;PMID: 2874666
;source_file_1801.mrg
;Release 0.9 of PennBioIE
;Funded by NSF ITR EIA-0205448

;0)section:[e:0..35] = [t:0..35]
;1)sentence:[e:41..223] = [t:41..223]
;2)section:[e:227..292] = [t:227..292]
;3)sentence:[e:296..680] = [t:296..680]
;4)sentence:[e:682..932] = [t:682..932]
;5)sentence:[e:933..1009] = [t:933..1009]
;6)sentence:[e:1010..1180] = [t:1010..1180]
;7)sentence:[e:1181..1377] = [t:1181..1377]
;8)sentence:[e:1378..1564] = [t:1378..1564]
;9)sentence:[e:1565..1699] = [t:1565..1699]
;10)sentence:[e:1700..1830] = [t:1700..1830]
;11)sentence:[e:1831..2047] = [t:1831..2047]
;12)sentence:[e:2048..2256] = [t:2048..2256]
;13)sentence:[e:2257..2430] = [t:2257..2430]
;14)sentence:[e:2431..2675] = [t:2431..2675]
;15)sentence:[e:2676..2778] = [t:2676..2778]
;16)sentence:[e:2779..2937] = [t:2779..2937]
;17)section:[e:2941..2985] = [t:2941..2985]

;section 0 Span:0..35
;Xenobiotica. 1986 May;16(5):449-64.
(SEC
  (FRAG (NNP:[0..11] Xenobiotica) (IN:[11..12] .) (CD:[13..17] 1986)
        (NNP:[18..21] May) (CD:[21..24] ;16) (-LRB-:[24..25] -LRB-)
        (CD:[25..26] 5) (-RRB-:[26..27] -RRB-) (::[27..28] :)
        (CD:[28..34] 449-64) (.:[34..35] .)))

;sentence 1 Span:41..223
;The molecular mechanisms of two common polymorphisms of drug
;oxidation--evidence  for functional changes in cytochrome P-450 isozymes
;catalysing bufuralol and  mephenytoin oxidation.
;[97..101]:substance:"drug"
;[149..174]:cyp450:"cytochrome P-450 isozymes"
;[186..195]:substance:"bufuralol"
;[201..212]:substance:"mephenytoin"
(SENT
  (NP-HLN
    (NP
      (NP (DT:[41..44] The) (JJ:[45..54] molecular) (NNS:[55..65] mechanisms))
      (PP (IN:[66..68] of)
        (NP
          (NP (CD:[69..72] two) (JJ:[73..79] common)
              (NNS:[80..93] polymorphisms))
          (PP (IN:[94..96] of)
            (NP (NN:[97..101] drug) (NN:[102..111] oxidation))))))
    (::[111..113] --)
    (NP
      (NP (NN:[113..121] evidence))
      (PP (IN:[123..126] for)
        (NP
          (NP (JJ:[127..137] functional) (NNS:[138..145] changes))
          (PP (IN:[146..148] in)
            (NP
              (NP
                (NML (NN:[149..159] cytochrome) (NN:[160..165] P-450))
                (NNS:[166..174] isozymes))
              (VP (VBG:[175..185] catalysing)
                (NP
                  (NP (NN:[186..195] bufuralol)
                    (NML-1 (-NONE-:[195..195] *P*)))
                  (CC:[196..199] and)
                  (NP (NN:[201..212] mephenytoin)
                    (NML-1 (NN:[213..222] oxidation))))))))))
    (.:[222..223] .)))

;section 2 Span:227..292
;Meyer UA, Gut J, Kronbach T, Skoda C, Meier UT, Catin T, Dayer P.
(SEC
  (FRAG (NNP:[227..232] Meyer) (NNP:[233..235] UA) (,:[235..236] ,)
        (NNP:[237..240] Gut) (NNP:[241..243] J,) (NNP:[244..252] Kronbach)
        (NNP:[253..254] T) (,:[254..255] ,) (NNP:[256..261] Skoda)
        (NNP:[262..263] C) (,:[263..264] ,) (NNP:[265..270] Meier)
        (NNP:[271..273] UT) (,:[273..274] ,) (NNP:[275..280] Catin)
        (NNP:[281..282] T) (,:[282..283] ,) (NNP:[284..289] Dayer)
        (NNP:[290..292] P.)))

;sentence 3 Span:296..680
;Using the stereospecific metabolism of (+)- and (-)-bufuralol and (+)- and 
;(-)-metoprolol as model reactions, we have characterized the enzymic
;deficiency  of the debrisoquine/sparteine-type polymorphism by comparing
;kinetic data of  subjects in vivo with their microsomal activities in vitro
;and with  reconstituted activities of cytochrome P-450 isozymes purified from
;human liver.
;[335..339]...[348..357]:substance:"(+)-"..."bufuralol"
;[344..357]:substance:"(-)-bufuralol"
;[362..366]...[376..386]:substance:"(+)-"..."metoprolol"
;[372..386]:substance:"(-)-metoprolol"
;[460..472]:substance:"debrisoquine"
;[473..482]:substance:"sparteine"
;[628..653]:cyp450:"cytochrome P-450 isozymes"
(SENT
  (S
    (S-MNR
      (NP-SBJ (-NONE-:[296..296] *))
      (VP (VBG:[296..301] Using)
        (NP
          (NP (DT:[302..305] the) (JJ:[306..320] stereospecific)
              (NN:[321..331] metabolism))
          (PP (IN:[332..334] of)
            (NP
              (NP
                (NP
                  (ADJP (-LRB-:[335..336] -LRB-) (SYM:[336..337] +)
                        (-RRB-:[337..338] -RRB-))
                  (HYPH:[338..339] -)
                  (NML-2 (-NONE-:[339..339] *P*)))
                (CC:[340..343] and)
                (NP
                  (ADJP (-LRB-:[344..345] -LRB-) (SYM:[345..346] -)
                        (-RRB-:[346..347] -RRB-))
                  (HYPH:[347..348] -)
                  (NML-2 (NN:[348..357] bufuralol))))
              (CC:[358..361] and)
              (NP
                (NP
                  (ADJP (-LRB-:[362..363] -LRB-) (SYM:[363..364] +)
                        (-RRB-:[364..365] -RRB-))
                  (HYPH:[365..366] -)
                  (NML-1 (-NONE-:[366..366] *P*)))
                (CC:[367..370] and)
                (NP
                  (ADJP (-LRB-:[372..373] -LRB-) (SYM:[373..374] -)
                        (-RRB-:[374..375] -RRB-))
                  (HYPH:[375..376] -)
                  (NML-1 (NN:[376..386] metoprolol)))))))
        (PP (IN:[387..389] as)
          (NP (JJ:[390..395] model) (NNS:[396..405] reactions)))))
    (,:[405..406] ,)
    (NP-SBJ (PRP:[407..409] we))
    (VP (VBP:[410..414] have)
      (VP (VBN:[415..428] characterized)
        (NP
          (NP (DT:[429..432] the) (JJ:[433..440] enzymic)
              (NN:[441..451] deficiency))
          (PP (IN:[453..455] of)
            (NP (DT:[456..459] the)
              (ADJP
                (NML (NN:[460..472] debrisoquine) (SYM:[472..473] /)
                     (NN:[473..482] sparteine))
                (HYPH:[482..483] -) (NN:[483..487] type))
              (NN:[488..500] polymorphism))))
        (PP (IN:[501..503] by)
          (S-NOM
            (NP-SBJ (-NONE-:[503..503] *))
            (VP (VBG:[504..513] comparing)
              (NP
                (NP (JJ:[514..521] kinetic) (NNS:[522..526] data))
                (PP (IN:[527..529] of)
                  (NP
                    (NP (NNS:[531..539] subjects))
                    (ADVP (FW:[540..542] in) (FW:[543..547] vivo)))))
              (PP-CLR
                (PP (IN:[548..552] with)
                  (NP
                    (NP (PRP$:[553..558] their) (JJ:[559..569] microsomal)
                        (NNS:[570..580] activities))
                    (ADJP (FW:[581..583] in) (FW:[584..589] vitro))))
                (CC:[590..593] and)
                (PP (IN:[594..598] with)
                  (NP
                    (NP (VBN:[600..613] reconstituted)
                        (NNS:[614..624] activities))
                    (PP (IN:[625..627] of)
                      (NP
                        (NP
                          (NML (NN:[628..638] cytochrome) (NN:[639..644] P-450))
                          (NNS:[645..653] isozymes))
                        (VP (VBN:[654..662] purified)
                          (NP (-NONE-:[662..662] *))
                          (PP (IN:[663..667] from)
                            (NP (JJ:[668..673] human) (NN:[674..679] liver))))))))))))))
    (.:[679..680] .)))

;sentence 4 Span:682..932
;The metabolism of bufuralol in liver microsomes of in vivo phenotyped 'poor 
;metabolizers' of debrisoquine and/or sparteine is characterized by a marked 
;increase in Km, a decrease in Vmax and a virtual loss of the
;stereoselectivity  of the reaction.
;[700..709]:substance:"bufuralol"
;[759..771]:substance:"metabolizers"
;[776..788]:substance:"debrisoquine"
;[796..805]:substance:"sparteine"
;[848..850]:quantitative-name:"Km"
;[866..870]:quantitative-name:"Vmax"
(SENT
  (S
    (NP-SBJ-1
      (NP (DT:[682..685] The) (NN:[686..696] metabolism))
      (PP (IN:[697..699] of)
        (NP (NN:[700..709] bufuralol)))
      (PP-LOC (IN:[710..712] in)
        (NP
          (NP (NN:[713..718] liver) (NNS:[719..729] microsomes))
          (PP (IN:[730..732] of)
            (NP
              (NP
                (ADJP
                  (ADVP (FW:[733..735] in) (FW:[736..740] vivo))
                  (VBN:[741..751] phenotyped))
                (``:[752..753] ') (JJ:[753..757] poor)
                 (NNS:[759..771] metabolizers) ('':[771..772] '))
              (PP (IN:[773..775] of)
                (NP (NN:[776..788] debrisoquine) (CC:[789..795] and/or)
                    (NN:[796..805] sparteine))))))))
    (VP (VBZ:[806..808] is)
      (VP (VBN:[809..822] characterized)
        (NP-1 (-NONE-:[822..822] *))
        (PP (IN:[823..825] by)
          (NP-LGS
            (NP
              (NP (DT:[826..827] a) (JJ:[828..834] marked)
                  (NN:[836..844] increase))
              (PP (IN:[845..847] in)
                (NP (NN:[848..850] Km))))
            (,:[850..851] ,)
            (NP
              (NP (DT:[852..853] a) (NN:[854..862] decrease))
              (PP (IN:[863..865] in)
                (NP (NN:[866..870] Vmax))))
            (CC:[871..874] and)
            (NP
              (NP (DT:[875..876] a) (JJ:[877..884] virtual) (NN:[885..889] loss))
              (PP (IN:[890..892] of)
                (NP
                  (NP (DT:[893..896] the) (NN:[897..914] stereoselectivity))
                  (PP (IN:[916..918] of)
                    (NP (DT:[919..922] the) (NN:[923..931] reaction))))))))))
    (.:[931..932] .)))

;sentence 5 Span:933..1009
;These parameters apparently allow the 'phenotyping' of  microsomes in vitro.
(SENT
  (S
    (NP-SBJ (DT:[933..938] These) (NNS:[939..949] parameters))
    (ADVP (RB:[950..960] apparently))
    (VP (VBP:[961..966] allow)
      (NP
        (NP (DT:[967..970] the) (``:[971..972] ') (NN:[972..983] phenotyping)
            ('':[983..984] '))
        (PP (IN:[985..987] of)
          (NP (NNS:[989..999] microsomes))))
      (ADVP (FW:[1000..1002] in) (FW:[1003..1008] vitro)))
    (.:[1008..1009] .)))

;sentence 6 Span:1010..1180
;A structural model of the active site of a cytochrome P-450  for
;stereospecific metabolism of bufuralol and other polymorphically metabolized 
;substrates was constructed.
;[1053..1069]:cyp450:"cytochrome P-450"
;[1104..1113]:substance:"bufuralol"
;[1153..1163]:substance:"substrates"
(SENT
  (S
    (NP-SBJ-1
      (NP (DT:[1010..1011] A) (JJ:[1012..1022] structural)
          (NN:[1023..1028] model))
      (PP (IN:[1029..1031] of)
        (NP
          (NP (DT:[1032..1035] the) (JJ:[1036..1042] active)
              (NN:[1043..1047] site))
          (PP (IN:[1048..1050] of)
            (NP (DT:[1051..1052] a)
               (NN:[1053..1063] cytochrome) (NN:[1064..1069] P-450)))
          (PP (IN:[1071..1074] for)
            (NP
              (NP (JJ:[1075..1089] stereospecific) (NN:[1090..1100] metabolism))
              (PP (IN:[1101..1103] of)
                (NP
                  (NP (NN:[1104..1113] bufuralol))
                  (CC:[1114..1117] and)
                  (NP (JJ:[1118..1123] other)
                    (ADJP (RB:[1124..1139] polymorphically)
                          (VBN:[1140..1151] metabolized))
                    (NNS:[1153..1163] substrates)))))))))
    (VP (VBD:[1164..1167] was)
      (VP (VBN:[1168..1179] constructed)
        (NP-1 (-NONE-:[1179..1179] *))))
    (.:[1179..1180] .)))

;sentence 7 Span:1181..1377
;Two cytochrome P-450 isozymes, P-450 buf I and P-450  buf II, both with MW
;50,000 Da, were purified from human liver on the basis of  their ability to
;metabolize bufuralol to 1'-hydroxy-bufuralol.
;[1185..1210]:cyp450:"cytochrome P-450 isozymes"
;[1212..1223]:cyp450:"P-450 buf I"
;[1228..1241]:cyp450:"P-450  buf II"
;[1253..1255]:quantitative-name:"MW"
;[1256..1262]:quantitative-value:"50,000"
;[1263..1265]:quantitative-units:"Da"
;[1343..1352]:substance:"bufuralol"
;[1356..1376]:substance:"1'-hydroxy-bufuralol"
(SENT
  (S
    (NP-SBJ-1
      (NP (CD:[1181..1184] Two)
        
        (NML (NN:[1185..1195] cytochrome) (NN:[1196..1201] P-450))
        (NNS:[1202..1210] isozymes))
      (,:[1210..1211] ,)
      (NP
        (NP
          (NP (NN:[1212..1217] P-450) (NN:[1218..1221] buf) (CD:[1222..1223] I))
          (CC:[1224..1227] and)
          (NP (NN:[1228..1233] P-450) (NN:[1235..1238] buf) (CD:[1239..1241] II)))
        (,:[1241..1242] ,)
        (NP
          (NP (DT:[1243..1247] both))
          (PP (IN:[1248..1252] with)
            (NP (NN:[1253..1255] MW) (CD:[1256..1262] 50,000)
                (NN:[1263..1265] Da))))))
    (,:[1265..1266] ,)
    (VP (VBD:[1267..1271] were)
      (VP (VBN:[1272..1280] purified)
        (NP-1 (-NONE-:[1280..1280] *))
        (PP (IN:[1281..1285] from)
          (NP (JJ:[1286..1291] human) (NN:[1292..1297] liver)))
        (PP (IN:[1298..1300] on)
          (NP
            (NP (DT:[1301..1304] the) (NN:[1305..1310] basis))
            (PP (IN:[1311..1313] of)
              (NP (PRP$:[1315..1320] their) (NN:[1321..1328] ability)
                (S
                  (NP-SBJ (-NONE-:[1328..1328] *))
                  (VP (TO:[1329..1331] to)
                    (VP (VB:[1332..1342] metabolize)
                      (NP (NN:[1343..1352] bufuralol))
                      (PP (TO:[1353..1355] to)
                        (NP (NN:[1356..1376] 1'-hydroxy-bufuralol))))))))))))
    (.:[1376..1377] .)))

;sentence 8 Span:1378..1564
;However, P-450  buf I metabolized bufuralol in a highly stereoselective
;fashion ((-)/(+) ratio  0.16) as compared to P-450 buf II (ratio 0.99) and
;had a markedly lower Km for  bufuralol.
;[1387..1399]:cyp450:"P-450  buf I"
;[1412..1421]:substance:"bufuralol"
;[1459..1466]:quantitative-name:"(-)/(+)"
;[1474..1478]:quantitative-value:"0.16"
;[1495..1507]:cyp450:"P-450 buf II"
;[1515..1519]:quantitative-value:"0.99"
;[1546..1548]:quantitative-name:"Km"
;[1554..1563]:substance:"bufuralol"
(SENT
  (S
    (ADVP (RB:[1378..1385] However))
    (,:[1385..1386] ,)
    (NP-SBJ (NN:[1387..1392] P-450) (NN:[1394..1397] buf) (CD:[1398..1399] I))
    (VP
      (VP (VBD:[1400..1411] metabolized)
        (NP (NN:[1412..1421] bufuralol))
        (PP (IN:[1422..1424] in)
          (NP (DT:[1425..1426] a)
            (ADJP (RB:[1427..1433] highly) (JJ:[1434..1449] stereoselective))
            (NN:[1450..1457] fashion)))
        (PRN (-LRB-:[1458..1459] -LRB-)
          (FRAG
            (NP
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                   (-RRB-:[1461..1462] -RRB-) (SYM:[1462..1463] /)
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                   (-RRB-:[1465..1466] -RRB-))
              (NN:[1467..1472] ratio))
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          (-RRB-:[1478..1479] -RRB-))
        (PP (IN:[1480..1482] as)
          (S-NOM
            (NP-SBJ-1 (-NONE-:[1482..1482] *))
            (VP (VBN:[1483..1491] compared)
              (NP-1 (-NONE-:[1491..1491] *))
              (PP-CLR (TO:[1492..1494] to)
                (NP
                   (NN:[1495..1500] P-450) (NN:[1501..1504] buf)
                   (CD:[1505..1507] II)
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                    (FRAG
                      (NP (NN:[1509..1514] ratio))
                      (NP (CD:[1515..1519] 0.99)))
                    (-RRB-:[1519..1520] -RRB-))))))))
      (CC:[1521..1524] and)
      (VP (VBD:[1525..1528] had)
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          (NP (DT:[1529..1530] a)
            (ADJP (RB:[1531..1539] markedly) (JJR:[1540..1545] lower))
            (NN:[1546..1548] Km))
          (PP (IN:[1549..1552] for)
            (NP (NN:[1554..1563] bufuralol))))))
    (.:[1563..1564] .)))

;sentence 9 Span:1565..1699
;Moreover, bufuralol 1'-hydroxylation by P-450 buf I was uniquely 
;characterized by its extreme sensitivity to inhibition by quinidine.
;[1575..1584]:substance:"bufuralol"
;[1605..1616]:cyp450:"P-450 buf I"
;[1689..1698]:substance:"quinidine"
(SENT
  (S
    (ADVP (RB:[1565..1573] Moreover))
    (,:[1573..1574] ,)
    (NP-SBJ-1
      (NP (NN:[1575..1584] bufuralol) (NN:[1585..1601] 1'-hydroxylation))
      (PP (IN:[1602..1604] by)
        (NP (NN:[1605..1610] P-450) (NN:[1611..1614] buf) (CD:[1615..1616] I))))
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              (NP
                (NP (NN:[1675..1685] inhibition))
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                  (NP (NN:[1689..1698] quinidine)))))))))
    (.:[1698..1699] .)))

;sentence 10 Span:1700..1830
;Antibodies  against P-450 buf I and P-450 buf II inhibited bufuralol
;metabolism in  microsomes and with the reconstituted enzymes.
;[1700..1710]:substance:"Antibodies"
;[1720..1731]:cyp450:"P-450 buf I"
;[1736..1748]:cyp450:"P-450 buf II"
;[1759..1768]:substance:"bufuralol"
;[1822..1829]:cyp450:"enzymes"
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  (S
    (NP-SBJ
      (NP (NNS:[1700..1710] Antibodies))
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        (NP
          (NP (NN:[1720..1725] P-450) (NN:[1726..1729] buf) (CD:[1730..1731] I))
          (CC:[1732..1735] and)
          (NP (NN:[1736..1741] P-450) (NN:[1742..1745] buf) (CD:[1746..1748] II)))))
    (VP (VBD:[1749..1758] inhibited)
      (NP (NN:[1759..1768] bufuralol) (NN:[1769..1779] metabolism))
      (PP
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          (NP (NNS:[1784..1794] microsomes)))
        (CC:[1795..1798] and)
        (PP (IN:[1799..1803] with)
          (NP (DT:[1804..1807] the) (VBN:[1808..1821] reconstituted)
              (NNS:[1822..1829] enzymes)))))
    (.:[1829..1830] .)))

;sentence 11 Span:1831..2047
;Immunochemical studies with these  antibodies with microsomes and
;translations in vitro of RNA from livers of  extensive and poor metabolizers
;showed no evidence for a decrease in the  recognized protein or its mRNA.
;[1866..1876]:substance:"antibodies"
;[1922..1925]:substance:"RNA"
;[1961..1973]:substance:"metabolizers"
;[2027..2034]:substance:"protein"
;[2042..2046]:substance:"mRNA"
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  (S
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    (.:[2046..2047] .)))

;sentence 12 Span:2048..2256
;Because the antibodies do not discriminate  between P-450 buf I and P-450 buf
;II, both a decreased content of P-450 buf I or  its functional alteration
;could explain the polymorphic metabolism in  microsomes.
;[2060..2070]:substance:"antibodies"
;[2100..2111]:cyp450:"P-450 buf I"
;[2116..2128]:cyp450:"P-450 buf II"
;[2158..2169]:cyp450:"P-450 buf I"
(SENT
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    (SBAR-PRP (IN:[2048..2055] Because)
      (S
        (NP-SBJ (DT:[2056..2059] the) (NNS:[2060..2070] antibodies))
        (VP (VBP:[2071..2073] do) (RB:[2074..2077] not)
          (VP (VB:[2078..2090] discriminate)
            (PP (IN:[2092..2099] between)
              (NP
                (NP (NN:[2100..2105] P-450) (NN:[2106..2109] buf)
                    (CD:[2110..2111] I))
                (CC:[2112..2115] and)
                (NP (NN:[2116..2121] P-450) (NN:[2122..2125] buf)
                    (CD:[2126..2128] II))))))))
    (,:[2128..2129] ,)
    (NP-SBJ (CC:[2130..2134] both)
      (NP
        (NP (DT:[2135..2136] a) (VBN:[2137..2146] decreased)
            (NN:[2147..2154] content))
        (PP (IN:[2155..2157] of)
          (NP (NN:[2158..2163] P-450) (NN:[2164..2167] buf) (CD:[2168..2169] I))))
      (CC:[2170..2172] or)
      (NP (PRP$:[2174..2177] its) (JJ:[2178..2188] functional)
          (NN:[2189..2199] alteration)))
    (VP (MD:[2200..2205] could)
      (VP (VB:[2206..2213] explain)
        (NP
          (NP (DT:[2214..2217] the) (JJ:[2218..2229] polymorphic)
              (NN:[2230..2240] metabolism))
          (PP-LOC (IN:[2241..2243] in)
            (NP (NNS:[2245..2255] microsomes))))))
    (.:[2255..2256] .)))

;sentence 13 Span:2257..2430
;The genetically defective stereospecific metabolism of mephenytoin  was
;determined in liver microsomes of extensive and poor metabolizers of 
;mephenytoin phenotyped in vivo.
;[2312..2323]:substance:"mephenytoin"
;[2382..2394]:substance:"metabolizers"
;[2399..2410]:substance:"mephenytoin"
(SENT
  (S
    (NP-SBJ-2
      (NP (DT:[2257..2260] The)
        (ADJP (RB:[2261..2272] genetically) (JJ:[2273..2282] defective))
        (JJ:[2283..2297] stereospecific) (NN:[2298..2308] metabolism))
      (PP (IN:[2309..2311] of)
        (NP (NN:[2312..2323] mephenytoin))))
    (VP (VBD:[2325..2328] was)
      (VP (VBN:[2329..2339] determined)
        (NP-2 (-NONE-:[2339..2339] *))
        (PP-LOC (IN:[2340..2342] in)
          (NP
            (NP (NN:[2343..2348] liver) (NNS:[2349..2359] microsomes))
            (PP (IN:[2360..2362] of)
              (NP
                (NP
                  (NP
                    (NP (JJ:[2363..2372] extensive)
                      (NML-1 (-NONE-:[2372..2372] *P*)))
                    (CC:[2373..2376] and)
                    (NP (JJ:[2377..2381] poor)
                      (NML-1 (NNS:[2382..2394] metabolizers))))
                  (PP (IN:[2395..2397] of)
                    (NP (NN:[2399..2410] mephenytoin))))
                (VP (VBN:[2411..2421] phenotyped)
                  (NP (-NONE-:[2421..2421] *))
                  (ADVP (FW:[2422..2424] in) (FW:[2425..2429] vivo)))))))))
    (.:[2429..2430] .)))

;sentence 14 Span:2431..2675
;Microsomes of poor metabolizers were  characterized by an increased Km and a
;decreased Vmax for S-mephenytoin  hydroxylation as compared to extensive
;metabolizers and a loss of  stereospecificity for the hydroxylation of
;S-versus R-mephenytoin.
;[2450..2462]:substance:"metabolizers"
;[2499..2501]:quantitative-name:"Km"
;[2518..2522]:quantitative-name:"Vmax"
;[2527..2540]:substance:"S-mephenytoin"
;[2581..2593]:substance:"metabolizers"
;[2652..2654]...[2663..2674]:substance:"S-"..."mephenytoin"
;[2661..2674]:substance:"R-mephenytoin"
(SENT
  (S
    (NP-SBJ-2
      (NP (NNS:[2431..2441] Microsomes))
      (PP (IN:[2442..2444] of)
        (NP (JJ:[2445..2449] poor) (NNS:[2450..2462] metabolizers))))
    (VP (VBD:[2463..2467] were)
      (VP (VBN:[2469..2482] characterized)
        (NP-2 (-NONE-:[2482..2482] *))
        (PP (IN:[2483..2485] by)
          (NP-LGS
            (NP
              (NP
                (NP (DT:[2486..2488] an) (VBN:[2489..2498] increased)
                    (NN:[2499..2501] Km))
                (CC:[2502..2505] and)
                (NP (DT:[2506..2507] a) (VBN:[2508..2517] decreased)
                    (NN:[2518..2522] Vmax)))
              (PP (IN:[2523..2526] for)
                (NP (NN:[2527..2540] S-mephenytoin)
                    (NN:[2542..2555] hydroxylation)))
              (PP (IN:[2556..2558] as)
                (S-NOM
                  (NP-SBJ-1 (-NONE-:[2558..2558] *))
                  (VP (VBN:[2559..2567] compared)
                    (NP-1 (-NONE-:[2567..2567] *))
                    (PP-CLR (TO:[2568..2570] to)
                      (NP (JJ:[2571..2580] extensive)
                          (NNS:[2581..2593] metabolizers)))))))
            (CC:[2594..2597] and)
            (NP
              (NP (DT:[2598..2599] a) (NN:[2600..2604] loss))
              (PP (IN:[2605..2607] of)
                (NP
                  (NP (NN:[2609..2626] stereospecificity))
                  (PP (IN:[2627..2630] for)
                    (NP
                      (NP (DT:[2631..2634] the) (NN:[2635..2648] hydroxylation))
                      (PP (IN:[2649..2651] of)
                        (NP
                          (NP (NN:[2652..2653] S) (HYPH:[2653..2654] -)
                            (NML-3 (-NONE-:[2654..2654] *P*)))
                          (IN:[2654..2660] versus)
                          (NP (NN:[2661..2662] R) (HYPH:[2662..2663] -)
                            (NML-3 (NN:[2663..2674] mephenytoin))))))))))))))
    (.:[2674..2675] .)))

;sentence 15 Span:2676..2778
;A cytochrome  P-450 with high activity for mephenytoin 4-hydroxylation was
;purified from human  liver.
;[2678..2695]:cyp450:"cytochrome  P-450"
;[2719..2730]:substance:"mephenytoin"
(SENT
  (S
    (NP-SBJ-1
      (NP (DT:[2676..2677] A)
         (NN:[2678..2688] cytochrome) (NN:[2690..2695] P-450))
      (PP (IN:[2696..2700] with)
        (NP (JJ:[2701..2705] high) (NN:[2706..2714] activity)))
      (PP (IN:[2715..2718] for)
        (NP (NN:[2719..2730] mephenytoin) (NN:[2731..2746] 4-hydroxylation))))
    (VP (VBD:[2747..2750] was)
      (VP (VBN:[2751..2759] purified)
        (NP-1 (-NONE-:[2759..2759] *))
        (PP (IN:[2760..2764] from)
          (NP (JJ:[2765..2770] human) (NN:[2772..2777] liver)))))
    (.:[2777..2778] .)))

;sentence 16 Span:2779..2937
;Immunochemical studies with inhibitory antibodies against this isozyme 
;suggest the presence in poor-metabolizer microsomes of a functionally altered
; enzyme.
;[2818..2828]:substance:"antibodies"
;[2842..2849]:substance:"isozyme"
;[2880..2891]:substance:"metabolizer"
;[2930..2936]:substance:"enzyme"
(SENT
  (S
    (NP-SBJ
      (NP (JJ:[2779..2793] Immunochemical) (NNS:[2794..2801] studies))
      (PP (IN:[2802..2806] with)
        (NP
          (NP (JJ:[2807..2817] inhibitory) (NNS:[2818..2828] antibodies))
          (PP (IN:[2829..2836] against)
            (NP (DT:[2837..2841] this) (NN:[2842..2849] isozyme))))))
    (VP (VBP:[2851..2858] suggest)
      (NP
        (NP (DT:[2859..2862] the) (NN:[2863..2871] presence))
        (PP-LOC (IN:[2872..2874] in)
          (NP
            (NP
              (NML (JJ:[2875..2879] poor) (HYPH:[2879..2880] -)
                   (NN:[2880..2891] metabolizer))
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            (PP (IN:[2903..2905] of)
              (NP (DT:[2906..2907] a)
                (ADJP (RB:[2908..2920] functionally) (VBN:[2921..2928] altered))
                (NN:[2930..2936] enzyme)))))))
    (.:[2936..2937] .)))

;section 17 Span:2941..2985
;PMID: 2874666 [PubMed - indexed for MEDLINE]
(SEC
  (FRAG (NNP:[2941..2945] PMID) (::[2945..2946] :) (CD:[2947..2954] 2874666)
        (NN:[2955..2956] -LSB-) (NNP:[2956..2962] PubMed) (::[2963..2964] -)
        (NN:[2965..2972] indexed) (IN:[2973..2976] for)
        (NNP:[2977..2985] MEDLINE-RSB-)))