;PMID: 8291265 ;source_file_1734.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..35] = [t:0..35] ;1)sentence:[e:41..188] = [t:41..188] ;2)section:[e:192..228] = [t:192..228] ;3)section:[e:232..342] = [t:232..342] ;4)sentence:[e:346..348] = [t:346..348] ;5)sentence:[e:349..623] = [t:349..623] ;6)sentence:[e:625..751] = [t:625..751] ;7)sentence:[e:752..881] = [t:752..881] ;8)sentence:[e:882..884] = [t:882..884] ;9)sentence:[e:885..998] = [t:885..998] ;10)sentence:[e:999..1173] = [t:999..1173] ;11)sentence:[e:1175..1177] = [t:1175..1177] ;12)sentence:[e:1178..1403] = [t:1178..1403] ;13)sentence:[e:1404..1406] = [t:1404..1406] ;14)sentence:[e:1407..1614] = [t:1407..1614] ;15)sentence:[e:1615..1617] = [t:1615..1617] ;16)sentence:[e:1618..1919] = [t:1618..1919] ;17)section:[e:1923..1967] = [t:1923..1967] ;section 0 Span:0..35 ;Xenobiotica. 1993 Sep;23(9):973-82. (SEC (FRAG (NNP:[0..11] Xenobiotica) (,:[11..12] .) (CD:[13..17] 1993) (CC:[18..25] Sep;23-LRB-) (CD:[25..26] 9) (-RRB-:[26..27] -RRB-) (::[27..28] :) (CD:[28..31] 973) (::[31..32] -) (CD:[32..34] 82) (.:[34..35] .))) ;sentence 1 Span:41..188 ;Microbial models of mammalian metabolism: involvement of cytochrome P450 in ;the N-demethylation of N-methylcarbazole by Cunninghamella echinulata. ;[98..113]:cyp450:"cytochrome P450" ;[141..158]:substance:"N-methylcarbazole" (SENT (NP-HLN (NP (NP (JJ:[41..50] Microbial) (NNS:[51..57] models)) (PP (IN:[58..60] of) (NP (JJ:[61..70] mammalian) (NN:[71..81] metabolism)))) (::[81..82] :) (NP (NP (NN:[83..94] involvement)) (PP (IN:[95..97] of) (NP (NN:[98..108] cytochrome) (NN:[109..113] P450))) (PP (IN:[114..116] in) (NP (NP (DT:[117..120] the) (NN:[122..137] N-demethylation)) (PP (IN:[138..140] of) (NP (NN:[141..158] N-methylcarbazole))) (PP (IN:[159..161] by) (NP (NNP:[162..176] Cunninghamella) (NNP:[177..187] echinulata)))))) (.:[187..188] .))) ;section 2 Span:192..228 ;Yang W, Jiang T, Acosta D, Davis PJ. (SEC (FRAG (NNP:[192..196] Yang) (NNP:[197..198] W) (,:[198..199] ,) (NNP:[200..205] Jiang) (NNP:[206..207] T) (,:[207..208] ,) (NNP:[209..215] Acosta) (NNP:[216..217] D) (,:[217..218] ,) (NNP:[219..224] Davis) (NNP:[225..228] PJ.))) ;section 3 Span:232..342 ;Division of Medicinal and Natural Products Chemistry, College of Pharmacy, ;University of Texas, Austin 78712. (SEC (FRAG (NNP:[232..240] Division) (IN:[241..243] of) (NNP:[244..253] Medicinal) (CC:[254..257] and) (NNP:[258..265] Natural) (NNP:[266..274] Products) (NNP:[275..284] Chemistry) (,:[284..285] ,) (NNP:[286..293] College) (IN:[294..296] of) (NNP:[297..305] Pharmacy) (,:[305..306] ,) (NNP:[308..318] University) (IN:[319..321] of) (NNP:[322..327] Texas) (,:[327..328] ,) (NNP:[329..335] Austin) (CD:[336..341] 78712) (.:[341..342] .))) ;sentence 4 Span:346..348 ;1. (SENT (NP (LS:[346..348] 1.))) ;sentence 5 Span:349..623 ;As previously reported (Yang and Davis 1992), N-methylcarbazole (NMC) is ;converted to N-hydroxymethylcarbazole (NHMC), and ;3-hydroxy-N-hydroxymethylcarbazole (3-OH-NHMC), two relatively stable ;carbinolamine metabolites by the fungus Cunninghamella echinulata (ATCC ;9244). ;[395..412]:substance:"N-methylcarbazole" ;[414..417]:substance:"NMC" ;[436..460]:substance:"N-hydroxymethylcarbazole" ;[462..466]:substance:"NHMC" ;[474..508]:substance:"3-hydroxy-N-hydroxymethylcarbazole" ;[510..519]:substance:"3-OH-NHMC" ;[545..570]:substance:"carbinolamine metabolites" (SENT (S (PP (IN:[349..351] As) (S-NOM (NP-SBJ (-NONE-:[351..351] *)) (VP (ADVP-TMP (RB:[352..362] previously)) (VBN:[363..371] reported) (FRAG (-LRB-:[372..373] -LRB-) (NNP:[373..377] Yang) (CC:[378..381] and) (NNP:[382..387] Davis) (CD:[388..392] 1992) (-RRB-:[392..393] -RRB-))))) (,:[393..394] ,) (NP-SBJ-1 (NP (NN:[395..412] N-methylcarbazole)) (NP (-LRB-:[413..414] -LRB-) (NN:[414..417] NMC) (-RRB-:[417..418] -RRB-))) (VP (VBZ:[419..421] is) (VP (VBN:[423..432] converted) (NP-1 (-NONE-:[432..432] *)) (PP-CLR (TO:[433..435] to) (NP (NP (NP (NP (NN:[436..460] N-hydroxymethylcarbazole)) (NP (-LRB-:[461..462] -LRB-) (NN:[462..466] NHMC) (-RRB-:[466..467] -RRB-))) (,:[467..468] ,) (CC:[469..472] and) (NP (NP (NN:[474..508] 3-hydroxy-N-hydroxymethylcarbazole)) (NP (-LRB-:[509..510] -LRB-) (NN:[510..519] 3-OH-NHMC) (-RRB-:[519..520] -RRB-)))) (,:[520..521] ,) (NP (CD:[522..525] two) (ADJP (RB:[526..536] relatively) (JJ:[537..543] stable)) (NN:[545..558] carbinolamine) (NNS:[559..570] metabolites)))) (PP (IN:[571..573] by) (NP-LGS (NP (NP (DT:[574..577] the) (NN:[578..584] fungus)) (NP (NNP:[585..599] Cunninghamella) (NNP:[600..610] echinulata))) (NP (-LRB-:[611..612] -LRB-) (NN:[612..616] ATCC) (CD:[617..621] 9244) (-RRB-:[621..622] -RRB-)))))) (.:[622..623] .))) ;sentence 6 Span:625..751 ;Decomposition of these two carbinolamines yields the corresponding ;dealkylated metabolites, carbazole and 3-hydroxycarbazole. ;[652..666]:substance:"carbinolamines" ;[705..716]:substance:"metabolites" ;[718..727]:substance:"carbazole" ;[732..750]:substance:"3-hydroxycarbazole" (SENT (S (NP-SBJ (NP (NN:[625..638] Decomposition)) (PP (IN:[639..641] of) (NP (DT:[642..647] these) (CD:[648..651] two) (NNS:[652..666] carbinolamines)))) (VP (VBZ:[667..673] yields) (NP (NP (DT:[674..677] the) (VBG:[678..691] corresponding) (VBN:[692..703] dealkylated) (NNS:[705..716] metabolites)) (,:[716..717] ,) (NP (NN:[718..727] carbazole) (CC:[728..731] and) (NN:[732..750] 3-hydroxycarbazole)))) (.:[750..751] .))) ;sentence 7 Span:752..881 ;In the present study, the possible involvement of cytochrome P450 in the ;requisite N-alkyl hydroxylation reaction was examined. ;[803..818]:cyp450:"cytochrome P450" (SENT (S (PP-LOC (IN:[752..754] In) (NP (DT:[755..758] the) (JJ:[759..766] present) (NN:[767..772] study))) (,:[772..773] ,) (NP-SBJ-1 (NP (DT:[774..777] the) (JJ:[779..787] possible) (NN:[788..799] involvement)) (PP (IN:[800..802] of) (NP (NN:[803..813] cytochrome) (NN:[814..818] P450))) (PP (IN:[819..821] in) (NP (DT:[822..825] the) (JJ:[826..835] requisite) (NML (NN:[836..843] N-alkyl) (NN:[844..857] hydroxylation)) (NN:[859..867] reaction)))) (VP (VBD:[868..871] was) (VP (VBN:[872..880] examined) (NP-1 (-NONE-:[880..880] *)))) (.:[880..881] .))) ;sentence 8 Span:882..884 ;2. (SENT (NP (LS:[882..884] 2.))) ;sentence 9 Span:885..998 ;Carbon monoxide, a classical P450 inhibitor, markedly inhibited the ;formation of NHMC, as did potassium cyanide. ;[885..900]:substance:"Carbon monoxide" ;[914..918]:cyp450:"P450" ;[919..928]:substance:"inhibitor" ;[967..971]:substance:"NHMC" ;[980..997]:substance:"potassium cyanide" (SENT (S (NP-SBJ (NP (NN:[885..891] Carbon) (NN:[892..900] monoxide)) (,:[900..901] ,) (NP (DT:[902..903] a) (JJ:[904..913] classical) (NN:[914..918] P450) (NN:[919..928] inhibitor))) (,:[928..929] ,) (ADVP-MNR (RB:[930..938] markedly)) (VP (VBD:[940..949] inhibited) (NP (NP (DT:[950..953] the) (NN:[954..963] formation)) (PP (IN:[964..966] of) (NP (NN:[967..971] NHMC)))) (,:[971..972] ,) (SBAR (IN:[973..975] as) (SINV (VP (VBD:[976..979] did) (VP (-NONE-:[979..979] *?*))) (NP-SBJ (NN:[980..989] potassium) (NN:[990..997] cyanide))))) (.:[997..998] .))) ;sentence 10 Span:999..1173 ;1-Benzylimidazole, piperonyl butoxide and SKF-525A inhibited the formation ;of both NHMC and 3-OH-NHMC, while beta-naphthoflavone (5,6-benzoflavone) ;induced their formation. ;[999..1016]:substance:"1-Benzylimidazole" ;[1019..1037]:substance:"piperonyl butoxide" ;[1042..1050]:substance:"SKF-525A" ;[1083..1087]:substance:"NHMC" ;[1093..1102]:substance:"3-OH-NHMC" ;[1110..1129]:substance:"beta-naphthoflavone" ;[1131..1147]:substance:"5,6-benzoflavone" (SENT (S (NP-SBJ (NP (NN:[999..1016] 1-Benzylimidazole)) (,:[1016..1017] ,) (NP (NN:[1019..1028] piperonyl) (NN:[1029..1037] butoxide)) (CC:[1038..1041] and) (NP (NN:[1042..1050] SKF-525A))) (VP (VBD:[1051..1060] inhibited) (NP (NP (DT:[1061..1064] the) (NN:[1065..1074] formation)) (PP (IN:[1075..1077] of) (NP (CC:[1078..1082] both) (NN:[1083..1087] NHMC) (CC:[1088..1091] and) (NN:[1093..1102] 3-OH-NHMC)))) (,:[1102..1103] ,) (SBAR-ADV (IN:[1104..1109] while) (S (NP-SBJ (NP (NN:[1110..1129] beta-naphthoflavone)) (NP (-LRB-:[1130..1131] -LRB-) (NN:[1131..1147] 5,6-benzoflavone) (-RRB-:[1147..1148] -RRB-))) (VP (VBD:[1149..1156] induced) (NP (PRP$:[1157..1162] their) (NN:[1163..1172] formation)))))) (.:[1172..1173] .))) ;sentence 11 Span:1175..1177 ;3. (SENT (NP (LS:[1175..1177] 3.))) ;sentence 12 Span:1178..1403 ;The source of the oxygen atom in the metabolite NHMC was examined by GC/MS ;analysis of NHMC formed during incubation of NMC in H218O-enriched medium ;which resulted in no incorporation of labelled oxygen into the metabolite. ;[1196..1202]:substance:"oxygen" ;[1215..1225]:substance:"metabolite" ;[1226..1230]:substance:"NHMC" ;[1266..1270]:substance:"NHMC" ;[1299..1302]:substance:"NMC" ;[1306..1311]:substance:"H218O" ;[1321..1327]:substance:"medium" ;[1376..1382]:substance:"oxygen" ;[1392..1402]:substance:"metabolite" (SENT (S (NP-SBJ-2 (NP (DT:[1178..1181] The) (NN:[1182..1188] source)) (PP (IN:[1189..1191] of) (NP (DT:[1192..1195] the) (NN:[1196..1202] oxygen) (NN:[1203..1207] atom))) (PP-LOC (IN:[1208..1210] in) (NP (DT:[1211..1214] the) (NN:[1215..1225] metabolite) (NN:[1226..1230] NHMC)))) (VP (VBD:[1231..1234] was) (VP (VBN:[1235..1243] examined) (NP-2 (-NONE-:[1243..1243] *)) (PP-MNR (IN:[1244..1246] by) (NP (NP (NML (NN:[1247..1249] GC) (SYM:[1249..1250] /) (NN:[1250..1252] MS)) (NN:[1254..1262] analysis)) (PP (IN:[1263..1265] of) (NP (NP (NN:[1266..1270] NHMC)) (VP (VBN:[1271..1277] formed) (NP (-NONE-:[1277..1277] *)) (PP-TMP (IN:[1278..1284] during) (NP (NP (NP (NN:[1285..1295] incubation)) (PP (IN:[1296..1298] of) (NP (NN:[1299..1302] NMC))) (PP-LOC (IN:[1303..1305] in) (NP (ADJP (NN:[1306..1311] H218O) (HYPH:[1311..1312] -) (VBN:[1312..1320] enriched)) (NN:[1321..1327] medium)))) (SBAR (WHNP-1 (WDT:[1328..1333] which)) (S (NP-SBJ-1 (-NONE-:[1333..1333] *T*)) (VP (VBD:[1335..1343] resulted) (PP-CLR (IN:[1344..1346] in) (NP (NP (DT:[1347..1349] no) (NN:[1350..1363] incorporation)) (PP (IN:[1364..1366] of) (NP (VBN:[1367..1375] labelled) (NN:[1376..1382] oxygen))) (PP (IN:[1383..1387] into) (NP (DT:[1388..1391] the) (NN:[1392..1402] metabolite))))))))))))))))) (.:[1402..1403] .))) ;sentence 13 Span:1404..1406 ;4. (SENT (NP (LS:[1404..1406] 4.))) ;sentence 14 Span:1407..1614 ;An intermolecular isotope effect was not observed for the formation of NHMC ;suggesting that C-H bond cleavage is not a rate limiting step in the ;formation of this metabolite under the conditions examined. ;[1479..1483]:substance:"NHMC" ;[1573..1583]:substance:"metabolite" (SENT (S (NP-SBJ-1 (DT:[1407..1409] An) (JJ:[1411..1425] intermolecular) (NN:[1426..1433] isotope) (NN:[1434..1440] effect)) (VP (VBD:[1441..1444] was) (RB:[1445..1448] not) (VP (VBN:[1449..1457] observed) (NP-1 (-NONE-:[1457..1457] *)) (PP (IN:[1458..1461] for) (NP (NP (DT:[1462..1465] the) (NN:[1466..1475] formation)) (PP (IN:[1476..1478] of) (NP (NN:[1479..1483] NHMC))))) (S-ADV (NP-SBJ (-NONE-:[1483..1483] *)) (VP (VBG:[1485..1495] suggesting) (SBAR (IN:[1496..1500] that) (S (NP-SBJ (NML (NML (NN:[1501..1502] C) (HYPH:[1502..1503] -) (NN:[1503..1504] H)) (NN:[1505..1509] bond)) (NN:[1510..1518] cleavage)) (VP (VBZ:[1519..1521] is) (RB:[1522..1525] not) (NP-PRD (NP (DT:[1526..1527] a) (ADJP (NN:[1528..1532] rate) (VBG:[1533..1541] limiting)) (NN:[1542..1546] step)) (PP (IN:[1547..1549] in) (NP (NP (DT:[1550..1553] the) (NN:[1554..1563] formation)) (PP (IN:[1565..1567] of) (NP (DT:[1568..1572] this) (NN:[1573..1583] metabolite))) (PP (IN:[1584..1589] under) (NP (NP (DT:[1590..1593] the) (NNS:[1594..1604] conditions)) (VP (VBN:[1605..1613] examined) (NP (-NONE-:[1613..1613] *))))))))))))))) (.:[1613..1614] .))) ;sentence 15 Span:1615..1617 ;5. (SENT (NP (LS:[1615..1617] 5.))) ;sentence 16 Span:1618..1919 ;It was concluded that P450 enzymes may be involved in the N-demethylation of ;NMC catalyzed by this fungal model of mammalian metabolism, and provides ;further support for biochemical and mechanistic parallels between mammalian ;metabolism and microbial systems catalyzing phase-1 biotransformations. ;[1640..1653]:cyp450:"P450 enzymes" ;[1696..1699]:substance:"NMC" (SENT (S (NP-SBJ-3 (NP (PRP:[1618..1620] It)) (SBAR-4 (-NONE-:[1620..1620] *EXP*))) (VP (VP (VBD:[1621..1624] was) (VP (VBN:[1625..1634] concluded) (NP-3 (-NONE-:[1634..1634] *)) (SBAR-4 (IN:[1635..1639] that) (S (NP-SBJ-2 (NN:[1640..1644] P450) (NNS:[1646..1653] enzymes)) (VP (MD:[1654..1657] may) (VP (VB:[1658..1660] be) (VP (VBN:[1661..1669] involved) (NP-2 (-NONE-:[1669..1669] *)) (PP-CLR (IN:[1670..1672] in) (NP (NP (NP (DT:[1673..1676] the) (NN:[1677..1692] N-demethylation)) (PP (IN:[1693..1695] of) (NP (NN:[1696..1699] NMC)))) (VP (VBN:[1700..1709] catalyzed) (NP (-NONE-:[1709..1709] *)) (PP (IN:[1710..1712] by) (NP-LGS (NP (DT:[1713..1717] this) (JJ:[1718..1724] fungal) (NN:[1726..1731] model)) (PP (IN:[1732..1734] of) (NP (JJ:[1735..1744] mammalian) (NN:[1745..1755] metabolism))))))))))))))) (,:[1755..1756] ,) (CC:[1757..1760] and) (VP (VBZ:[1761..1769] provides) (NP (NP (JJR:[1770..1777] further) (NN:[1778..1785] support)) (PP (IN:[1786..1789] for) (NP (NP (NP (JJ:[1790..1801] biochemical) (NML-1 (-NONE-:[1801..1801] *P*))) (CC:[1802..1805] and) (NP (JJ:[1807..1818] mechanistic) (NML-1 (NNS:[1819..1828] parallels)))) (PP (IN:[1829..1836] between) (NP (NP (JJ:[1837..1846] mammalian) (NN:[1847..1857] metabolism)) (CC:[1858..1861] and) (NP (NP (JJ:[1862..1871] microbial) (NNS:[1872..1879] systems)) (VP (VBG:[1881..1891] catalyzing) (NP (NN:[1892..1899] phase-1) (NNS:[1900..1918] biotransformations))))))))))) (.:[1918..1919] .))) ;section 17 Span:1923..1967 ;PMID: 8291265 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1923..1927] PMID) (::[1927..1928] :) (CD:[1929..1936] 8291265) (NN:[1937..1938] -LSB-) (NNP:[1938..1944] PubMed) (::[1945..1946] -) (NN:[1947..1954] indexed) (IN:[1955..1958] for) (NNP:[1959..1967] MEDLINE-RSB-)))