-ecepirhcfeicseodelrcGhuramoolusitIuonsmesol given) 1ao4srws2io0os4m 44o8022n0071i atleosne s0Ma7%mIeomUns- wis 15 C0COTK -- rr -------------------------- . o G(EiC 21:314.123[)7w]asAmCeaosuAr:ed cuhsaldeesscerriobledacbyuaPnadriehraasasre- 2 0| --i 7 (ACAT) was measured according to Rusian etal. (28) 1s pb Pa uC pPnehdaasiudrtvehiedhy aawn5ncdtlheaesmseiirnsveaedsoafsbnsde.pVthaosnshcepoehvsapet(hi9rad1ytldOsOveytcrhhieonrroen,sen.gapyhwmoyaes:ss 3 | 1 IE1 E3i TmenaspurroetdeinbyatshecmseimtahroeddobfyLtahbearbcuaareatndmePcahiogdenof(3b1Y) 43 3 :ior mtheetLhimanenetarhlodl(i3p:oi1f.dsLov/wwoir)ry.eeTtreaulx.cigr[3ha2cc].eedrolwsithwaschdleorreromfionremd oo, of cormTe, PEO 106 & ol PFOA 8EeTm ts. ddOieorer,cmtliyNnooernwdatvh)be.y dNrFiyrecedoeteexsattnrdackittesWtimeterhitfhi3eodKditcfmhooerltehsctoheodrloe(lsNiYewCraOes.l (0350C1ht%egFuEtoOsAt.ab.Hg0l0t8b%eouFsRhOreSAo,.eTomoedotdseve03n5rSesontion (chNreoom)ataofgerraphs,epaSreartuiomn choofletshteeroelxaancdt Tnoancsitghiivnelsaryoelrs Vas measured disecly by the kit methods. Fig. 1B shows the effect of clofbate, PFOA and Resuls PtdhaFeyOcoSofAmtprooenautntmdreisnatc,ryelsgAulflyttceeerrdol7isn disaniygstn,ihfeciocrafanbttrsacethreaunmga.ensdNoaPnfFeerOoA1f dietTabrleest1esdhoiwns3thlaotwe0r.02b5o%dyPFweOiAghtoraPteFrOS7Adaiynsthoef ranedsnio fiunrtrheedrucrteiqounct1i0onshwoasw G6b0i%ainoefdsaontthrlfovratlhuee rfeaedeinget3s c(o0m3p5a)reiddwitmohtthaefeccotnttohle grraotupw.eiTghhte. dTohfe 3re0a%tmeanntd.20P%FOoSfAco7medoucevda.lutwiaafceirhe1earnagls2 fwoeeakbsouotf si0up with restricted food intake that of the PFOSA treatment. The significant reduston obtained by fast Agfirlvoeutpwheehiaghdcto,ambpSooiumutinltdahsre csriaefsmeuetliwoeednigtihhnte aavs r4th0ew-eP6i0Fg%OhtSihAnacsgrreboaeuspee.nd observed earlier in rats fed clofibrate [9,10,33). aCnhianPgeFsOSinAserum and lve lids by clofibrate, PFOA. ducFiegd. s1eArusmhowchsoltehsatteroall.l trTneealdl iesatsimgeninf:icangtrloyupes+, Cchoonltersotle)roalftewras26sihg.nifDiiectaanrty rterdeuactemden(t1ofoSr0-270w%eekosf rmeosruel.teIdn iangrfeuermtehenrt cwhiotlhesttheerorlobrseecruvcaitioonnss,blyas0in%g foorr C2hadnagyess.did not bring show significant cholesterol idginregotufpbo,rutt2herdeassytersricuwtmaeds(ratsoacetixhgptyecetcreoodn.lssuIwmnaestdhe2b.yr4a3ttshe0fe1Pd3FsOtmoSMcAk Sa{fiitgeenrisft1ioccwakendetikeltoow3fedrtirtethaautn)meo,nbtse(rnvoetd sihnotwhne)cwohntircohl ou is not aol"gThabcleeroIlsshcoownstetnhtat10PmFoOSeAthianncr3ea.smeedsthteh licveormroi] cvalleuaer,ly TinhicsontSriaesctttoofthPeFffOeScAt oofnloriibaacthecaenrdoPlFwOaAs wclheiacrhlydiinddincoatteasfftehcattthPeFcOoSntAenitnhoifbittrsiatyhleghevxccerreotlisonanodf ttirciulaacr.lyPceFrOoSlAs.oimncretahseedI.vert.heBoItvherPFcoOnAtenatndofin npoanr esterified cholestrol. In contrat 1 ths, a Significant TCoansetieon of led usec no Cet cere hpiof ts ed deen 6s for 7d SCTeuihbeirsas2measwhoae 5d25.0m5Sv5tu%.coTei(t13a3mnndPs.PoFVnOue(dsntw1PeFmO-eAma1sSS0E25%TCoirnttlewrdiree.fTorsosabcrdoanutcocenesrdnnieohfv1i."3 CTsiroon.oefvoobselirenddh(hs"sCwhsertohnendn TE TT mn Cd aa Se me BAT Sw Fox e FoR [ECERChihemaiioennemermrae wweNHh:eIeiila nWReSz toiiBfmeoorer iaSI zIEeNst 2a0mFaEEiFzudar 000g --- dCToaAnLsneEnrimof o[f0"pCleplalmbttrcabysAico o"Colf aetds Jfdunfyfearceen eansg seCTroAnBeleLr.EiPoIpnVaosfo1c: sonsecrisn oefCp.nelateydceon:iodos nand ch, oTfe1a -c*nCcleancieriatieonasndof[c2 o*mCploouynrdusvante everdeieats nddesctrhibecdonicnenTiurlateio1n.s Toe concemraion of (U-Cloairtuc was 05 mM. Valuer are Tc1elhhl pccroountceeeinndr0at41i0o1mn3ao%f h1a-av*unCmhsicneEriunntc3eemwtaRtosohmnMHeTamonakdtotmhnesvncieobeatsnionntsy baller. The concenaton lTaEcms=arSeEgivTehnerew<er004% S+hen7ut<i0o0n1s viy.n ccaocmhetrorws.pFars 7 VFiableerssw7e mvaelauness rSeESTheonro+ef+amPoi<oe0l0fp1oemssbecsonmoaenrmoonausnmnesro smmas Sibarwte (ToCmaLasbeulbedseinSurssonemtgaDeNA 4) xa@weF n em "Ciabea liea teFCaan bmeelres ss t (Cee S BIE Wo SS n 7R70eAi i T FROc ST A Crue 222 RIB Is ms 3e New cCohmeetes r usrbbonms fgose saDRATHT wm zs maw (C nmol sm usie oxdicsaeinmDNATMh) TTSeAhonies Za1r4sa3 02n0mBn 20[0%iyinr Gd moriw o weto PeOAersFOes RAw bros 6 Zoe 1908 Zee trheedutcrteiaotned(r1a0taspp(rPoFx.OAStOr%e)atiendersattesrinfoitedmcehaosluersetedr)olwaisn found. aCtoonctyeiressioofnroaftlsabfeeldldeidffseurbesnttradtieessinto cholesterboyl hepatoTmasblefrIoImshodwifsfetrheentilyncolrapboerlalteidon aocfetlaatbee,llepdyrcwavrabtoen, Tmhevealmoanjaotrepoainndt ehmyedrrogoimnegthfyrlogmlutthaisritcablaeciids t(hHaMtGt)h.e frartoemoafllchsoulbessttreartoels swyhnitchhesiasrewapsrosxiigmnaiflictaontltyhereHdMucGe-d cCoontArasdte,hycdhroolgeestnearsoel ssimcipheisnisallfrtroematmmeevnatlognraoutpes.waIsn notTarbeldeuceIdI isnhaonwysotfhtehesygnrtohuepssi.s of fatty acids from pyruvate and acetate. Both PFOA and PFOSA treat- v`amteentirnedtuhecePd FliOpAid sgyrnotuhpe)s.isN(onotresdiugcntifiiocnanitnffraotmtypsyeri.d tsyrnetahteesdisaniwmaasls.foTuhned tianblehepfuarttohceyrtesshofwrsomthactlotfhiebrpaeire.. ocrxeiassoemdalraitneduocferpsa,lmaistateexpeocxtieddat,ionres(uallttehdouginh aPn.FOinA. mdiedntnsotdorensoutlt exinclaudesigtnhiefipcoasnstibiinlcirteyasteh)a.t The experi. intraceliolor (croenvteernstibloef) tehfefecttesotnedfactotmypaocuidndasndmcihgohlteshtaevreolasydnitvheee:t tsiisoninsivnicveo.tSheucchomefpfoeuctnsdscomuildghhtavheaveesbceaependwoausrheddetoeuct. ddiurreicntginthhiebicteolrly eifsfoelcattsioonfptrhoecseeddurrueg.s,Tothetessytntphoesssiisbloef tfaitotnys oafcitdhse acnodmpcohuonledsstetrooltheininhceupbaattoicoyntemsedwiituhm awdedrie pcelorffiobrrimceadci(d.TaPblFeOIAV).anTdhFePtOabSlAe sihnhoiwbsittehdatthe1 cmhoMleso:f Taste v ATAhhCe csoounsocfe.nein*aityPom<enssro0feclio+e0md+p70o5u<tn0ed.;s0n5,ne+fsho.d<ife0th.0ow1eervneme.crslodemascenrifgbrreoydup.ianciTdsabinlbeI.oVfalreassafed differen disfor 7 dvs given 35means 5.6. Thee wer four beers in Em om mm) ClPirnoewdsyGneinessnee ATPcrate hse Smo oomvisooin domme o0m9mi0o0ns Fox 0o03e0m0s wom o1302m39 e `MMAaacilseaisee ddteimoeakritomsseyenidc(rNAoDPg)(Geecnurbaonisaioeg) 8I7se3z0oss D03i62e005 5o7m2ao0s8s m08e2s00a51 o35i30- s 217M2:206054+ 07242o0m0e6r 1m9i2 o2o0r Gileonsr dpehyoisrpongasendsesm(roAgDenPase T00u30o10 oanniooass- 027x1 o00e+ amn2t oonne DHCMG.CCon reduetne (amo procin min") OTVIEEoOmW OWoamsOommr omomreawRtc onimmeee ogee wo TE oni si mms Sn So of Erne ed tothe ones ofc mbeal. [e3st4] wassreealedsoaco ooynfiOrNu mo edh. eCc leoafiddriocmSacoiedu prerrduacs edndretohe hfteesrTrma,enbl(nCeMoVImCypAshoTotw)arseostFhsaEtntSaSca,ylny-CotwAh:chSccthhoalodoessteehruoeleancarylbotrrmd2aanssn- e eo oe t 8abert mnEon oma he reaction of Isr chonleocr(ATLaTlEeTi)hhebhlee aoe ed ee er Con Tao i oe nmeao nHaCn 1og F 0Seoad,MeTvreere DmplaoemimctatraTa hreiaentdeny isthhooefmrbsofsmhdoapamhyattoaefenirneee To rey ei Erma ler 0 th gts ofsett ondfo ei ehems o 0 usnmalilbse an S cmEanetewsse ere Eapstne daetroges, cirwe iaRtFsooffexIxees laeedAdto ghorghcoolttdesomabiedsshiant ra a e Tos gFiescaymonheAaTyE ene analy oO To ey Joelasote,ioon msae2e3softo0er3acmtodonsrieeidneabdcyiindbtothtaehg Peuotinned, Smpounts FEO ad 3panier e monaremae in patAeSAPofsgp resaote mreoss oPFEEaOOnTPSEEeSOshoaan SproranongshesotIfsbnsioirnmaalmiweniehfao0n5ttymheM EA eg Es nobel helices. Te eaFmeooye ta nye somlodneSSoaplye TTHamFaaElgOeSahSanc0lafniso2Sshrmaeiles,mvrhipheecn0iveerle1y wmriedtuched)0fhe3o pee a ep ornatedcompounds vere aJv ! cocoms 1% STamneeirwoef ems et 0 pd sn he Cosonsm1 efctc i PEON nd PFOSA Syinhoearde.dsi.onSatt ecSdoucmriopnoooff the saeyromfosSomeoSefnTzaEybmeMer routon ens 10.90 om TEoSTIroS s adcTSamI eamounoftM sure DMSO.TTThe SS TT Hoverlo i2t1%i3o5n0 Lich Increase obseried afer feeding pesivorianes 3 memolehecormne.nSb elewes Si e pe TTT Cx m RIT eeeSOhMebpOswUi.Rtda fse.ossarecHndlouweneetvheorne.e wsetrriosncpe probeaabrlygmhcanoofimSgmoiiruuSennglesasTheriee0c-s Acy-CoA Iysophosphatidyl (35.36). Sr SE O ospteoi WY ned alet wraesy pmr one 10 zWsE BmaEs RmDr cChnoC lolefsatneHere oeMldaOindCt bfOraayrraaeciodvsmssewniiahemsies ee n on vnodm de eeten The fect of the compounds on the civ of 0a he0nreesSuiimoenOnhpoomorepmsedovaLluooannamtie0enhbwenaorsfeeo duceninnstehp wsreesrtusdeys. AeConCmtApaoTtuinowdnasst(ehoesteAdsChAoonTuly)aaciv1i0y0 AwNiEs aunndsfweictihedhibsyctonme iianosnchsilsDioSnt3yy0)TaEedvurcemnthoe EpMem Co-CfonHsMGo-An mChoerA brsleeedrucaco.. Discussion Reduction of the scadysate eves of serum lids Fm(rhliouis,nedGucoceesms,ynMotnEoDatItbCewAa 1Sa6h:nascemnsovseesbineemapf osis:is (1335, bog her hts me cons ce Tmaiydsoyentihessailsooedinac5eshseedrcleesssnofcsdoowmnrepgudlaat,ionThoef daonsetphaiSaatieNIaG SCe Fmoecuns,eOOUfcTholbeisetrro:l ifmaimeemsraseorfnatnItthvipsoeersbotsxeuidrsiyonomwanahls:eptrowoipeltvihsafle3uri1astorersseteohmen ce3coffmsepecrotiTsuehnsoedfosftrhwoeremems.e TtoebrtaoialnincoeefdonmbeyoAdzasrronmaokfnf aem eteali. o[1n0o ] wahfocfogoucfunnddMEtahDatIccChhiAollees1s6- SdKloieemwcrinutrciecneggntueeltrahnitefiicSomnnbisooeonfrfecedhHnoMseaGismrt-eaeCrtoao(AnAhsCAeriTensd)utschteTahacseeno,dvseottfshreehatomreaectsne,t. tes and. production of cholestrol 3nd iden Insc oPsvnoeRsAgOTuSoPt-echbiattdrenasteeucmleyopanseans(c3oe9er),dy nclo,fihbrrin ceceacoind,SAP1PT8FFP8OO-AASradaotnwnnedd: Slt mas wom ne rey amiTsron.This ihInvaetmr secuceclhhlcapnrnoamviecdemysesaionsmuiehreesmiupempanoctdrosofraorena(chaenrdesasslchauemdnpgtHieeohsne on the mechanism of he hale cects of he tpLeoraonlngsayoporfaasmnehssea ecoae rhSeeessrss 1Ioftschehnomleaeisrn: NABPH sentra prrsoLesum eedonoeof the s7She6onltessshtoevrweosg3einaiCciorerpdealtahitnweadiyss<fisTnetcoth.eoTnIon hsweeocooGmprppeoeurnnidmsenndsdo. To in vir experiments indica ta there ie dee wteoronoopcnatcnhrassctensdl,wrehdpfasroaieTchaerfnieoSrSoVAtIDeMPsHOegN(eENnAedDrPea) om er caepfrrifeipesmcuutemlatabcrileooynnicrfeevTemerhrrsaeeiibmlolenah,srainspenrtcosh,hoasose1nlyatlbhraseeikpsr,roepestdeannnatfceaehrsnangdgTeiehesseasrn ftys sCeasTnrneoeot1mssyyehdsvueocvetdo1oitnf p(PB coay aevcio despfoeemo eeaceedtatl 1OetForhApbe rTvescEt:e CRhEaTnhgSeehsopleiernsflFeurOoor-BienCnaicoendpacmtohmawpaonyunoadrs wsioznceldaeidn twhiishstutdhye eons loca tans, The mame acions ould 0Brp0oeebrroysa. mmneotnrri1eh6dyPtRSoOENseA.dsserhoen iaientssnm2eneoef Trtay of tes hence on woSeCumultion 50 0 Tepurdcd 5 mare une od sie se 36d smn hs rn ee aeton of ft cocoze [4 . choenoc iniliid meThoolimsim mousst n4e 1mofronod nrelcfsor n rSehdeunceofreBleEasBeEof AiLdsOTfroImh[evervawasprpbroabtalyy aann Sndmhto Oinf irpos6oa mhesvceris eovnenrsah(8oShoeftcsoemd cersoans oasn raiseerss bby boout2S08o%in ir pound WY-14.643. pSarLoiccisesCoofToncrhsdeiatecisorn.tsoto1rv0earsnpgopisprrerormoattirnaye.1sAVLmDL TcrnaSribnemceoSynincuotiesnrfdoeeerdenenhcdeoenaweieodtdhnuhethaneognsoIynntthSrehsielsaenoshfretcrshelol1eastme2reyl Co seein un gn Soumeguiaton ofHMG. iFnShigicnchilcsyhesd3ofi0acn1edesrdeteredhiueecepecdadhioacclerhtsaatlbeherenoesrlosolhfoefanhedespsapsHcohcemoosmsppoohnvoeennr,s || epaCeohniB2sflTsooaesksmceonaedl1oocoe V3p rIDhph eafeoctnsennBceeatndledebceodym CTsaErG"itnTchtodthoe(fpTtabaetbrielacedcc)e1o)nvnStdneinaFworEhfeOhsrSaeiAcs(kftreswedinuscshosebe(aesPirFnweeOaddsAOwrfyeiodsdAuvrc0 ioe.dt abblyoomsenrSiereeegmnnisenhFpeaoennnreota feriengIwpdheiscpheohdeslpveerea,rmlyhycs TRTaeenneesoaflGcoh8oml)memseweanithlichooneerolfpehvenbocAscCoKn TmdrmooeprreEsrRscsSh a tered mal ese on a whieh war Sheos f othe pe Acknowledgements GPpiooronuotnrkdaassiyoinsodsffnrltoetesoAmnnoeohoterttaheeneencdsa)nmatneyVcmaeebnyc1Se0tE0e[5I5]C1ohmmogfpiohicuehndccsoon+. CFoeFuninnianacinal Toe tCsoruosprpepawamosTrSDeSceievedsLfoArmNnomdoerrNwsoeJmgaeirgaeinsn on oof Scene, Norway, and oCSeenmsSsyenofenshoosfhpehslrsucpssmaawye ogveeminnoSrkSeohfeIrpdopren.y BDresRepom forhreelnpe]dgisecu,ssDieonnmark, We thank TaICalbslcacrmeneThoaaflfhfDOouoEfvsoer,pfthtWaesceddpuoicneedtsornosomesesnooy Retrenes 1 Lamon. 5.S9c 7 197 st hPFpsyaenireatfhtlheiusooinarsiirnpailotiaeeyndsc<acofoarmooPlpneoh(ui2nn7osd)tesshS,eerpulssiiehpnicsadei-srttmehdeehpusoceoimnwhrgahedfefoteedcnitrsSeyocumftepdtsirhs,ne. B+2 f SSoetg oo LaAoKr.0X12p 0neSeaipeR eOok5.T 01589)s Bmeennand rLanmaarhoaseni, N.D. ma I eis ane win, $ Lie. pe, 1nd chr, 4 0 erippisa, Weofonundshtdhiaerssnetweownmigy DiHnWBabh . Pn d ecrsateolyhiinheibditehdtbyhithseopemrfeluorwionsatsed ceomponundes. nWe 7 llee, TT.oOke. 1. an Susans M. (1982) Metabolism 31 No. 10), soPabayitrnde0t.hr5eaasmTasshrMeiasihh(pyTaiaaeagbtsrlreeeaeld3.sVuI(cc2Ie7o)wd1m.iarhsOanldueritaTlhsodselaoetoabfaiydnipo1anmnseoMtreemspopuofpercplcioleprodoftisnbtnribhigcyec 89 10111g 2SbAAir5tOori7iR,o%C.tR.iS1(1u9Mn8a1mE)LeaE(nAc1e0ts5m.idi, 1o3u62l., RG. and Bam, 8 co. 095K6)9LoidtRies te, sss hereffect cofaothmeescoomfpoounhdsspwheohlavestesstesd. may py Inhibition 3, of 12 Go phones Bar-Tana, J. RoseKahn. G. and Srebnik, M. (1985) J. Biol. ole. rRedeTuocedadutcreeerlseassheeooflnlipeids fhfroonmIenthsee lfioovemrrhecehra(d1ol0e01818 ABtheerosler, Res. 6. 55-504. Go BtBiornee30.Ea7A(Absetri ). r5ProS th 8.81.00 SsAhsedicTcrkeo iCsniodfmtrmaunstthTfen desxcemkrooemirionnstPipForOnoAcToefEEtnyeardmlowmfiarkaie 1s7 BhSoosEenTSANAAbefn oEri h Sen e ocoosy 20 no 1 HiaBtpm.a rePebtoKe a ayI Eotm .eJoeKmoT hTeTo1n08s3 s L82oLyoim,,OpCOeHll.,eSonrne thgs ,Fo AL rd ort ms mn 2LBaa EyEe eA rie a y Rin I s aEhno r,ss. 2 BSE E BEotGe aR GrtOngiI nr aEee 5235 SolpnomEma Rta t s1dTmaannt,or08590BweBoesnnssa2m0 rnss5.1-33i 38 SBeESiE.ap.A04RBCTnB,,Y1.r82e.A8recotm.e0, R A mERaiE n SeAiyT. 1 ton, wa, oy men Lon teas Ta fSE nm rSL yEoeBL,YLooetm. m25tH,sST.ethie7n01m5. v EIeE n gelEnmfStS en saU soosI a0yXJ SmJE -- co003X 2)