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I Nhibition by Folate Derivatives, Folate

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I Nhibition by Folate Derivatives, Folate ,r', ,i$ìffi&bìls r8t-'tt öÚ.'t (x)21 l()4?/¡r?/01() I -(X¡'ì8/$02. 75/{t s I rY J o ur ntl rtJ N e urt'( ht tttt RÍìvetr ll'ess, Now Yolk ,';,^* - il';!'l iei ìrtz ln,"tno,ional Society lirr Ncurrrhcmistry f CcËç y drofo late In Vitn¡ Studies of 5, iO- fvf . t h y l e ne tetrah v v\) FolateL Reductase: Il nhibitionnhtbttton byDy Folater olatç Derivatives,L)çr I v cLLr ' Antagonists, and Monoamine Derivatives Hontmcs"l'h' J' J' M' vAr-t de Wiel' 'r'J. [-' Hollinger' O' R' -f i. C. N. Kok' ancl M' 'l' ' Jansen N i'i ttt t g c tt t t N t' Í h<' rl u ntl't l )t' ptt rl tttt t t l tll N t' rt rtt lt t gt" "l'l an inhibitory Abstract: F.r¿rte rn.nogrutarnates and foratc antag()nists .have activitvaclrvrtv .,i"''ìiil'"i"ìiti-ìì"t..t"r'v¡','l-l'l.l,t:.:1:':iì:,'Î,iÎl':'i'il; ¿rctio,r:rctiorr on thetnt: "' ;l'i,i"'iirìi;;.J'f..;; üilrv'trofolic itcitl using the Ihe tYPe of inhibititr alkaloids' the in t,"n'ü"'ì*'iit"t' iu*e of !h9 ni..rnoamine [-ineweavcr.--gr.k reductase, have either a Iif|o pr.oducts of 5,,,,ìì"iiìvi"ìì"ì.,ti,,hy,trnf.rlare Key Words:5'10- or inhibitort on thc en/yrne activity' stinrulittoly "ft¡tt tler-iv¿rtives-F'olate antago- Mcthyle'etetrahytlr..liríirt"."i".1,r.,,,r"-pol¿rtc tt,rttirrg"r J. t. et al. rtt t'itro studies of 5,10- rrists_Monoan'in" ¡",iu,ìi¡u".. ives, fo- l nhibition bv tblate de rivat merhy leneter rur,v¡r.rti, iuìï' i"¡u.ìr.r"," j 642 tlerivatives' ' Ñ''u"'t'htnr' 38' 638- l4tc antagonists, antì "tt'ãtlt*¡"" il9ti2). lc' with irrclolamines of 1,2,3, -Ietrahydro-p-carbo- 'l'he enzyme 5, l0-methylenetetrahydl-otìrlatc catalyzes the rc¿rçtron: line" s. cluctase lgC. t' 1.68) ;ii,. physiological and pathologica.l significance of H' * monoamine alkaloids is' -5,1O-methylene-TFlIì + NADPH I tn. ïo,lnlr,t¿ehyãe-derived F + NAI)l'' at pl't; sct'tt, being studied' -5-methYl-'l'H --- (1979) clemonstrated the ol' Rommelspachlr' et al' irr tlre pt'csence t he This reaction is revcl-siblc t rahvd ro-13.-c' arbt-rline' (Ktltz-birch irncl -; ti; ;;; o'r o-n vo.o vte nonspecific elcctrtln acccptol's " ^ antl formaldehy.de' both in 'i;;Ñ;¡, acid)' 'l'he alkaloitl fì-on.r serotoniñ l97l) (THþ- - tetrahvtl'ol'olic The alkaloid from tryptarnine ancl tìrr- le(ltlct.irsL' is cirpit' ,rìr,,.t rat. i,ió-î*ìitvLnetctrlhytllo[ol¿tlc ntrìiìüv¿""".r ( l'2,3'4-tetrahvclro-p-carboline) has I e nc tc t Iil h tl ro f'o I il tc' lri; ;ï-i;; i ng 5' I 0- nrc t h v v yivo in rat brain by Balkcr cl al' t'caction yie lds i-,""n l.fé",ifiecl irr *ñi.n because- oi an ec¡uilibl'itrm Folate compounds atlministet'ccl cxoge- rrcitl ( [)onalclson iiçr91. io.*.f¿"tty¿e and tetr¿,rhytlrolirlic to Lause convulsive activity (()b- plcscrìr'c trl' lrigh con- nously are known u"ni'ri"t=titesy, 196 I )'nln thc 1973;Hommes et al'' l97c)).'fhe a cycliz-irtitlrt tll thc tr."t Hommes, ."ntrntionti ott monoami¡rcs' ìr"ìil.iitiri""""¡ tlerivatives 4-rnethoxy<loptrnrine and monoa,,-'in"withformalclchydeoccllfs.sl]()nIiIl]L'. ancl 1,2,3'4-tetrahvd'.t.limeth- of an trlicyclic irl- Ñ-;;i;ti¡,rpaminc' il.i;, ;ì;h resultant tìrlm¿rtìon have also been shown to cause con- et al" 19751 yl-lì-c,aritlline kaloitl (l-ar-rwct's et al', 1975; Meller rat, wheleas the alkaloid of clopa- 't'h9 rettcri.n .f nrot.to- íui*ions in the R;r;;;s;,;a;; et al'. 1975)' anticonvulsant activity (Hollinger and fblmalclehvde ithc Pictet Spcnglcr' "ri,ì" "^r.tiults Experiments have been ;;i;;;-;i,h ss' Fi.;;;;t, rrnpublished)' is a well-establisher'l pt.tlce determine. t.he efÏècts condensation) ittc ;;;;; .iut, iheretbLe' to 'Ihe leaction pt'oclttcts with catcchol¿tnlitles recluctase activity' tln the atrd .if' tn"r" substances on ¿"riuutiu"t; o1' l'2'3,4-tetrahycL oistlquirltllirtcs' Nertrrrltrgy .litlìScn. Radboutl University Hospital, Laboratoly of 15, 198()l lcvisecl July l7' lgtll; acce¡rtctl Received SePtenrbel N iimcuen.'l'hc Netherlands. ' '',tli,iÏ,r'ri,,t¡,,,r 'f 'lctlahydrofolic lcitl' August 20, 1981. to M I 'l ¡rr¿,/: Hl', Address corresPontlettce antl reprinl lcqtlcsls ó.1¡i TNO 1 6422 drd;rÊ{, ,i ¡# lN Vl'fRO S'lL/Dtl''S Ot" 5,t0 Ilt',1'ttl'1,þ)NI:"l l:'l'llAlly'l)ROl''Ol,A'l'l'; llLl)ll("1'ASI:- ó39 asslrnlption tlrat the corìvrllsive bch¿rvitlul. irttlt¡cccl 'f'AlJl-h, l. K, t'ultrt.s tt.l li¡lult dtrirtttitas ttttl t I tt I tt t t I tt tt i,¡ 1.¡ t r t I t t 5, I 0- t t tt t I t t lt tt t' I t' I rtt- try tblate is dcpentle nl upotì the fìllnt¿rtiort of'¿rlklt- lì t' 11o li It¡'lnt litIttte t ( I u( l tt.\( Ioitls as ¿ì r'esult of rcductase activity. 50% inhibition MATERIAl-S AN D M[ì'I'TIOI)S t,lo.lll." c()nccntfation 5 l"('Inrethyltetlirhydrofìrlic ¿rcitl brrt ittnt sirll, spe cilic 1lll1"Ì,,',"', r' activity -57 ¡nCi/nrn"rol. was pulchasctl fi'oltt I{atlioche nti' l)ilrydnrlìrlic acitl 7.0 ¡ l(l | c¿rl (-'cntre, Anret'sharlr, Iirtglancl. fiolic acicl, tlihyrllofìrlic I.'olic acitl l.-5 x l0 'Ictlahydrofitlic acitl, tetrirhytllofi¡lic acitl, ttrcthott cxirte, pyt-intct hartlirrc, acitl ' 1.0 x l0'l 5 t -gltrtamic Mclhot|cxato 1.7 x l0 sotliunl glutarnate, ancl N-¡rat'lr at.tti nobcrrztlyl- l purchasctl (lhenrical Pyrrmethamine 3.7 x l0 acid were from Signra Co.4- l.[l x l0¡ tlerivative, .! ldcnosyl-t methioninc Methoxydopamine HCll, 4-rnethoxydoparninc N-¡r-anrinobenzoyl'r.-glutanric acitl Ncl inhibition epirrinc, epinine dcrivative, and 1.2,3,4-tctr-ahydlo-2,9- SotliLlrn glutamate Ntl inhibition dinrcthyl-p-carboline wcle gilis fì'onr P. L¿tdur-on, Jansse tl [)harrnaceutica, Bcerse, Belgiunt. [jach valt¡c rcpÌesenls the incubation concentrutitrn (rnolt:s/liter) ot inhibitor nccessary to procluce a 50%, Preparation of rat brain homogenates inhibition of e nzynte activity with 5-[!rC]rnethyltett'a- Wistal r'¿rts ol 160- 200 g botìy weight wele killetl by hydrolìrlic acitl (1.74 nnrol/litcr) üs methyl donor antl decapitation. 'lheir brains were rapidly removcd ¿tnd 4-nrcthoxydopamine as the fìrlmalclehytle-bincling sub- washetl in 0.25 tr¿-ccllcl sucrose. 'lhe conrpletc bt'ain was stancc in rat blain homogcnates. homogenized lbr I nrin in l0 vol. o1'0.2.5 tvt-cold sucr()sc with a Potter-Elvejhern hornogcnizer. 'l'he suspensittn was ccrrtriluged for 20 min at 6009 to Icmove ccll cleblis. bintling subst¿rncc.'l'he incubation mixture cc¡ntainecl ptrosphate pH 6.4, 150 'Ihe supernatanl was storetl at 20"C until t-cquircd fìrr' 100 ¡rl t).5 tr¡-sotliurlr buttet', ¡rl (jnzyrne assays. glass-distilled walel or I00 ¡rl of'various concentrations of firlatc delivatives ol rnonoarnine derivatives, and 50 ¡rl Enzyme assays in rat brain hornogenatcs glass-distillecl watcr'. 100 ¡rl 4-methoxytlopamine 0. I tr¡, 50 'l'he -5, lO-methylenetetlahydr-ofìrl¿rte reduclasc w¿rs cs- ¡rl -5-lr'('lnrcthyltetlahyth-ofìrlic acid ( 10.0 ¡¿Ci), antl 100 tirnated in the revelse dircction. We clid nr)t r-rsc ¿ur clec- ¡rl cnz-ynre pr-eparatitln. The blank was prepared without tron acceptor in the incubation lnixttl-e becattse wc usctl enzynrr or with boilctl cnzynrc. Aficr incubation for 2 h in clude enzyrne pl'e parâtions. Cl'utle homogcnates con- a w¿rter bath at 37"(', the reaction was stopped by adding tainccl oxidizing substances, such as IìAD,'strflìcient that 1.0 rul ol'ir 0.-5 n¿.sodium borate buf'ler pH 10.0.'l'he leac- addition of such elect¡on ¿ìcceptors did not firlher s¡imu- tion plotlucls wcrc extt'actcd in I0.0 ml of a tol- late the enzyme activily. Only purilìed enz-yme dctnon- ucne isoanryl alcohol 2:3 rnixtur-e tì'tlm the aqt¡eous strated a requilemcnt fbr oxidizing substances in thc en- phrrsc. ¡rlcviously satur-atecl with lg sodiunr chloritle. zyme ¿rss¿ry (stcbbins et al., 1976). Alìcl nrixing t¡n ¿r Vor-tex mixer for I min, the tubes were 'Ihe method we used was based on lhat of l-atlttnrn e I ccntlifugctl fìr' l-5 nrin at l-545 g. F-oul nrilliliters of the al. ( 1975) with 4-methoxydopamine as the tìrlm¿rldchyrle- olganic phasc wcr.c adtled to a vial with 10.0 ml trnstagel x D¡hydrofolic ac¡d o Tetrahydrolol¡c acid + fo¡ir acid in vitro . À'letlìotrexale o Pyrioìetlì¿nìine 5, I0 - methylenetetrahydrofolate adenosyl ÍÌethron¡ne reduclase æt¡vity against c0nc. z€ro + 5 l- r2q I I \a-- . -__\ -. -\_o ---+---o--ì\ \-- 0.00 concentrat¡on in mol / I FlG. 1. lnhibition of the 5,10-methylenetetrahydrofolate reductase activtty by various concentrations of folate derivatives and folate antagonists in rat bra¡n homogenates in vitro. Reductase activity was measured with 4-methoxydopamine as the formaldehyde-binding substance. J. Nt'ttrochttn., Vol. 18, N,t. 3, 1932 , tÌ.i ,' .¡t. .., .1 . _i:.,, "i: l : ¡ ':nll¡,, ()40 J.
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