Organophosphorus Ester-Induced Delayed Neurotoxicity

38 Pages·2002·1.2 MB·English

AnnR.ev P.h armacoLT oxico1L9 8211.: S11-48
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ORGANOPHOSPHORUS +6805
ESTER-INDUCDEEDL AYED
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11-Y o In humanso,r ganophospehsotreurs- indduecleda yende urotoxicity
21:5SIT (OPIDN)r esuilnta fs l acpcairde wshiisc dhe veldoipsst ailntl hyle e gasn d
81.ER spreatdots h hea ndasn dt higIhnst .h lea tsetra gseysm,p toomfss p incaolr d
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ar neurotoxicity.
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Re befotrheeo nseotfc linical signs,b ewthwiec6eh an n rd1a 4nd gaeyss .
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diametpeerr iphneerravle s.
5.T hel esioanrsec haractebryit zheedd e generaotfti hoena xonwsi th
subsequseencto nddaergye neraotfmi yoenl in.
6.N ota laln imsaple ciaerses uscepttioOb PlIeD Nh;u manasr eb elieved
tob ea mongt hem osts ensistpievcei es.
7.S peciseesn sitivittyo b aerp epleaattroesa d g et;h aitsy .o uncgh icakrse
insensitive.
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512 ABOU-DONIA
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structoufor reg anophospehsotreaurnssd t heaibri ltioti yn dudceel ayed
neurotoxIitca iltsdyoi. s custsheebs i ochemtiacraglae stw elals f actors
affecttihnedg e velopmoefOn PtI DN.
HISTORY
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9V furthcoemrp licbaytt ehdpe o ssibtihlaistto ym eo ft hweo rkewresr sei mul­
ol. 1UNI taneouesxlpyo steosd o lvesnutcsah s t olueannedn -hexaCnaes.eo sfd istal
oxicKE neuropadtuhety o c hroneixcp osutrone - hexahnaev bee erne vea(l4e5d) .
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acol. by D THED EVELOPMENOTF AN EXPERIMENTAL
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(14l),a mb(s4 6s)h, ee(p4 7a),n dw atebru ffal(4o8 a),r es usceptRiabtlse,.
mic(e1 4)r,a bbigtusi,n peiag (s1 5)h,a mstearnsd,g erbidlisdn2 o ts how
consisdteelnaty reeds pontsoTe O CP,a lthoutghhea cuteeff ecwtesr e
seveDroeg.sc oulbdem adeat axibcy o raald ministroantliiyfeo mnu lsify­
inga genwtesr ien corporina ttheedd o sew,h icahp parenetnlhyan cgeads ­
trointestinalo faT bOsCoPr( 4p9t)i.o n
·Chemniacmaesal r lei sint Teda bll.e
2Abou-DMo.nB .iu,a n,p ubldaitas.h ed
ORGANOPHOSPHORUSN EUROTOXICITY 513
Tabl1e Chemicdaels ignatoifoo rngsa nophospehsotreumrses n tionientd e xt
Compound Chemicdaels ignation
Coumaphos O,O-Diethyl O-(3-chlo-rcoo-4u-mmaertihpnyhylol-s)7p horothionate
DEF S,S,S-Tri-pnh-obsupthyolr otrithioate
DFP Diisopropphyols phorofluoridate
Dichlorvos 2,2,-Dichlorodeitmheetnhpyyhllo sphate
EPN O-Eth0y-l4 -nitropphheennyyll phosphonothioate
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or Leptophos 0-4-Bromo-2,5-dichOl-omreotphhpyehlne ynly lphosphonothioate
ws. Malathion Dieth(ydli methoxyphosphitnhoitohbiuotyaln)e dioate
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vi Merphos S,S,S-Tri-n-butyl phosphorotrithioite
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alr Mipafox N,N-'D iisopropylphosphofrloudoiraimdied ic
nu Parathion O,O-Diet0h-y4l-i ntrophepnhyols phate
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a TOCP Tri-o-tolyl phosphate
m arjournals.nal use only. TrOicPhIloDrcNpho oun2 n,l2od,bt2 ,e -p Trriolc-dhhluyoidcrrnoeoe- xadyrep sthlhotyysulp hdoininamet oes n ke(y1s5o )r
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11-Y o Malldaurcdk l(i5n7wg)es,rs eh owtnob es enstioet xipvoes tuoor reg ano­
21:5SIT phosphcoormupso uPnadrst.r( i5da6gn)eqd u a(i5lw8 e)r neos te nstiot ive
81.ER as indgolseoe fD FPT.h ead uclhti chkaebsne euns eadst htee asnti mal
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newc ompoubnedimsna gd eea cyhe ar.
6.T hec hicckaebnne e astirleya btyde edr moarol r aald minisotfr ation
thoer ganophocsopmhpooruunsd .
7.T hceh icikrsee na daivlayi lraebalseo,pn raibclaeynde d,a styoh andle.
AgeS ensitivity
Agsee etmobs ea s igniffiaccaitnntot hrd e e veloopfdme elnatny eeudr otox­
ici(t5y9A ) s.i nogrldaeol s oefD FPd indo cta udseel anyeedu rotoxicity
514
ABOU-OONIA
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Re dosceasbn u iulptd o c audseel anyeeudr ot(o3x5iT)ch.iiw tsay fs o utnod
nu. bet ruweh edna iolryaa ld minisotfsr maatdliolos noe fTs O CPt oh ens
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A causpeadr al(y57s,5i7 ,s6 S )i.m icluamru laetffiewvcietts Dh F P( 75a)n d
tri-p-etphhyolspphahenandmty oeln o-o-dpir-opp-yelt hpyhlopsh­enyl
pha(t7ew) e roeb tained later.
Recesnttu doisfeu sb chorroaannlidd ce rmaadlm inisotflr eapttioopnh os
(6613,6,5 E)P,N ( 64)D,E F( 72m)e,r ph(o7s3d )i,c hlaonrtdvr oisc hlor­
phohna2vs eh otwhnta htte o taadlm inidsotsneeer eedtdeop d r odautcaex ia
wadsi repcrtolpyo rttoti hoseni aozlfet hdea idloys e.
4.R ouotfae d minisMtorsaattn iiomdnaa.lta av ailarafebr losemt udies
thuaste sdi nogrldaeol s aelst,h tohusegk hii asnn i mporptoarnottfea nlt ry.
Dermaabls oropfrt aidoino TaOcCthPia vbseee nd emonsint rdaotgaesnd d
ORGANOPHOSPHORUNSE UROTOXICITY 515
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toc audseel anyeeudr otuonxdiecmriegttoya baocltiicvt aomt oirpoeon t ent
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21:5SIT
81.ER MECHANISMOSF DELAYEDN EUROTOXICITY
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TU causdienlgan yeeudr otaorxei ctihtayt p htohsepyhe osartaruenesrtd sh ey
acol. by D ardei roerci tn diirnechti boifet sotresr ases.
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An ernaelr vous DsFyP(s 9t96e7,m-s9:T9 O)C,P( 1956,- 1m0i8p)a,(f 9o6x,
109p)h,e nylphosphaonnadol tihpiheoasattt(iee6crs4 s,- 74).
Histopatahlotleoriganipt cei roinpsah necdre anltn rearlvt oiusssi une s
chicpkoeinsswo intetdhh enseeu rootrogxainco phoessptgheeornrseu rsa lly
depeonn(d a t)h ceo mpotuensdt( ebtd)h, se i ozfet haed minidsotseer,e d
(ct)h see veorfit thcyel inciocnadli (tdit)oh nle,e ngotfth h pee riod
betwoenesnoe fct l inicoafld esliangyeenudsr otoaxntidec rimtiyn ation,
and(e t)h sei otfet isssaumep ling Hi(s64t-o7p4a)tc.hh oalnoiggnei sc
periphneerrauvles su aalplpyee aarr ltihearn thosspei cnioanrl( d 6t 9h,e
971,0 2).
516 ABOU-DONIA
Three covaencrdly i niimcparlo veomfse onmcteh ickaefntdsee rv eloping
ataxoirpa a ralayrsiein st ereIstit sui nnlgi.k tehlatyth iism provement
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isn otty piocfta hlce e ntnrearlv soyusst (e1m1 O0n)t .h oet hhearn idit,s
posstihbatlthei e n ipteirailp dhaemraahglae bd e erne paoirrr eedg enerated
byt heen odf t heex perimpeenrti(ao1ld1 A1n)y.a cutree,ve rsspiibnlael
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nn aggregaantddi iosni nteogfrd aetgieonne mriattoecdh onnedurrioafi,l a­
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mentvse,s iacnlgder sa,n umlataerr ainia nlc;r ienta hsneeu mboefsr y naptic
vesicalnedss w;e llSiwnegl.la inndfg r agmenotfam tyieolanin nda xons
simitloca hra nignet shs ep icnoarlwd e rper esientn htle a teproarlto ifo n
thmee dullas,e cwthoiifol nesc eraenbdor putmli ocb weesr uen changed
(62).
PERIPHERNAELR VESE lectmriocnr ossctoupdinii cce hsi ckaencndas t s
treawtietTdhO CPs howtehdae ta rclhya nignet sh aex oplianscml uded
ORGANOPHOSPHORUNSE UROTOXICITY 517
aggregaactciuomnu,l aantpdia orntc ioanld ensoafnt eiuorno filaanmde nts
neurot(u1b0u3l-e11s10 97A), s. t rifkeiantgu rteh ew apsr oloiftf heer ation
agraneunldaorp lraestmiiccu lum. iInen atreslrtyea sogtfeai stn agxliya,,
mitochownedrnreoi itan voilnvte hdsi wse llIintn hgle.a tsetra agfetse r
onsoefpt a ralysis, oafmc ictuomcuhlowanatdesirv oiinad T ehnetss.te u dies
confirtmheahdti stopatchhoalnoiggnOei PscI aDlwN e roeft hWea llerian
degenetryapt(ei1 o0n5 -R1e2c0e)tn.et a sneedrf viebs etru dsiheoswt ehda t
g DFPi nduacf edo cdaelg eneirnta htdeii osnbt uantlo ,tt e rmianxaoilnn,s
or
s. thcea (t9 989,F) o.c sawle lliininn gtse rnsoedeemtseo bd ed uteov acuoliza­
w
vie tiobnostw hi thainondu tstihdaeex oTnh.ip sa ttiedsrni stidnicfftelrye nt
e
alr frotmh ne- hexaannrdee lactoemdp ouannddcs a rbdoins ulnfeiudreo pa­
u
n thi(e1s0T )h.ic sh emitcraaln seocftt haiexo ontn h epnr ecipitates Wallerian
n
a
m arjournals.nal use only. ddheeyggpeeonntetehrowhreaaftaasdtsn httiymi oe isiovot o narn dngl efi -ni osbedoarta urx acrgolkIoan twpn. eaao svsptuho hgolifnsgverepeesoturhs mhreot atotrehtpur(tde aso9r ta g98ahxr9,dyoa) i nd.tae il o nal
oo
oaded frFor pers PsEoRnIwePidHt TEhORS ACELPsN uSOgRgNYeEd sRaVtmEeaSdEt g aoser e lncislfieoibrrnesy (irt 1csu405a do,)lifpC . e ae strt ssrp oeonaist­e d
wnl10. witThO CPs howseedv dearmea tgose e nsaoprpya riantt huiesn terosseous
Do29/ anflde xdoirg itborreumvmui ssc olfte hsfe o (o5t1, 0 21,0 31,2 1E)l.ec tron
11-548. Y on 06/ TmOiCcPr-otssrcsteoluapodtloiweiofcs der he sian svs sneohe rorywtvv neae rc muoilnoiadzfttea iagtosebintnuoseend i rm,snati tthioen­ g
81.21:5ERSIT ccheol(nl5ds5dr )ii.sa t,e nded ernedtoipclauanlsvdume mis,ci.f c olrem aitnli iognh t
9V
ol. 1UNI NEUROMUSCULJAURN cnONSI nT OCP-trceaatttshen ede uromus­
oxicKE culjaurn ctsihoonwnseoh d i stopatahlotleorgbaiyltc iiagomlhni tsc roscopy
TU
acol. by D (o1s0m3iE)ol.peb hcoitmdlriitiocehcnrsac o tos nscttoadupiedinhgiceoee dwns ee,mvr iieantrtdo,eic dch taohstnpeyedr ndrea isvpaeeto,nsif cic e­
m
ar cleasn,sd m aellle ctrognr-adneuinlnste ehst e e rmianxaolp laesxmpiacn ­
h
P sioonft hnee uromusculoafri njtuenrcomtsuissoecnoNlsuoe sc s h.a nges
v.
e werree poirntt hepedr oer-p ostsynaptiSci mmieclmhabarrnw agenereses .
R
u. notiendc h icfkoeoentx tensmours calfetsTe OrC Pt reatwmheincctho, n ­
n
n
A sisotfte hdpe r eseofnlcaern guem beorfes n larroguends dyenda vpetsiicc les
(107).
MUSCLEA scattleoorsfmes ud s cfilbeea rnsrd e placbeycm oennnte ctive
tisasnufdea hta vbee efno uinnhd u mapna tiienln atstste a ogfeT OsC P
poiso(n40i)nS.gp ontafinberoiulspl oatteinowtnii trahul nsos fh igfhr e­
quendciys chwaerrgreee sp oritnee lde ctromysotgurdaoipfmeh usis cc les
ofT OCP-poicsaot(ns1e 0dL2 e)g.m uscflreosmm a nhye ntsr eawtietdh
leptosphhoowdsei ds soolfmu ittioocnh osnadrrcioapr,le atsimciaucnl du m,
518 ABOU-DONIA
othseurb celolruglaanr(e 6l2lW)ei.sn mgu scflreo amc hicekxehni bited
sevefroaoclifs malaln,g ulaattreodpfi hbiecr s.
ElectrophysiSotluodgiiceasl
Earfliyn dhianvglese t dot hceo nclutshianoten i tthhemeru scfliebn eorr
theen pdl awteersae ff ecitnae ndi meaxlhsi bdietliannygee udr otoaxnidc ity
that dmaumsabtgec e e nttrota hle sster uc(t1u6rR)ee.sc esnttu dhiaevse
g utiltihzpeeh de nomeonfro enp etitive eloefcp torsitctaelt aancitci vity
s.or stimuilnru ess potnohs iegf hr equency sotfsi omluemluoastt onireo rnv e
w
e toq uantitate moefca asmtuo rteonmree rntvtee r mifnuanlc tiinvo inv o
vi
alre (122-1U2s4i)tn.hgt i esc hnique,e taL l(o 1w2n15d2,e6s s)u ggetshtaetd
nu ani niftuinaclt dieofinciainlct a ttsr eabtyae ndi ntraairntjeercoitfail o n
n
m arjournals.anal use only. tDoieFnnfrePjot emu comriicoopynntuaklr a hrr aaailberttcltnsy er eoe hj delrf eec ghey caeiv totcnnelefsamedlid uoor m sftt(afbe oh1tusoder2inr 7ocien)ntgnem. iidro onivRtnfanIaeeoarlgnx rclo stjo o m.hoewnvis efchsmeoum ti,ofrObpci l tyFaaooeo PciDlni r urFl n tmPatnee toe ne rtrv ael
oo
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548. n 06/ BiochemiSctauld ies
11-Y o
81.21:5ERSIT eINvHeIinBndtI e TlIOaOFnNy Ee eSudTrE oRAStEowSxAa ilpscdh irotis(ydp1 gh3eos0 ru)oyg felg saetttsehitraoteAatnhd rs ie oen lfsieo.t r i al
9V braAiCnh E( 13in1 t)h mee chanoifds eml anyeeudr otowxaihscy iptoyt he­
ol. 1UNI sizHeodw.e vEearr&,l T homps(o1n31 23,3s )h owtehdaw th ihleebn r ain
oxicKE pseudochol[ibnuetsytreyrlacsheo( lBiunCehEsECt,3 e .r1a.sw1ea. ss8 e)­]
TU
acol. by D BlueCchtwEiia vnsteh hlipeybbr iyiTt mOeaCdrP Ay,iC nhtd Eaew rlagasuney neteau dffr eocTtthoeTexpdhyir.i hco syip ptotoysht.eah dte sis
m
ar hass ubsequbeeneetnll iym inbaytt hefied n dintghsa( t)a s omneo n­
h
v. P neurotoxailcsi one hsitBbeuirCtshi Ent hsea mwea y( 13a4n)(d bt)r i-4-
Re ethylphenyla npdoh tohsceporhm aptoeuc nadusds eel anyeeudr otoxicity
u. budto n ostu pprheesnbs r aBiunC h(E1 35).
n
An Poul&s Aelnd ri(d1g3pe6 o)i notuettdh set rucstiumriallba ertiwteye n
botphh enpyhle nyla(cPePtAaa)nt dep henyl-3-phen(yPlPpPr)o pionate
ansda ligceyncioln-i tco plhyols phtahnteee u,r otmoextiacbp orloidtuec ed
inv ivaof taed ro soefT OCP( 848,6 T)h.e oirri gsiungagle tshtaibtor na in
esterwahsiechshy droPlPyA z aen dP PPm ayb es elecitnihvieblbiyyt ed
delanyeeudr otoorxgiacn ophoesspthheoarrdstu osb ea bandohnoe­wd,
eveSru.b qsueesnttu dwiietashr anogfeo rganophosphorus compounds
faitloce odn fciorrmr elbaettiwoOenPesIn O aNn idn hibeiffteoocrfety i ther
oft heesnez ymienvs i v(o1 37).
ORGANOPHOSPHORUNSE UROTOXICITY 519
THEORYO F NEUROTOXIECS TERAS(EN TE)I nb otihnv ivaon di n
vitsrtou dJioehsn,(s 1o3n8 -1s4h0o)w aed di fferienin nchei beiffteoocnrt y
hebnr aeisnt earcatsiebv eittwyke neonw dne lanyeeudr oatnodnx oinc­
neuroctoomxpiocu An sdmsa.pl rlo por(6t%i)oo fnt hteo tPaPlA o-r
phenvyall erate-ahcytdirivonhil etybnyzr i ainissgnu scetpoit nihbilbei tion
onlbyyd elayed neurotsouxcaihsmc i pcao(fm1op4x1oC )uo.nm dpso unds
nocta paobfpl reo ducing delayseudca hspn aeruaroodxtonoo onxt,i city,
org inhitbheiintsz ymaacttii(cv1 i42tJ)yo. h ncsaolntl heeidns z ymaacttiicv ity
ws. neurotoexsitceo rraN sTeE ( 15a)n dp ropotsheaidttr eprestehnet ed
e
vi primsairotyfea ctioofnn e urootrogxainco phocsopmhpooruTunhsde s .
e
alr so-cnaelulreodet sotxeiercxa pslea nhaantsoi btoe neu nn ivearcscaelpltye d
u
n
an as thien ittairafgloe drte lanyeeudr otohxoiwceivfteoytrr,h, f e o llowing
om arjournals.onal use only. rabeet1.acaT dosxhpemoieeaveans re sta(l:el9o2 ray) panz sidse csi edor s .me a pscltttreoiogetrv rceeieoldtavy tybte h ytera 5hren0te d% io mtfneh oa ermn abilem faolr eh as
oaded frFor pers ca2.rS boaammcceiai chrd absva)bem se atestrnyeu nsct thrueearslnaiafdtlzto olPeeu yPAtddn o di( nphhieNabnTniyEadtlb c -etnizvyilt y
wnl10. (143H)o.w evneeri,t shienrng olrree peadtoesodef st hecsaer bamates
Do29/ proddueclea nyeeudr otoixnci hciictk(y1e 4n4Ts)h .e rsees uwletraset ­
548. n 06/ tribtuott heiedn staobfti hliein thyi beintzey(dm1 e3 8).
11-Y o 3.S ompeh osphiannadst uelsf folnuyolr pirdoedsau s ctea pbhloes ­
21:5SIT phinyolras tueldf oneynlzaytTmeheder. a otfer etutrnoo rigaicntailv ity
81.ER inv ivisosi mitlota hraa ftt ijenerc toifto hdnee lanyeeudr oetsotxDeiFrcP
ol. 19UNIV c(9a1,u4 s4Oi)YP.neI gctD o NTm.ope oxupbnletdalhsioe nnfst gieotin hndeigicst wnle aga ssssa usrgenegso ec ttsa htpaNeatTdob E fl e
oxicKE inhiwbiitttheh dee ssetc earnsn ot "uangdietnrhgguc,osa" u sniodn egl ayed
TU
acol. by D ne4u.Tr hosett o(rx1oi4nsc4gui)ept.spoy toft r htNe T Eh ypotchaemsfeir sot mhc eo rrela­
m
ar tiobnest wteheienn hibeiffteoocfrmt ya noyr ganophocsopmhpooruunsd s
h
v. P onN TEa ntdh eaibri ltiopt ryo ddueclea nyeeudr otoixnhi ecn(is9t )y.
Re Howevtehre,cs oer relhaatvnieoo btne se cno nsismtaeinnttlaFyio nre d.
nu. examapllteh,so euvgehdr iamle pthhoysl pchaauthseiesgi hn hiboiftt hieo n
n
A braNiTnE t,h sea mdeo sperso dnuoca et aixnih ae n(s14 5).
5.T heN TEh anso bte eins olaantidet pdsh ysiolobgiiocc heamnidc al
functairnoeon ktsn ow(n14 6).
6.T hihsy potdhoeenssoie tsx plsapiencs ieelse cotrai gvseie tnys itivity,
sincea cNtTiEhv abiset eyfn o uinnsd u sceapntndio bnlseu scseppetciibelse
andi nt hyeo unagsw elalst haed ualnti m(a89l, ) T.h ucsh,i caknsd
insensspietcidivienedso d te veOlPoIpD aNft esri ndgolseoe fds e layed
neuroatgoexnietcvs et,nh outghhen ieru roetsotxeiwrcaa issn eh ibited.
7.T hiesn zymatiicps r aecstieinnnv otin tnyea uswr eaasll ln eutriasls ue
520 ABOU-DONIA
oft hhee (n1 4T7h)u.ns o,n spbeicnidfiiiescnx gp ectoto ecdci unnr o ntarget
organs.
8.E xcefpottrh TeO CPm etaboslailtiegc,ey ncoil-nit cop lhyols phate,
theirsle i tsttlreu crteusreamlb bleatnwcteehe senu bstursaettdoea ss say
NTEa ctiavniodtt yhn eeru rotoxic orgeasntoeep.rhmgsoi.,sp pahfoorxu.s
Desptihteeex planoaffteirotenoads n umboeftr h epsoei ntthsei,rsn e o
conclusiovfte h teph reooaorsyfy e t.
g
or
ws. THES IGNIFICAONFC EI NHIBITIOOFN N ONSPECIFEISCT ERASES
e
vi Althotuhgiehn ietvieainlnOt P IDiNsg enerallyt ob bete hlpeih eovse­d
e
alr phoryloafats ipoencp irfoiticent i hnne e rvous tshpyehs otsepmh,o rylation
u
n
n ofn onspepcrifioct eiinncsl,uB duiCnhagEn NdT Em,a yp laayni mportant
a
om arjournals.onal use only. tsrteoeheilmeetxnedmp oph e o oadvrasveeaaneeplrs id ooyotm otp rfrsaftsm rotal h eongoffistsinm rn hysft aaienf o cgt dorueytrr et Nho tffeIeemhen nusoeceoiref.ttmnto h .tittoe aachorpsrlhbxigregleiisao eymnc ntt,id owem L ciphiaaanhinytplgocase hers sh csoro.ap ttw,t sh e­ e orcrstu s
oaded frFor pers eesvtetesrhrl,eso ps,wrre leo ylt emebaaiysaync re soed nv terrptisrobdio uebctvloeeeersi l snto, hpoc emfOo ePunIrotDsft Ne Bu. orn uonvde r
wnl10. oft hepsreo terienatsch,hne e urototxaircgTiehtteay.yc cumualtta htee
Do29/ neurototxairucgniettttiy hl er ye aacm hi nimum aomrto hurnetst hhoaltd
548. n 06/ cauOsPeIsD NA.t hreshoclodu blleode b vtealif nroemds iano grml uel ti­
11-Y o pleex posTuhrete ism.re e quifroterhd ne o nspebciinfidrcie nlge,aa nsde ,
21:5SIT accumuloaftt hioeor ng anophoesspthaeottrr h unese urototxaircgietty
81.ER maya ccoautln eta isnpt a rftot rh tey pidceallpa eyr iboedf oorneso eft
ol. 19UNIV ataxia faos lilnaogdwlmiein ng istration.
oxicKE EFFECOTN ACIDP HOSPHATAASCET IVITPYl asamcaip dh osphatase
TU
acol. by D adcetpieivnnmidcaternynen ti(aen 6asr 11le h4,lde8 T n)ths.rie en acwtrieetaldahce s ippedhtd oo osprpTh hOoaaCsctP ita naiis d vnehoi estney ­
m
ar plasimnad icpaotsesisinv b ilvleoa biolfli ytsyo somal wmietmthbh rea nes
h
v. P releoafts heie sn zyLmeep. topahnodTs O CPm ayc aulsiev deamra ge,
Re whiicnht umw oullde atdor eleoafas ceip dh osphTahtiamsse ec.h anism
nu. iisn a greewmiettnhhtf e i nd(i1n4tg9h )am ta latrheiloenaa rsyelds ulfatase
n
A frorma lti vleyrs osomes.
Iti sa lspoo sstihbalttehs eo urocfae c ipdh osphiasnt earstveie s sue
lysosTohmiesssu .g geisist nia ognr eewmietnththi en crienaa csiepd h os­
phataacstei ivnni etryva ennsde uroogfTl OiCaP -trheean(ts5e 2dT) h.e se
resuhlatvlsee tdo t hseu ggetshtailtoy ns oseonmzaylmm easyp laayn
imporrtoalnett hdieen v eloopfmn eenrdtve eg ene(r6a1t1,4i 8oT)nh. i s
hypotihasel sisinohs a rmowniytt hhfi en ditnhgat thm ee mbrpaenrem ea­
biloiftl yys osoofmi ensj ucreeludln sd ercghoaensdg uersi ng Wallerian
degene(r1a5t0i)o.n