;PMID: 8847965 ;source_file_1731.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..37] = [t:0..37] ;1)sentence:[e:43..226] = [t:43..226] ;2)section:[e:230..286] = [t:230..286] ;3)section:[e:290..361] = [t:290..361] ;4)sentence:[e:365..515] = [t:365..515] ;5)sentence:[e:516..623] = [t:516..623] ;6)sentence:[e:624..716] = [t:624..716] ;7)sentence:[e:717..824] = [t:717..824] ;8)sentence:[e:825..927] = [t:825..927] ;9)sentence:[e:928..1026] = [t:928..1026] ;10)sentence:[e:1027..1175] = [t:1027..1175] ;11)sentence:[e:1176..1412] = [t:1176..1412] ;12)sentence:[e:1413..1540] = [t:1413..1540] ;13)sentence:[e:1541..1726] = [t:1541..1726] ;14)section:[e:1730..1774] = [t:1730..1774] ;section 0 Span:0..37 ;Life Sci. 1995 Nov 17;57(26):2439-46. (SEC (FRAG (NNP:[0..4] Life) (NNP:[5..8] Sci) (.:[8..9] .) (CD:[10..14] 1995) (IN:[15..18] Nov) (CD:[19..24] 17;57) (-LRB-:[24..25] -LRB-) (CD:[25..27] 26) (-RRB-:[27..28] -RRB-) (CD:[28..33] :2439) (CD:[33..36] -46) (.:[36..37] .))) ;sentence 1 Span:43..226 ;Studies on the metabolism of haloperidol (HP): the role of CYP3A in the ;production of the neurotoxic pyridinium metabolite HPP+ found in rat brain ;following ip administration of HP. ;[72..83]:substance:"haloperidol" ;[85..87]:substance:"HP" ;[102..107]:cyp450:"CYP3A" ;[145..166]:substance:"pyridinium metabolite" ;[167..171]:substance:"HPP+" ;[223..225]:substance:"HP" (SENT (NP-HLN (NP (NP (NNS:[43..50] Studies)) (PP (IN:[51..53] on) (NP (NP (DT:[54..57] the) (NN:[58..68] metabolism)) (PP (IN:[69..71] of) (NP (NP (NN:[72..83] haloperidol)) (NP (-LRB-:[84..85] -LRB-) (NN:[85..87] HP) (-RRB-:[87..88] -RRB-))))))) (::[88..89] :) (NP (NP (DT:[90..93] the) (NN:[94..98] role)) (PP (IN:[99..101] of) (NP (NN:[102..107] CYP3A))) (PP (IN:[108..110] in) (NP (NP (DT:[111..114] the) (NN:[116..126] production)) (PP (IN:[127..129] of) (NP (NP (NP (DT:[130..133] the) (JJ:[134..144] neurotoxic) (NN:[145..155] pyridinium) (NN:[156..166] metabolite)) (NP (NN:[167..170] HPP) (SYM:[170..171] +))) (VP (VBN:[172..177] found) (NP (-NONE-:[177..177] *)) (PP-LOC (IN:[178..180] in) (NP (NN:[181..184] rat) (NN:[185..190] brain))) (S-TMP (NP-SBJ (-NONE-:[190..190] *)) (VP (VBG:[192..201] following) (NP (NP (JJ:[202..204] ip) (NN:[205..219] administration)) (PP (IN:[220..222] of) (NP (NN:[223..225] HP)))))))))))) (.:[225..226] .))) ;section 2 Span:230..286 ;Igarashi K, Kasuya F, Fukui M, Usuki E, Castagnoli N Jr. (SEC (FRAG (NNP:[230..238] Igarashi) (NNP:[239..241] K,) (NNP:[242..248] Kasuya) (NNP:[249..250] F) (,:[250..251] ,) (NNP:[252..257] Fukui) (NNP:[258..260] M,) (NNP:[261..266] Usuki) (NNP:[267..268] E) (,:[268..269] ,) (NNP:[270..280] Castagnoli) (NNP:[281..282] N) (NNP:[283..285] Jr) (.:[285..286] .))) ;section 3 Span:290..361 ;Faculty of Pharmaceutical Sciences, Kobegakuin University, Kobe, Japan. (SEC (FRAG (IN:[290..297] Faculty) (IN:[298..300] of) (NNP:[301..315] Pharmaceutical) (NNPS:[316..324] Sciences) (,:[324..325] ,) (NNP:[326..336] Kobegakuin) (NNP:[337..347] University) (,:[347..348] ,) (NNP:[349..353] Kobe) (,:[353..354] ,) (NNP:[355..360] Japan) (.:[360..361] .))) ;sentence 4 Span:365..515 ;The levels of haloperidol (HP) and its pyridinium metabolite HPP+ were ;estimated in plasma and brain tissues of rats treated i.p. with HP (10 ;mg/kg). ;[379..390]:substance:"haloperidol" ;[392..394]:substance:"HP" ;[404..425]:substance:"pyridinium metabolite" ;[426..430]:substance:"HPP+" ;[501..503]:substance:"HP" ;[505..507]:quantitative-value:"10" ;[508..513]:quantitative-units:"mg/kg" (SENT (S (NP-SBJ-1 (NP (DT:[365..368] The) (NNS:[369..375] levels)) (PP (IN:[376..378] of) (NP (NP (NP (NN:[379..390] haloperidol)) (NP (-LRB-:[391..392] -LRB-) (NN:[392..394] HP) (-RRB-:[394..395] -RRB-))) (CC:[396..399] and) (NP (NP (PRP$:[400..403] its) (NN:[404..414] pyridinium) (NN:[415..425] metabolite)) (NP (NN:[426..429] HPP) (SYM:[429..430] +)))))) (VP (VBD:[431..435] were) (VP (VBN:[436..445] estimated) (NP-1 (-NONE-:[445..445] *)) (PP-LOC (IN:[447..449] in) (NP (NP (NP (NN:[450..456] plasma)) (CC:[457..460] and) (NP (NN:[461..466] brain) (NNS:[467..474] tissues))) (PP (IN:[475..477] of) (NP (NP (NNS:[478..482] rats)) (VP (VBN:[483..490] treated) (NP (-NONE-:[490..490] *)) (ADVP (RB:[491..495] i.p.)) (PP (IN:[496..500] with) (NP (NP (NN:[501..503] HP)) (PP (-LRB-:[504..505] -LRB-) (NP (NP (CD:[505..507] 10) (NN:[508..510] mg)) (PP (SYM:[510..511] /) (NP (NN:[511..513] kg)))) (-RRB-:[513..514] -RRB-))))))))))) (.:[514..515] .))) ;sentence 5 Span:516..623 ;HP and HPP+ levels in plasma decreased linearly during the 0-3 hour period ;following drug administration. ;[516..518]:substance:"HP" ;[523..527]:substance:"HPP+" ;[576..579]:quantitative-value:"0-3" ;[580..584]:quantitative-units:"hour" ;[602..606]:substance:"drug" (SENT (S (NP-SBJ (NP (NP (NML (NN:[516..518] HP)) (NML-1 (-NONE-:[518..518] *P*))) (CC:[519..522] and) (NP (NML (NN:[523..526] HPP) (SYM:[526..527] +)) (NML-1 (NNS:[529..535] levels)))) (PP-LOC (IN:[536..538] in) (NP (NN:[539..545] plasma)))) (VP (VBD:[546..555] decreased) (ADVP (RB:[556..564] linearly)) (PP-TMP (IN:[565..571] during) (NP (NP (DT:[572..575] the) (NML (QP (CD:[576..577] 0) (HYPH:[577..578] -) (CD:[578..579] 3)) (NN:[580..584] hour)) (NN:[585..591] period)) (VP (VBG:[592..601] following) (NP (NN:[602..606] drug) (NN:[608..622] administration)))))) (.:[622..623] .))) ;sentence 6 Span:624..716 ;On the other hand, HPP+ levels in brain tissues increased gradually during ;the same period. ;[643..647]:substance:"HPP+" (SENT (S (PP (IN:[624..626] On) (NP (DT:[627..630] the) (JJ:[631..636] other) (NN:[637..641] hand))) (,:[641..642] ,) (NP-SBJ (NP (NML (NN:[643..646] HPP) (SYM:[646..647] +)) (NNS:[648..654] levels)) (PP-LOC (IN:[655..657] in) (NP (NN:[658..663] brain) (NNS:[664..671] tissues)))) (VP (VBD:[672..681] increased) (ADVP-MNR (RB:[683..692] gradually)) (PP-TMP (IN:[693..699] during) (NP (DT:[700..703] the) (JJ:[704..708] same) (NN:[709..715] period)))) (.:[715..716] .))) ;sentence 7 Span:717..824 ;HPP+ levels in brain tissues increased further when HP (10 mg/kg) was ;injected for three consecutive days. ;[717..721]:substance:"HPP+" ;[770..772]:substance:"HP" ;[774..776]:quantitative-value:"10" ;[777..782]:quantitative-units:"mg/kg" ;[801..806]:quantitative-value:"three" ;[819..823]:quantitative-units:"days" (SENT (S (NP-SBJ (NP (NML (NN:[717..720] HPP) (SYM:[720..721] +)) (NNS:[722..728] levels)) (PP-LOC (IN:[729..731] in) (NP (NN:[732..737] brain) (NNS:[738..745] tissues)))) (VP (VBD:[746..755] increased) (ADVP-EXT (RBR:[756..763] further)) (SBAR-ADV (WHADVP-2 (WRB:[765..769] when)) (S (NP-SBJ-1 (NN:[770..772] HP) (PRN (-LRB-:[773..774] -LRB-) (NP (NP (CD:[774..776] 10) (NN:[777..779] mg)) (PP (SYM:[779..780] /) (NP (NN:[780..782] kg)))) (-RRB-:[782..783] -RRB-))) (VP (VBD:[784..787] was) (VP (VBN:[788..796] injected) (NP-1 (-NONE-:[796..796] *)) (PP-TMP (IN:[797..800] for) (NP (CD:[801..806] three) (JJ:[807..818] consecutive) (NNS:[819..823] days))) (ADVP-TMP-2 (-NONE-:[823..823] *T*))))))) (.:[823..824] .))) ;sentence 8 Span:825..927 ;The formation of HPP+ also was studied in rat brain mitochondrial and liver ;microsomal preparations. ;[843..847]:substance:"HPP+" (SENT (S (NP-SBJ-3 (NP (DT:[825..828] The) (NN:[829..838] formation)) (PP (IN:[839..841] of) (NP (NN:[843..846] HPP) (SYM:[846..847] +)))) (ADVP (RB:[848..852] also)) (VP (VBD:[853..856] was) (VP (VBN:[857..864] studied) (NP-3 (-NONE-:[864..864] *)) (PP-LOC (IN:[865..867] in) (NP (NP (NML-1 (NN:[868..871] rat)) (NN:[872..877] brain) (JJ:[878..891] mitochondrial) (NML-2 (-NONE-:[891..891] *P*))) (CC:[892..895] and) (NP (NML-1 (-NONE-:[895..895] *P*)) (NN:[896..901] liver) (JJ:[902..912] microsomal) (NML-2 (NNS:[914..926] preparations))))))) (.:[926..927] .))) ;sentence 9 Span:928..1026 ;Enzyme activity responsible for the conversion of HP to HPP+ was not found ;in brain mitochondria. ;[928..934]:substance:"Enzyme" ;[978..980]:substance:"HP" ;[984..988]:substance:"HPP+" (SENT (S (NP-SBJ-1 (NP (NN:[928..934] Enzyme) (NN:[935..943] activity)) (ADJP (JJ:[944..955] responsible) (PP (IN:[956..959] for) (NP (NP (DT:[960..963] the) (NN:[964..974] conversion)) (NP (IN:[975..977] of) (NP (NN:[978..980] HP))) (PP (TO:[981..983] to) (NP (NN:[984..987] HPP) (SYM:[987..988] +))))))) (VP (VBD:[989..992] was) (RB:[994..997] not) (VP (VBN:[998..1003] found) (NP-1 (-NONE-:[1003..1003] *)) (PP-LOC (IN:[1004..1006] in) (NP (NN:[1007..1012] brain) (NNS:[1013..1025] mitochondria))))) (.:[1025..1026] .))) ;sentence 10 Span:1027..1175 ;Liver microsomal enzymes catalyzed the oxidation of HP and its ;tetrahydropyridine dehydration product HPTP to HPP+ with about the same ;efficiency. ;[1044..1051]:substance:"enzymes" ;[1080..1082]:substance:"HP" ;[1091..1109]:substance:"tetrahydropyridine" ;[1130..1134]:substance:"HPTP" ;[1138..1142]:substance:"HPP+" (SENT (S (NP-SBJ (NN:[1027..1032] Liver) (JJ:[1033..1043] microsomal) (NNS:[1044..1051] enzymes)) (VP (VBD:[1052..1061] catalyzed) (NP (NP (DT:[1062..1065] the) (NN:[1067..1076] oxidation)) (PP (IN:[1077..1079] of) (NP (NP (NN:[1080..1082] HP)) (CC:[1083..1086] and) (NP (PRP$:[1087..1090] its) (NP (NP (NN:[1091..1109] tetrahydropyridine) (NN:[1110..1121] dehydration) (NN:[1122..1129] product)) (NP (NN:[1130..1134] HPTP)))))) (PP (TO:[1135..1137] to) (NP (NN:[1138..1141] HPP) (SYM:[1141..1142] +)))) (PP-MNR (IN:[1143..1147] with) (NP (RB:[1149..1154] about) (DT:[1155..1158] the) (JJ:[1159..1163] same) (NN:[1164..1174] efficiency)))) (.:[1174..1175] .))) ;sentence 11 Span:1176..1412 ;Studies employing several cytochrome P450 inhibitors and anti-cytochrome ;P450 antibodies were carried out in an effort to identify the forms of ;cytochrome P450 that are responsible for catalyzing the oxidation of HP and ;HPTP to HPP+. ;[1202..1217]:cyp450:"cytochrome P450" ;[1218..1228]:substance:"inhibitors" ;[1234..1265]:substance:"anti-cytochrome P450 antibodies" ;[1322..1337]:cyp450:"cytochrome P450" ;[1392..1394]:substance:"HP" ;[1399..1403]:substance:"HPTP" ;[1407..1411]:substance:"HPP+" (SENT (ADJP (NP-SBJ-2 (NP (NNS:[1176..1183] Studies)) (VP (VBG:[1184..1193] employing) (NP (JJ:[1194..1201] several) (NP (NML (NN:[1202..1212] cytochrome) (NN:[1213..1217] P450)) (NNS:[1218..1228] inhibitors)) (CC:[1230..1233] and) (NP (NML (AFX:[1234..1238] anti) (HYPH:[1238..1239] -) (NN:[1239..1249] cytochrome) (NN:[1250..1254] P450)) (NNS:[1255..1265] antibodies))))) (VP (VBD:[1266..1270] were) (VP (VBN:[1271..1278] carried) (PRT (RP:[1279..1282] out)) (NP-2 (-NONE-:[1282..1282] *)) (PP (IN:[1283..1285] in) (NP (NP (DT:[1286..1288] an) (NN:[1289..1295] effort)) (SBAR (WHNP-3 (-NONE-:[1295..1295] 0)) (S (NP-SBJ-3 (-NONE-:[1295..1295] *)) (VP (TO:[1296..1298] to) (VP (VB:[1299..1307] identify) (NP (NP (NP (DT:[1309..1312] the) (NNS:[1313..1318] forms)) (PP (IN:[1319..1321] of) (NP (NN:[1322..1332] cytochrome) (NN:[1333..1337] P450)))) (SBAR (WHNP-1 (WDT:[1338..1342] that)) (S (NP-SBJ-1 (-NONE-:[1342..1342] *T*)) (VP (VBP:[1343..1346] are) (ADJP-PRD (JJ:[1347..1358] responsible) (PP (IN:[1359..1362] for) (S-NOM (NP-SBJ (-NONE-:[1362..1362] *)) (VP (VBG:[1363..1373] catalyzing) (NP (NP (DT:[1374..1377] the) (NN:[1378..1387] oxidation)) (PP (IN:[1389..1391] of) (NP (NN:[1392..1394] HP) (CC:[1395..1398] and) (NN:[1399..1403] HPTP))) (PP (TO:[1404..1406] to) (NP (NN:[1407..1410] HPP) (SYM:[1410..1411] +)))))))))))))))))))) (.:[1411..1412] .))) ;sentence 12 Span:1413..1540 ;The formation of HPP+ in liver microsomes was strongly inhibited by ;ketoconazole and nifedipine and by an anti-CYP3A antibody. ;[1430..1434]:substance:"HPP+" ;[1482..1494]:substance:"ketoconazole" ;[1499..1509]:substance:"nifedipine" ;[1520..1539]:substance:"anti-CYP3A antibody" (SENT (S (NP-SBJ-1 (NP (DT:[1413..1416] The) (NN:[1417..1426] formation)) (PP (IN:[1427..1429] of) (NP (NN:[1430..1433] HPP) (SYM:[1433..1434] +))) (PP-LOC (IN:[1435..1437] in) (NP (NN:[1438..1443] liver) (NNS:[1444..1454] microsomes)))) (VP (VBD:[1455..1458] was) (ADVP (RB:[1459..1467] strongly)) (VP (VBN:[1469..1478] inhibited) (NP-1 (-NONE-:[1478..1478] *)) (PP (PP (IN:[1479..1481] by) (NP-LGS (NN:[1482..1494] ketoconazole) (CC:[1495..1498] and) (NN:[1499..1509] nifedipine))) (CC:[1510..1513] and) (PP (IN:[1514..1516] by) (NP-LGS (DT:[1517..1519] an) (NML (AFX:[1520..1524] anti) (HYPH:[1524..1525] -) (NN:[1525..1530] CYP3A)) (NN:[1531..1539] antibody)))))) (.:[1539..1540] .))) ;sentence 13 Span:1541..1726 ;These results suggest that formation of HPP+ from HP and HPTP in rat liver ;microsomes is catalyzed mainly by CYP3A although the participation of other ;P450 forms cannot be ruled out. ;[1582..1586]:substance:"HPP+" ;[1592..1594]:substance:"HP" ;[1599..1603]:substance:"HPTP" ;[1652..1657]:cyp450:"CYP3A" ;[1694..1698]:cyp450:"P450" (SENT (S (NP-SBJ (DT:[1541..1546] These) (NNS:[1548..1555] results)) (VP (VBP:[1556..1563] suggest) (SBAR (IN:[1564..1568] that) (S (NP-SBJ-1 (NP (NN:[1569..1578] formation)) (PP (IN:[1579..1581] of) (NP (NN:[1582..1585] HPP) (SYM:[1585..1586] +))) (PP (IN:[1587..1591] from) (NP (NN:[1592..1594] HP) (CC:[1595..1598] and) (NN:[1599..1603] HPTP))) (PP (IN:[1604..1606] in) (NP (NN:[1607..1610] rat) (NN:[1611..1616] liver) (NNS:[1617..1627] microsomes)))) (VP (VBZ:[1629..1631] is) (VP (VBN:[1632..1641] catalyzed) (NP-1 (-NONE-:[1641..1641] *)) (ADVP (RB:[1642..1648] mainly)) (PP (IN:[1649..1651] by) (NP-LGS (NN:[1652..1657] CYP3A))) (SBAR-ADV (IN:[1658..1666] although) (S (NP-SBJ-2 (NP (DT:[1667..1670] the) (NN:[1671..1684] participation)) (PP (IN:[1685..1687] of) (NP (JJ:[1688..1693] other) (NN:[1694..1698] P450) (NNS:[1699..1704] forms)))) (VP (MD:[1706..1712] cannot) (VP (VB:[1713..1715] be) (VP (VBN:[1716..1721] ruled) (PRT (RP:[1722..1725] out)) (NP-2 (-NONE-:[1725..1725] *)))))))))))) (.:[1725..1726] .))) ;section 14 Span:1730..1774 ;PMID: 8847965 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1730..1734] PMID) (::[1734..1735] :) (CD:[1736..1743] 8847965) (NN:[1744..1745] -LSB-) (NNP:[1745..1751] PubMed) (::[1752..1753] -) (NN:[1754..1761] indexed) (IN:[1762..1765] for) (NNP:[1766..1774] MEDLINE-RSB-)))