;PMID: 8117926 ;source_file_1794.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..43] = [t:0..43] ;1)sentence:[e:49..112] = [t:49..112] ;2)section:[e:116..146] = [t:116..146] ;3)section:[e:150..239] = [t:150..239] ;4)sentence:[e:243..458] = [t:243..458] ;5)sentence:[e:459..602] = [t:459..602] ;6)sentence:[e:603..736] = [t:603..736] ;7)sentence:[e:737..858] = [t:737..858] ;8)sentence:[e:859..1094] = [t:859..1094] ;9)sentence:[e:1095..1354] = [t:1095..1354] ;10)sentence:[e:1355..1505] = [t:1355..1505] ;11)sentence:[e:1506..1682] = [t:1506..1682] ;12)sentence:[e:1683..1854] = [t:1683..1854] ;13)sentence:[e:1855..2010] = [t:1855..2010] ;14)section:[e:2010..2044] = [t:2010..2044] ;15)section:[e:2048..2092] = [t:2048..2092] ;section 0 Span:0..43 ;Chem Res Toxicol. 1993 Nov-Dec;6(6):866-71. (SEC (FRAG (NNP:[0..4] Chem) (NNP:[5..8] Res) (NNP:[9..16] Toxicol) (.:[16..17] .) (CD:[18..22] 1993) (NN:[23..31] Nov-Dec;) (CD:[31..32] 6) (NN:[32..33] -LRB-) (NN:[33..34] 6) (NN:[34..35] -RRB-) (::[35..36] :) (CD:[36..40] 866-) (CD:[40..42] 71) (.:[42..43] .))) ;sentence 1 Span:49..112 ;Epoxidation of acrylonitrile by rat and human cytochromes P450. ;[64..77]:substance:"acrylonitrile" ;[95..111]:cyp450:"cytochromes P450" (SENT (NP-HLN (NP (NN:[49..60] Epoxidation)) (PP (IN:[61..63] of) (NP (NN:[64..77] acrylonitrile))) (PP (IN:[78..80] by) (NP (NP (NN:[81..84] rat) (NML-1 (-NONE-:[84..84] *P*))) (CC:[85..88] and) (NP (JJ:[89..94] human) (NML-1 (NNS:[95..106] cytochromes) (NN:[107..111] P450))))) (.:[111..112] .))) ;section 2 Span:116..146 ;Kedderis GL, Batra R, Koop DR. (SEC (FRAG (NNP:[116..124] Kedderis) (NNP:[125..127] GL) (,:[127..128] ,) (NNP:[129..134] Batra) (NNP:[135..136] R) (,:[136..137] ,) (NNP:[138..142] Koop) (NNP:[143..146] DR.))) ;section 3 Span:150..239 ;Chemical Industry Institute of Toxicology, Research Triangle Park, North ;Carolina 27709. (SEC (FRAG (NNP:[150..158] Chemical) (NNP:[159..167] Industry) (NNP:[168..177] Institute) (IN:[178..180] of) (NNP:[181..191] Toxicology) (,:[191..192] ,) (NNP:[193..201] Research) (NNP:[202..210] Triangle) (NNP:[211..215] Park) (,:[215..216] ,) (NNP:[217..222] North) (NNP:[224..232] Carolina) (.:[233..238] 27709) (.:[238..239] .))) ;sentence 4 Span:243..458 ;The cytochromes P450 (P450) involved in the epoxidation of the rat carcinogen ; acrylonitrile (ACN) to the mutagen 2-cyanoethylene oxide (CEO) have been ;investigated in hepatic microsomes from F-344 rats and humans. ;[247..263]:cyp450:"cytochromes P450" ;[265..269]:cyp450:"P450" ;[310..320]:substance:"carcinogen" ;[322..335]:substance:"acrylonitrile" ;[337..340]:substance:"ACN" ;[349..356]:substance:"mutagen" ;[357..378]:substance:"2-cyanoethylene oxide" ;[380..383]:substance:"CEO" (SENT (S (NP-SBJ-1 (NP (NP (DT:[243..246] The) (NNS:[247..258] cytochromes) (NN:[259..263] P450)) (NP (-LRB-:[264..265] -LRB-) (NN:[265..269] P450) (-RRB-:[269..270] -RRB-))) (VP (VBN:[271..279] involved) (NP (-NONE-:[279..279] *)) (PP-CLR (IN:[280..282] in) (NP (NP (DT:[283..286] the) (NN:[287..298] epoxidation)) (PP (IN:[299..301] of) (NP (NP (DT:[302..305] the) (NN:[306..309] rat) (NN:[310..320] carcinogen)) (NP (NP (NN:[322..335] acrylonitrile)) (NP (-LRB-:[336..337] -LRB-) (NN:[337..340] ACN) (-RRB-:[340..341] -RRB-))))) (PP (TO:[342..344] to) (NP (NP (DT:[345..348] the) (NN:[349..356] mutagen)) (NP (NP (NN:[357..372] 2-cyanoethylene) (NN:[373..378] oxide)) (NP (-LRB-:[379..380] -LRB-) (NN:[380..383] CEO) (-RRB-:[383..384] -RRB-))))))))) (VP (VBP:[385..389] have) (VP (VBN:[390..394] been) (VP (VBN:[396..408] investigated) (NP-1 (-NONE-:[408..408] *)) (PP-LOC (IN:[409..411] in) (NP (NP (JJ:[412..419] hepatic) (NNS:[420..430] microsomes)) (PP (IN:[431..435] from) (NP (NP (NN:[436..441] F-344) (NNS:[442..446] rats)) (CC:[447..450] and) (NP (NNS:[451..457] humans))))))))) (.:[457..458] .))) ;sentence 5 Span:459..602 ;Induction of P450 2E1 by acetone treatment increased the Vmax for rat ;microsomal CEO formation 5-fold, while ACN treatment had little effect. ;[472..481]:cyp450:"P450 2E1" ;[485..492]:substance:"acetone" ;[517..521]:quantitative-name:"Vmax" ;[541..544]:substance:"CEO" ;[556..562]:quantitative-value:"5-fold" ;[570..573]:substance:"ACN" (SENT (S (NP-SBJ (NP (NN:[459..468] Induction)) (PP (IN:[469..471] of) (NP (NN:[472..476] P450) (NN:[478..481] 2E1))) (PP (IN:[482..484] by) (NP (NN:[485..492] acetone) (NN:[493..502] treatment)))) (VP (VBD:[503..512] increased) (NP (NP (DT:[513..516] the) (NN:[517..521] Vmax)) (PP (IN:[522..525] for) (NP (NN:[526..529] rat) (JJ:[530..540] microsomal) (NN:[541..544] CEO) (NN:[545..554] formation)))) (ADVP-EXT (CD:[556..557] 5) (HYPH:[557..558] -) (RB:[558..562] fold)) (,:[562..563] ,) (SBAR-ADV (IN:[564..569] while) (S (NP-SBJ (NN:[570..573] ACN) (NN:[574..583] treatment)) (VP (VBD:[584..587] had) (NP (JJ:[588..594] little) (NN:[595..601] effect)))))) (.:[601..602] .))) ;sentence 6 Span:603..736 ;Treatment with beta-naphthoflavone, dexamethasone, and phenobarbital had ;little effect upon Vmax but increased the KM 3- to 5-fold. ;[619..638]:substance:"beta-naphthoflavone" ;[640..653]:substance:"dexamethasone" ;[659..672]:substance:"phenobarbital" ;[697..701]:quantitative-name:"Vmax" ;[720..722]:quantitative-name:"KM" ;[723..735]:quantitative-value:"3- to 5-fold" (SENT (S (NP-SBJ (NP (NN:[603..612] Treatment)) (PP (IN:[613..617] with) (NP (NN:[619..638] beta-naphthoflavone) (,:[638..639] ,) (NN:[640..653] dexamethasone) (,:[653..654] ,) (CC:[655..658] and) (NN:[659..672] phenobarbital)))) (VP (VP (VBD:[673..676] had) (NP (NP (JJ:[677..683] little) (NN:[684..690] effect)) (PP (IN:[691..695] upon) (NP (NN:[697..701] Vmax))))) (CC:[702..705] but) (VP (VBD:[706..715] increased) (NP (DT:[716..719] the) (NN:[720..722] KM)) (ADVP-EXT (QP (CD:[723..724] 3) (HYPH:[724..725] -) (TO:[726..728] to) (CD:[729..730] 5)) (HYPH:[730..731] -) (RB:[731..735] fold)))) (.:[735..736] .))) ;sentence 7 Span:737..858 ;The P450 ligand 1-phenylimidazole and substrate ethanol were potent ;inhibitors of ACN epoxidation after all treatments. ;[741..745]:cyp450:"P450" ;[746..752]:substance:"ligand" ;[753..770]:substance:"1-phenylimidazole" ;[776..785]:substance:"substrate" ;[786..793]:substance:"ethanol" ;[806..816]:substance:"inhibitors" ;[820..823]:substance:"ACN" (SENT (S (NP-SBJ (NP (NP (DT:[737..740] The) (NML-1 (NN:[741..745] P450)) (NN:[746..752] ligand)) (NP (NN:[753..770] 1-phenylimidazole))) (CC:[771..774] and) (NP (NP (NML-1 (-NONE-:[774..774] *P*)) (NN:[776..785] substrate)) (NP (NN:[786..793] ethanol)))) (VP (VBD:[794..798] were) (NP-PRD (NP (JJ:[799..805] potent) (NNS:[806..816] inhibitors)) (PP (IN:[817..819] of) (NP (NN:[820..823] ACN) (NN:[824..835] epoxidation))) (PP-TMP (IN:[836..841] after) (NP (DT:[842..845] all) (NNS:[847..857] treatments))))) (.:[857..858] .))) ;sentence 8 Span:859..1094 ;2-(Diethylamino)ethyl 2,2-diphenylvalerate (SKF 525A; 0.1 mM) was not an ;effective inhibitor with microsomes from untreated or acetone-treated rats, ;but inhibited approximately 50% following dexamethasone or phenobarbital ;treatment. ;[859..901]:substance:"2-(Diethylamino)ethyl 2,2-diphenylvalerate" ;[903..911]:substance:"SKF 525A" ;[913..916]:quantitative-value:"0.1" ;[917..919]:quantitative-units:"mM" ;[943..952]:substance:"inhibitor" ;[987..994]:substance:"acetone" ;[1024..1041]:quantitative-value:"approximately 50%" ;[1052..1065]:substance:"dexamethasone" ;[1069..1082]:substance:"phenobarbital" (SENT (S (NP-SBJ (NP (NN:[859..880] 2--LRB-Diethylamino-RRB-ethyl) (NN:[881..901] 2,2-diphenylvalerate)) (PRN (-LRB-:[902..903] -LRB-) (NP (NN:[903..906] SKF) (NN:[907..911] 525A)) (::[911..912] ;) (NP (CD:[913..916] 0.1) (NN:[917..919] mM)) (-RRB-:[919..920] -RRB-))) (VP (VP (VBD:[921..924] was) (RB:[926..929] not) (NP-PRD (NP (DT:[930..932] an) (JJ:[933..942] effective) (NN:[943..952] inhibitor)) (PP (IN:[953..957] with) (NP (NP (NNS:[958..968] microsomes)) (PP (IN:[969..973] from) (NP (NP (JJ:[974..983] untreated) (NML-2 (-NONE-:[983..983] *P*))) (CC:[984..986] or) (NP (ADJP (NN:[987..994] acetone) (HYPH:[994..995] -) (VBN:[995..1002] treated)) (NML-2 (NNS:[1004..1008] rats))))))))) (,:[1008..1009] ,) (CC:[1010..1013] but) (VP (VBD:[1014..1023] inhibited) (NP-EXT (QP (RB:[1024..1037] approximately) (CD:[1038..1040] 50)) (NN:[1040..1041] %)) (S-TMP (NP-SBJ (-NONE-:[1041..1041] *)) (VP (VBG:[1042..1051] following) (NP (NP (NN:[1052..1065] dexamethasone) (NML-1 (-NONE-:[1065..1065] *P*))) (CC:[1066..1068] or) (NP (NN:[1069..1082] phenobarbital) (NML-1 (NN:[1084..1093] treatment)))))))) (.:[1093..1094] .))) ;sentence 9 Span:1095..1354 ;Antibodies to P450 2E1 inhibited > 85% of the ACN epoxidation activity in ;microsomes from untreated or beta-naphthoflavone- or acetone-treated rats, ;but only produced 40% and 60% inhibition following dexamethasone or ;phenobarbital treatments, respectively. ;[1095..1105]:substance:"Antibodies" ;[1109..1117]:cyp450:"P450 2E1" ;[1128..1133]:quantitative-value:"> 85%" ;[1141..1144]:substance:"ACN" ;[1199..1218]:substance:"beta-naphthoflavone" ;[1223..1230]:substance:"acetone" ;[1264..1267]:quantitative-value:"40%" ;[1272..1275]:quantitative-value:"60%" ;[1297..1310]:substance:"dexamethasone" ;[1315..1328]:substance:"phenobarbital" (SENT (S (NP-SBJ (NP (NNS:[1095..1105] Antibodies)) (PP (TO:[1106..1108] to) (NP (NN:[1109..1113] P450) (NN:[1114..1117] 2E1)))) (VP (VP (VBD:[1118..1127] inhibited) (NP (NP (QP (SYM:[1128..1129] >) (CD:[1130..1132] 85)) (NN:[1132..1133] %)) (PP (IN:[1134..1136] of) (NP (DT:[1137..1140] the) (NML (NN:[1141..1144] ACN) (NN:[1145..1156] epoxidation)) (NN:[1158..1166] activity)))) (PP-LOC (IN:[1167..1169] in) (NP (NP (NNS:[1170..1180] microsomes)) (PP (IN:[1181..1185] from) (NP (NP (JJ:[1186..1195] untreated) (NML-4 (-NONE-:[1195..1195] *P*))) (CC:[1196..1198] or) (NP (NP (ADJP (NN:[1199..1218] beta-naphthoflavone) (HYPH:[1218..1219] -) (ADJP-3 (-NONE-:[1219..1219] *P*))) (NML-4 (-NONE-:[1219..1219] *P*))) (CC:[1220..1222] or) (NP (ADJP (NN:[1223..1230] acetone) (HYPH:[1230..1231] -) (ADJP-3 (VBN:[1231..1238] treated))) (NML-4 (NNS:[1240..1244] rats))))))))) (,:[1244..1245] ,) (CC:[1246..1249] but) (VP (ADVP (RB:[1250..1254] only)) (VBD:[1255..1263] produced) (NP (NP (NML-EXT (CD:[1264..1266] 40) (NN:[1266..1267] %)) (NML-2 (-NONE-:[1267..1267] *P*))) (CC:[1268..1271] and) (NP (NML-EXT (CD:[1272..1274] 60) (NN:[1274..1275] %)) (NML-2 (NN:[1276..1286] inhibition)))) (S-TMP (NP-SBJ (-NONE-:[1286..1286] *)) (VP (VBG:[1287..1296] following) (NP (NP (NN:[1297..1310] dexamethasone) (NML-1 (-NONE-:[1310..1310] *P*))) (CC:[1311..1313] or) (NP (NN:[1315..1328] phenobarbital) (NML-1 (NNS:[1329..1339] treatments)))) (,:[1339..1340] ,) (ADVP (RB:[1341..1353] respectively)))))) (.:[1353..1354] .))) ;sentence 10 Span:1355..1505 ;These results indicate that P450 2E1 is the major catalyst of ACN ;epoxidation in untreated rats and that other forms of P450 can also ;epoxidize ACN. ;[1383..1391]:cyp450:"P450 2E1" ;[1406..1414]:substance:"catalyst" ;[1418..1421]:substance:"ACN" ;[1477..1481]:cyp450:"P450" ;[1501..1504]:substance:"ACN" (SENT (S (NP-SBJ (DT:[1355..1360] These) (NNS:[1361..1368] results)) (VP (VBP:[1369..1377] indicate) (SBAR (SBAR (IN:[1378..1382] that) (S (NP-SBJ (NN:[1383..1387] P450) (NN:[1388..1391] 2E1)) (VP (VBZ:[1392..1394] is) (NP-PRD (NP (DT:[1396..1399] the) (JJ:[1400..1405] major) (NN:[1406..1414] catalyst)) (PP (IN:[1415..1417] of) (NP (NN:[1418..1421] ACN) (NN:[1422..1433] epoxidation))) (PP-LOC (IN:[1434..1436] in) (NP (JJ:[1437..1446] untreated) (NNS:[1447..1451] rats))))))) (CC:[1452..1455] and) (SBAR (IN:[1456..1460] that) (S (NP-SBJ (NP (JJ:[1461..1466] other) (NNS:[1467..1472] forms)) (PP (IN:[1473..1475] of) (NP (NN:[1477..1481] P450)))) (VP (MD:[1482..1485] can) (ADVP (RB:[1486..1490] also)) (VP (VB:[1491..1500] epoxidize) (NP (NN:[1501..1504] ACN)))))))) (.:[1504..1505] .))) ;sentence 11 Span:1506..1682 ;Diethyldithiocarbamate (0.1 mM) was a potent irreversible inhibitor of ACN ;epoxidation after all of the induction treatments, indicating that it is not ;specific for P450 2E1. ;[1506..1528]:substance:"Diethyldithiocarbamate" ;[1530..1533]:quantitative-value:"0.1" ;[1534..1536]:quantitative-units:"mM" ;[1565..1574]:substance:"inhibitor" ;[1578..1581]:substance:"ACN" ;[1673..1681]:cyp450:"P450 2E1" (SENT (S (NP-SBJ (NN:[1506..1528] Diethyldithiocarbamate) (PRN (-LRB-:[1529..1530] -LRB-) (NP (CD:[1530..1533] 0.1) (NN:[1534..1536] mM)) (-RRB-:[1536..1537] -RRB-))) (VP (VBD:[1538..1541] was) (NP-PRD (NP (DT:[1542..1543] a) (JJ:[1544..1550] potent) (JJ:[1552..1564] irreversible) (NN:[1565..1574] inhibitor)) (PP (IN:[1575..1577] of) (NP (NN:[1578..1581] ACN) (NN:[1582..1593] epoxidation)))) (PP-TMP (IN:[1594..1599] after) (NP (NP (DT:[1600..1603] all)) (PP (IN:[1604..1606] of) (NP (DT:[1607..1610] the) (NN:[1611..1620] induction) (NNS:[1621..1631] treatments))))) (,:[1631..1632] ,) (S-ADV (NP-SBJ (-NONE-:[1632..1632] *)) (VP (VBG:[1634..1644] indicating) (SBAR (IN:[1645..1649] that) (S (NP-SBJ (PRP:[1650..1652] it)) (VP (VBZ:[1653..1655] is) (RB:[1656..1659] not) (ADJP-PRD (JJ:[1660..1668] specific) (PP (IN:[1669..1672] for) (NP (NN:[1673..1677] P450) (NN:[1678..1681] 2E1)))))))))) (.:[1681..1682] .))) ;sentence 12 Span:1683..1854 ;Chlorzoxazone (2 mM) produced 75-90% inhibition after all of the induction ;treatments, indicating that it interacts with several rodent P450 isoforms ;in addition to 2E1. ;[1683..1696]:substance:"Chlorzoxazone" ;[1698..1699]:quantitative-value:"2" ;[1700..1702]:quantitative-units:"mM" ;[1714..1720]:quantitative-value:"75-90%" ;[1821..1834]:cyp450:"P450 isoforms" ;[1850..1853]:cyp450:"2E1" (SENT (S (NP-SBJ (NN:[1683..1696] Chlorzoxazone) (PRN (-LRB-:[1697..1698] -LRB-) (NP (CD:[1698..1699] 2) (NN:[1700..1702] mM)) (-RRB-:[1702..1703] -RRB-))) (VP (VBD:[1704..1712] produced) (NP (NML-EXT (QP (CD:[1714..1716] 75) (HYPH:[1716..1717] -) (CD:[1717..1719] 90)) (NN:[1719..1720] %)) (NN:[1721..1731] inhibition)) (PP-TMP (IN:[1732..1737] after) (NP (NP (DT:[1738..1741] all)) (PP (IN:[1742..1744] of) (NP (DT:[1745..1748] the) (NN:[1749..1758] induction) (NNS:[1759..1769] treatments))))) (,:[1769..1770] ,) (S-ADV (NP-SBJ (-NONE-:[1770..1770] *)) (VP (VBG:[1771..1781] indicating) (SBAR (IN:[1782..1786] that) (S (NP-SBJ (PRP:[1787..1789] it)) (VP (VBZ:[1791..1800] interacts) (PP (IN:[1801..1805] with) (NP (NP (JJ:[1806..1813] several) (NN:[1814..1820] rodent) (NN:[1821..1825] P450) (NNS:[1826..1834] isoforms)) (PP (IN:[1835..1837] in) (NP (NP (NN:[1838..1846] addition)) (PP (TO:[1847..1849] to) (NP (NN:[1850..1853] 2E1))))))))))))) (.:[1853..1854] .))) ;sentence 13 Span:1855..2010 ;Human hepatic microsomes (n = 6) epoxidized ACN with Vmax'S ranging from 129 ;to 315 pmol of CEO formed/(min.mg of protein) and KM's from 12 to 18 ;microM. ;[1900..1903]:substance:"ACN" ;[1909..1915]:quantitative-name:"Vmax'S" ;[1929..1939]:quantitative-value:"129 to 315" ;[1940..1979]:quantitative-units:"pmol of CEO formed/(min.mg of protein)" ;[1984..1988]:quantitative-name:"KM's" ;[1994..2002]:quantitative-value:"12 to 18" ;[2003..2009]:quantitative-units:"microM" (SENT (S (NP-SBJ (JJ:[1855..1860] Human) (JJ:[1861..1868] hepatic) (NNS:[1870..1880] microsomes) (PRN (-LRB-:[1881..1882] -LRB-) (S (NP-SBJ (NN:[1882..1883] n)) (VP (SYM:[1884..1885] =) (NP (CD:[1886..1887] 6)))) (-RRB-:[1887..1888] -RRB-))) (VP (VBD:[1889..1899] epoxidized) (NP (NN:[1900..1903] ACN)) (PP (IN:[1904..1908] with) (NP (NP (NP (NNS:[1909..1915] Vmax'S)) (VP (VBG:[1916..1923] ranging) (PP (PP (IN:[1924..1928] from) (NP (NP (CD:[1929..1932] 129) (NML-1 (-NONE-:[1932..1932] *RNR*))) (PP-2 (-NONE-:[1932..1932] *RNR*)))) (PP (TO:[1933..1935] to) (NP (NP (CD:[1936..1939] 315) (NML-1 (-NONE-:[1939..1939] *RNR*))) (PP-2 (-NONE-:[1939..1939] *RNR*)))) (NML-1 (NN:[1940..1944] pmol)) (PP-2 (IN:[1945..1947] of) (NP (NP (NP (NN:[1949..1952] CEO)) (VP (VBN:[1953..1959] formed) (NP (-NONE-:[1959..1959] *)))) (PP (SYM:[1959..1960] /) (NP (-LRB-:[1960..1961] -LRB-) (NP (NN:[1961..1964] min)) (PP (.:[1964..1965] .) (NP (NP (NN:[1965..1967] mg)) (PP (IN:[1968..1970] of) (NP (NN:[1971..1978] protein))))) (-RRB-:[1978..1979] -RRB-)))))))) (CC:[1980..1983] and) (NP (NP (NNS:[1984..1988] KM's)) (PP (PP (IN:[1989..1993] from) (NP (CD:[1994..1996] 12) (NML-3 (-NONE-:[1996..1996] *RNR*)))) (PP (TO:[1997..1999] to) (NP (CD:[2000..2002] 18) (NML-3 (-NONE-:[2002..2002] *RNR*)))) (NML-3 (NN:[2003..2009] microM))))))) (.:[2009..2010] .))) ;section 14 Span:2010..2044 ;(ABSTRACT TRUNCATED AT 250 WORDS) (SEC (FRAG (-LRB-:[2010..2011] -LRB-) (NN:[2011..2019] ABSTRACT) (VBN:[2020..2029] TRUNCATED) (IN:[2031..2033] AT) (CD:[2034..2037] 250) (NNS:[2038..2043] WORDS) (-RRB-:[2043..2044] -RRB-))) ;section 15 Span:2048..2092 ;PMID: 8117926 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[2048..2052] PMID) (::[2052..2053] :) (CD:[2054..2061] 8117926) (NN:[2062..2063] -LSB-) (NNP:[2063..2069] PubMed) (::[2070..2071] -) (NN:[2072..2079] indexed) (IN:[2080..2083] for) (NNP:[2084..2092] MEDLINE-RSB-)))