;PMID: 10216279 ;source_file_1897.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..48] = [t:0..48] ;1)sentence:[e:54..163] = [t:54..163] ;2)section:[e:167..186] = [t:167..186] ;3)section:[e:190..343] = [t:190..343] ;4)sentence:[e:347..460] = [t:347..460] ;5)sentence:[e:461..701] = [t:461..701] ;6)sentence:[e:702..910] = [t:702..910] ;7)sentence:[e:911..1048] = [t:911..1048] ;8)sentence:[e:1050..1098] = [t:1050..1098] ;9)sentence:[e:1099..1292] = [t:1099..1292] ;10)sentence:[e:1294..1456] = [t:1294..1456] ;11)sentence:[e:1457..1604] = [t:1457..1604] ;12)sentence:[e:1605..1771] = [t:1605..1771] ;13)sentence:[e:1772..1902] = [t:1772..1902] ;14)sentence:[e:1903..2018] = [t:1903..2018] ;15)sentence:[e:2019..2130] = [t:2019..2130] ;16)sentence:[e:2131..2300] = [t:2131..2300] ;17)section:[e:2304..2349] = [t:2304..2349] ;section 0 Span:0..48 ;Biochim Biophys Acta. 1999 Apr 19;1438(1):47-54. (SEC (FRAG (NNP:[0..7] Biochim) (NNP:[8..15] Biophys) (NNP:[16..20] Acta) (.:[20..21] .) (CD:[22..26] 1999) (CC:[27..30] Apr) (CD:[31..38] 19;1438) (-LRB-:[38..39] -LRB-) (CD:[39..40] 1) (-RRB-:[40..41] -RRB-) (CD:[41..44] :47) (::[44..45] -) (CD:[45..47] 54) (.:[47..48] .))) ;sentence 1 Span:54..163 ;6alpha-hydroxylation of taurochenodeoxycholic acid and lithocholic acid by ;CYP3A4 in human liver microsomes. ;[78..104]:substance:"taurochenodeoxycholic acid" ;[109..125]:substance:"lithocholic acid" ;[130..136]:cyp450:"CYP3A4" (SENT (NP-HLN (NP (NN:[54..74] 6alpha-hydroxylation)) (PP (IN:[75..77] of) (NP (NP (JJ:[78..99] taurochenodeoxycholic) (NN:[100..104] acid)) (CC:[105..108] and) (NP (JJ:[109..120] lithocholic) (NN:[121..125] acid)))) (PP (IN:[126..128] by) (NP (NN:[130..136] CYP3A4))) (PP-LOC (IN:[137..139] in) (NP (JJ:[140..145] human) (NN:[146..151] liver) (NNS:[152..162] microsomes))) (.:[162..163] .))) ;section 2 Span:167..186 ;Araya Z, Wikvall K. (SEC (FRAG (NNP:[167..172] Araya) (NNP:[173..174] Z) (,:[174..175] ,) (NNP:[176..183] Wikvall) (NNP:[184..186] K.))) ;section 3 Span:190..343 ;Division of Biochemistry, Department of Pharmaceutical Biosciences, ;University of Uppsala, Box 578, S-751 23, Uppsala, Sweden. ;zufan.araya@farmbio.uu.se (SEC (FRAG (NNP:[190..198] Division) (IN:[199..201] of) (NNP:[202..214] Biochemistry) (,:[214..215] ,) (NNP:[216..226] Department) (IN:[227..229] of) (NNP:[230..244] Pharmaceutical) (NNP:[245..256] Biosciences) (,:[256..257] ,) (NNP:[258..268] University) (IN:[270..272] of) (NNP:[273..280] Uppsala) (,:[280..281] ,) (NNP:[282..285] Box) (CD:[286..289] 578) (,:[289..290] ,) (NN:[291..293] S-) (CD:[293..296] 751) (CD:[297..299] 23) (,:[299..300] ,) (NNP:[301..308] Uppsala) (,:[308..309] ,) (NNP:[310..316] Sweden) (.:[316..317] .) (NNP:[318..323] zufan) (VBD:[323..343] .araya@farmbio.uu.se))) ;sentence 4 Span:347..460 ;The aim of the present study was to identify the enzymes in human liver ;catalyzing hydroxylations of bile acids. ;[396..403]:substance:"enzymes" ;[449..459]:substance:"bile acids" (SENT (S (NP-SBJ-1 (NP (DT:[347..350] The) (NN:[351..354] aim)) (PP (IN:[355..357] of) (NP (DT:[358..361] the) (JJ:[362..369] present) (NN:[370..375] study)))) (VP (VBD:[376..379] was) (S-PRP-PRD (NP-SBJ-1 (-NONE-:[379..379] *)) (VP (TO:[380..382] to) (VP (VB:[383..391] identify) (NP (NP (DT:[392..395] the) (NNS:[396..403] enzymes)) (PP-LOC (IN:[404..406] in) (NP (NP (ADJP (NML (JJ:[407..412] human) (NN:[413..418] liver)) (VBG:[420..430] catalyzing)) (NNS:[431..445] hydroxylations)) (PP (IN:[446..448] of) (NP (NN:[449..453] bile) (NNS:[454..459] acids)))))))))) (.:[459..460] .))) ;sentence 5 Span:461..701 ;Fourteen recombinant expressed cytochrome P450 (CYP) enzymes, human liver ;microsomes from different donors, and selective cytochrome P450 inhibitors ;were used to study the hydroxylation of taurochenodeoxycholic acid and ;lithocholic acid. ;[493..522]:cyp450:"cytochrome P450 (CYP) enzymes" ;[585..600]:cyp450:"cytochrome P450" ;[601..611]:substance:"inhibitors" ;[653..679]:substance:"taurochenodeoxycholic acid" ;[684..700]:substance:"lithocholic acid" (SENT (S (NP-SBJ-1 (NP (CD:[461..469] Fourteen) (ADJP (JJ:[470..481] recombinant) (VBN:[482..491] expressed)) (NML (NML (NN:[493..503] cytochrome) (NN:[504..508] P450)) (NML (-LRB-:[509..510] -LRB-) (NN:[510..513] CYP) (-RRB-:[513..514] -RRB-))) (NNS:[515..522] enzymes)) (,:[522..523] ,) (NP (NP (JJ:[524..529] human) (NN:[530..535] liver) (NNS:[536..546] microsomes)) (PP (IN:[547..551] from) (NP (JJ:[552..561] different) (NNS:[562..568] donors)))) (,:[568..569] ,) (CC:[570..573] and) (NP (JJ:[575..584] selective) (NML (NN:[585..595] cytochrome) (NN:[596..600] P450)) (NNS:[601..611] inhibitors))) (VP (VBD:[612..616] were) (VP (VBN:[617..621] used) (NP-1 (-NONE-:[621..621] *)) (S-PRP (NP-SBJ-1 (-NONE-:[621..621] *)) (VP (TO:[622..624] to) (VP (VB:[625..630] study) (NP (NP (DT:[631..634] the) (NN:[635..648] hydroxylation)) (PP (IN:[649..651] of) (NP (NP (JJ:[653..674] taurochenodeoxycholic) (NN:[675..679] acid)) (CC:[680..683] and) (NP (JJ:[684..695] lithocholic) (NN:[696..700] acid)))))))))) (.:[700..701] .))) ;sentence 6 Span:702..910 ;Recombinant expressed CYP3A4 was the only enzyme that was active towards ;these bile acids and the enzyme catalyzed an efficient 6alpha-hydroxylation ;of both taurochenodeoxycholic acid and lithocholic acid. ;[724..730]:cyp450:"CYP3A4" ;[745..751]:cyp450:"enzyme" ;[782..792]:substance:"bile acids" ;[801..807]:substance:"enzyme" ;[861..887]:substance:"taurochenodeoxycholic acid" ;[893..909]:substance:"lithocholic acid" (SENT (S (S (NP-SBJ (JJ:[702..713] Recombinant) (VBN:[714..723] expressed) (NN:[724..730] CYP3A4)) (VP (VBD:[732..735] was) (NP-PRD (NP (DT:[736..739] the) (RB:[740..744] only) (NN:[745..751] enzyme)) (SBAR (WHNP-1 (WDT:[752..756] that)) (S (NP-SBJ-1 (-NONE-:[756..756] *T*)) (VP (VBD:[757..760] was) (ADJP-PRD (JJ:[761..767] active) (PP (IN:[768..775] towards) (NP (DT:[776..781] these) (NN:[782..786] bile) (NNS:[787..792] acids)))))))))) (CC:[793..796] and) (S (NP-SBJ (DT:[797..800] the) (NN:[801..807] enzyme)) (VP (VBD:[809..818] catalyzed) (NP (NP (DT:[819..821] an) (JJ:[822..831] efficient) (NN:[832..852] 6alpha-hydroxylation)) (PP (IN:[853..855] of) (NP (CC:[856..860] both) (NP (JJ:[861..882] taurochenodeoxycholic) (NN:[883..887] acid)) (CC:[889..892] and) (NP (JJ:[893..904] lithocholic) (NN:[905..909] acid))))))) (.:[909..910] .))) ;sentence 7 Span:911..1048 ;The Vmax for 6alpha-hydroxylation of taurochenodeoxycholic acid by CYP3A4 ;was 18.2 nmol/nmol P450/min and the apparent Km was 90 microM. ;[915..919]:quantitative-name:"Vmax" ;[948..975]:substance:"taurochenodeoxycholic acid" ;[979..985]:cyp450:"CYP3A4" ;[990..994]:quantitative-value:"18.2" ;[995..1013]:quantitative-units:"nmol/nmol P450/min" ;[1031..1033]:quantitative-name:"Km" ;[1038..1040]:quantitative-value:"90" ;[1041..1047]:quantitative-units:"microM" (SENT (S (S (NP-SBJ (NP (DT:[911..914] The) (NN:[915..919] Vmax)) (PP (IN:[920..923] for) (NP (NP (NN:[924..944] 6alpha-hydroxylation)) (PP (IN:[945..947] of) (NP (JJ:[948..969] taurochenodeoxycholic) (NN:[971..975] acid))) (PP (IN:[976..978] by) (NP (NN:[979..985] CYP3A4)))))) (VP (VBD:[986..989] was) (NP-PRD (NP (CD:[990..994] 18.2) (NN:[995..999] nmol)) (PP (SYM:[999..1000] /) (NP (NN:[1000..1004] nmol) (NN:[1005..1009] P450))) (PP (SYM:[1009..1010] /) (NP (NN:[1010..1013] min)))))) (CC:[1014..1017] and) (S (NP-SBJ (DT:[1018..1021] the) (JJ:[1022..1030] apparent) (NN:[1031..1033] Km)) (VP (VBD:[1034..1037] was) (NP-PRD (CD:[1038..1040] 90) (NN:[1041..1047] microM)))) (.:[1047..1048] .))) ;sentence 8 Span:1050..1098 ;Cytochrome b5 was required for maximal activity. ;[1050..1063]:cyp450:"Cytochrome b5" (SENT (S (NP-SBJ-1 (NN:[1050..1060] Cytochrome) (NN:[1061..1063] b5)) (VP (VBD:[1064..1067] was) (VP (VBN:[1068..1076] required) (NP-1 (-NONE-:[1076..1076] *)) (PP-PRP (IN:[1077..1080] for) (NP (JJ:[1081..1088] maximal) (NN:[1089..1097] activity))))) (.:[1097..1098] .))) ;sentence 9 Span:1099..1292 ;Human liver microsomes from 10 different donors, in which different P450 ;marker activities had been determined, were separately incubated with ;taurochenodeoxycholic acid and lithocholic acid. ;[1168..1172]:cyp450:"P450" ;[1244..1270]:substance:"taurochenodeoxycholic acid" ;[1275..1291]:substance:"lithocholic acid" (SENT (S (NP-SBJ-3 (NP (NP (JJ:[1099..1104] Human) (NN:[1105..1110] liver) (NNS:[1111..1121] microsomes)) (PP (IN:[1122..1126] from) (NP (CD:[1127..1129] 10) (JJ:[1131..1140] different) (NNS:[1141..1147] donors)))) (,:[1147..1148] ,) (SBAR (WHPP-2 (IN:[1149..1151] in) (WHNP (WDT:[1152..1157] which))) (S (NP-SBJ-1 (JJ:[1158..1167] different) (NN:[1168..1172] P450) (NN:[1173..1179] marker) (NNS:[1180..1190] activities)) (VP (VBD:[1191..1194] had) (VP (VBN:[1195..1199] been) (VP (VBN:[1200..1210] determined) (NP-1 (-NONE-:[1210..1210] *)) (PP-LOC-2 (-NONE-:[1210..1210] *T*)))))))) (,:[1210..1211] ,) (VP (VBD:[1213..1217] were) (ADVP (RB:[1218..1228] separately)) (VP (VBN:[1229..1238] incubated) (NP-3 (-NONE-:[1238..1238] *)) (PP-MNR (IN:[1239..1243] with) (NP (NP (JJ:[1244..1265] taurochenodeoxycholic) (NN:[1266..1270] acid)) (CC:[1271..1274] and) (NP (JJ:[1275..1286] lithocholic) (NN:[1287..1291] acid)))))) (.:[1291..1292] .))) ;sentence 10 Span:1294..1456 ;A strong correlation was found between 6alpha-hydroxylation of ;taurochenodeoxycholic acid, CYP3A levels (r2=0.97) and testosterone ;6beta-hydroxylation (r2=0.9). ;[1358..1384]:substance:"taurochenodeoxycholic acid" ;[1386..1391]:cyp450:"CYP3A" ;[1413..1425]:substance:"testosterone" (SENT (S (NP-SBJ-1 (NP (DT:[1294..1295] A) (JJ:[1296..1302] strong) (NN:[1303..1314] correlation)) (PP-2 (-NONE-:[1314..1314] *ICH*))) (VP (VBD:[1315..1318] was) (VP (VBN:[1319..1324] found) (NP-1 (-NONE-:[1324..1324] *)) (PP-2 (IN:[1325..1332] between) (NP (NP (NP (NN:[1333..1353] 6alpha-hydroxylation)) (PP (IN:[1354..1356] of) (NP (JJ:[1358..1379] taurochenodeoxycholic) (NN:[1380..1384] acid)))) (,:[1384..1385] ,) (NP (NP (NN:[1386..1391] CYP3A) (NNS:[1392..1398] levels)) (PRN (-LRB-:[1399..1400] -LRB-) (S (NP-SBJ (NN:[1400..1402] r2)) (VP (SYM:[1402..1403] =) (NP (CD:[1403..1407] 0.97)))) (-RRB-:[1407..1408] -RRB-))) (CC:[1409..1412] and) (NP (NP (NN:[1413..1425] testosterone) (NN:[1427..1446] 6beta-hydroxylation)) (PRN (-LRB-:[1447..1448] -LRB-) (S (NP-SBJ (NN:[1448..1450] r2)) (VP (SYM:[1450..1451] =) (NP (CD:[1451..1454] 0.9)))) (-RRB-:[1454..1455] -RRB-))))))) (.:[1455..1456] .))) ;sentence 11 Span:1457..1604 ;There was also a strong correlation between 6alpha-hydroxylation of ;lithocholic acid, CYP3A levels and testosterone 6beta-hydroxylation ;(r2=0.7). ;[1526..1542]:substance:"lithocholic acid" ;[1544..1549]:cyp450:"CYP3A" ;[1561..1573]:substance:"testosterone" (SENT (S (NP-SBJ (EX:[1457..1462] There)) (VP (VBD:[1463..1466] was) (ADVP (RB:[1467..1471] also)) (NP-PRD (NP (DT:[1472..1473] a) (JJ:[1474..1480] strong) (NN:[1481..1492] correlation)) (PP (IN:[1493..1500] between) (NP (NP (NP (NN:[1502..1522] 6alpha-hydroxylation)) (PP (IN:[1523..1525] of) (NP (JJ:[1526..1537] lithocholic) (NN:[1538..1542] acid)))) (,:[1542..1543] ,) (NP (NN:[1544..1549] CYP3A) (NNS:[1550..1556] levels)) (CC:[1557..1560] and) (NP (NN:[1561..1573] testosterone) (NN:[1575..1594] 6beta-hydroxylation)) (PRN (-LRB-:[1595..1596] -LRB-) (S (NP-SBJ (NN:[1596..1598] r2)) (VP (SYM:[1598..1599] =) (NP (CD:[1599..1602] 0.7)))) (-RRB-:[1602..1603] -RRB-)))))) (.:[1603..1604] .))) ;sentence 12 Span:1605..1771 ;Troleandomycin, a selective inhibitor of CYP3A enzymes, inhibited ;6alpha-hydroxylation of taurochenodeoxycholic acid almost completely at a 10 ;microM concentration. ;[1605..1619]:substance:"Troleandomycin" ;[1633..1642]:substance:"inhibitor" ;[1646..1660]:cyp450:"CYP3A enzymes" ;[1696..1722]:substance:"taurochenodeoxycholic acid" ;[1747..1749]:quantitative-value:"10" ;[1750..1756]:quantitative-units:"microM" (SENT (S (NP-SBJ (NP (NN:[1605..1619] Troleandomycin)) (,:[1619..1620] ,) (NP (NP (DT:[1621..1622] a) (JJ:[1623..1632] selective) (NN:[1633..1642] inhibitor)) (PP (IN:[1643..1645] of) (NP (NN:[1646..1651] CYP3A) (NNS:[1653..1660] enzymes))))) (,:[1660..1661] ,) (VP (VBD:[1662..1671] inhibited) (NP (NP (NN:[1672..1692] 6alpha-hydroxylation)) (PP (IN:[1693..1695] of) (NP (JJ:[1696..1717] taurochenodeoxycholic) (NN:[1718..1722] acid)))) (ADVP (RB:[1723..1729] almost) (RB:[1731..1741] completely)) (PP (IN:[1742..1744] at) (NP (DT:[1745..1746] a) (NML (CD:[1747..1749] 10) (NN:[1750..1756] microM)) (NN:[1757..1770] concentration)))) (.:[1770..1771] .))) ;sentence 13 Span:1772..1902 ;Other inhibitors, such as alpha-naphthoflavone, sulfaphenazole and ;tranylcypromine had very little or no effect on the activity. ;[1778..1788]:substance:"inhibitors" ;[1799..1819]:substance:"alpha-naphthoflavone" ;[1821..1835]:substance:"sulfaphenazole" ;[1840..1855]:substance:"tranylcypromine" (SENT (S (NP-SBJ (NP (JJ:[1772..1777] Other) (NNS:[1778..1788] inhibitors)) (,:[1788..1789] ,) (PP (JJ:[1790..1794] such) (IN:[1795..1797] as) (NP (NN:[1799..1819] alpha-naphthoflavone) (,:[1819..1820] ,) (NN:[1821..1835] sulfaphenazole) (CC:[1836..1839] and) (NN:[1840..1855] tranylcypromine)))) (VP (VBD:[1856..1859] had) (NP (NP (NP (ADJP (RB:[1860..1864] very) (JJ:[1865..1871] little)) (NML-1 (-NONE-:[1871..1871] *P*))) (CC:[1872..1874] or) (NP (DT:[1875..1877] no) (NML-1 (NN:[1879..1885] effect)))) (PP (IN:[1886..1888] on) (NP (DT:[1889..1892] the) (NN:[1893..1901] activity))))) (.:[1901..1902] .))) ;sentence 14 Span:1903..2018 ;The apparent Km for 6alpha-hydroxylation of taurochenodeoxycholic by human ;liver microsomes was high (716 microM). ;[1916..1918]:quantitative-name:"Km" ;[1948..1969]:substance:"taurochenodeoxycholic" ;[2006..2009]:quantitative-value:"716" ;[2010..2016]:quantitative-units:"microM" (SENT (S (NP-SBJ (NP (DT:[1903..1906] The) (JJ:[1907..1915] apparent) (NN:[1916..1918] Km)) (PP (IN:[1919..1922] for) (NP (NP (NN:[1923..1943] 6alpha-hydroxylation)) (PP (IN:[1944..1946] of) (NP (JJ:[1948..1969] taurochenodeoxycholic))) (PP (IN:[1970..1972] by) (NP (JJ:[1973..1978] human) (NN:[1979..1984] liver) (NNS:[1985..1995] microsomes)))))) (VP (VBD:[1996..1999] was) (ADJP-PRD (JJ:[2000..2004] high) (PRN (-LRB-:[2005..2006] -LRB-) (NP (CD:[2006..2009] 716) (NN:[2010..2016] microM)) (-RRB-:[2016..2017] -RRB-)))) (.:[2017..2018] .))) ;sentence 15 Span:2019..2130 ;This might give an explanation for the limited formation of ;6alpha-hydroxylated bile acids in healthy humans. ;[2100..2111]:substance:"bile acids" (SENT (S (NP-SBJ (DT:[2019..2023] This)) (VP (MD:[2025..2030] might) (VP (VB:[2031..2035] give) (NP (NP (DT:[2036..2038] an) (NN:[2039..2050] explanation)) (PP (IN:[2051..2054] for) (NP (NP (DT:[2055..2058] the) (VBN:[2059..2066] limited) (NN:[2067..2076] formation)) (PP (IN:[2077..2079] of) (NP (ADJP (NN:[2080..2086] 6alpha) (HYPH:[2086..2087] -) (VBN:[2087..2099] hydroxylated)) (NN:[2100..2104] bile) (NNS:[2106..2111] acids))) (PP-LOC (IN:[2112..2114] in) (NP (JJ:[2115..2122] healthy) (NNS:[2123..2129] humans)))))))) (.:[2129..2130] .))) ;sentence 16 Span:2131..2300 ;From the present results, it can be concluded that CYP3A4 is active in the ;6alpha-hydroxylation of both taurochenodeoxycholic acid and lithocholic acid ;in human liver. ;[2183..2189]:cyp450:"CYP3A4" ;[2236..2262]:substance:"taurochenodeoxycholic acid" ;[2268..2284]:substance:"lithocholic acid" (SENT (S (PP (IN:[2131..2135] From) (NP (DT:[2136..2139] the) (JJ:[2140..2147] present) (NNS:[2148..2155] results))) (,:[2155..2156] ,) (NP-SBJ-1 (NP (PRP:[2157..2159] it)) (SBAR-2 (-NONE-:[2159..2159] *EXP*))) (VP (MD:[2160..2163] can) (VP (VB:[2164..2166] be) (VP (VBN:[2167..2176] concluded) (NP-1 (-NONE-:[2176..2176] *)) (SBAR-2 (IN:[2177..2181] that) (S (NP-SBJ (NN:[2183..2189] CYP3A4)) (VP (VBZ:[2190..2192] is) (ADJP-PRD (JJ:[2193..2199] active)) (PP (IN:[2200..2202] in) (NP (NP (DT:[2203..2206] the) (NN:[2207..2227] 6alpha-hydroxylation)) (PP (IN:[2228..2230] of) (NP (CC:[2231..2235] both) (NP (JJ:[2236..2257] taurochenodeoxycholic) (NN:[2258..2262] acid)) (CC:[2264..2267] and) (NP (JJ:[2268..2279] lithocholic) (NN:[2280..2284] acid)))) (PP-LOC (IN:[2285..2287] in) (NP (JJ:[2288..2293] human) (NN:[2294..2299] liver))))))))))) (.:[2299..2300] .))) ;section 17 Span:2304..2349 ;PMID: 10216279 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[2304..2308] PMID) (::[2308..2309] :) (CD:[2310..2318] 10216279) (-LRB-:[2319..2320] -LSB-) (NNP:[2320..2326] PubMed) (HYPH:[2327..2328] -) (NN:[2329..2336] indexed) (IN:[2337..2340] for) (NNP:[2341..2348] MEDLINE) (-RRB-:[2348..2349] -RSB-)))