0 8 Cellular cellular JJ 9 20 disposition disposition NN 21 23 of of IN 24 41 sulphamethoxazole sulphamethoxazole NN 42 45 and and CC 46 49 its its PRP$ 50 61 metabolites metabolite NNS 61 62 : : : 63 75 implications implication NNS 76 79 for for IN 80 96 hypersensitivity hypersensitivity NN 96 97 . . . 99 100 1 1 LS 100 101 . . . 102 115 Bioactivation Bioactivation NNP 116 118 of of IN 119 136 sulphamethoxazole sulphamethoxazole NN 137 138 ( ( ( 138 141 SMX SMX NNP 141 142 ) ) ) 143 145 to to TO 146 165 chemically-reactive chemically-reactive JJ 166 177 metabolites metabolite NNS 178 181 and and CC 182 192 subsequent subsequent JJ 193 200 protein protein NN 201 212 conjugation conjugation NN 213 215 is be VBZ 216 223 thought think VBN 224 226 to to TO 227 229 be be VB 230 238 involved involve VBN 239 241 in in IN 242 245 SMX SMX NNP 246 262 hypersensitivity hypersensitivity NN 262 263 . . . 264 266 We we PRP 267 271 have have VBP 272 281 therefore therefore RB 282 290 examined examine VBN 291 294 the the DT 295 303 cellular cellular JJ 304 314 metabolism metabolism NN 314 315 , , , 316 327 disposition disposition NN 328 331 and and CC 332 343 conjugation conjugation NN 344 346 of of IN 347 350 SMX SMX NNP 351 354 and and CC 355 358 its its PRP$ 359 370 metabolites metabolite NNS 371 373 in in FW 374 379 vitro vitro FW 379 380 . . . 381 382 2 2 LS 382 383 . . . 384 388 Flow Flow NNP 389 398 cytometry cytometry NN 399 407 revealed reveal VBD 408 415 binding binding NN 416 418 of of IN 419 428 N-hydroxy N-hydroxy NNP 429 430 ( ( ( 430 438 SMX-NHOH SMX-NHOH NNP 438 439 ) ) ) 440 443 and and CC 444 451 nitroso nitroso NN 452 453 ( ( ( 453 459 SMX-NO smx-no NN 459 460 ) ) ) 461 472 metabolites metabolite NNS 473 475 of of IN 476 479 SMX SMX NNP 479 480 , , , 481 484 but but CC 485 488 not not RB 489 491 of of IN 492 495 SMX SMX NNP 496 502 itself itself PRP 502 503 , , , 504 506 to to TO 507 510 the the DT 511 518 surface surface NN 519 521 of of IN 522 528 viable viable JJ 529 534 white white JJ 535 540 blood blood NN 541 546 cells cell NNS 546 547 . . . 548 556 Cellular cellular JJ 557 568 haptenation haptenation NN 569 571 by by IN 572 578 SMX-NO SMX-NO NNP 579 582 was be VBD 583 590 reduced reduce VBN 591 593 by by IN 594 603 exogenous exogenous JJ 604 615 glutathione glutathione NN 616 617 ( ( ( 617 620 GSH GSH NNP 620 621 ) ) ) 621 622 . . . 623 624 3 3 LS 624 625 . . . 626 634 SMX-NHOH SMX-NHOH NNP 635 638 and and CC 639 645 SMX-NO SMX-NO NNP 646 650 were be VBD 651 658 rapidly rapidly RB 659 666 reduced reduce VBN 667 671 back back RB 672 674 to to TO 675 678 the the DT 679 685 parent parent NN 686 694 compound compound NN 695 697 by by IN 698 706 cysteine cysteine NN 707 708 ( ( ( 708 711 CYS CYS NNP 711 712 ) ) ) 712 713 , , , 714 717 GSH GSH NNP 717 718 , , , 719 724 human human JJ 725 735 peripheral peripheral JJ 736 741 blood blood NN 742 747 cells cell NNS 748 751 and and CC 752 758 plasma plasma NN 758 759 , , , 760 770 suggesting suggest VBG 771 775 that that IN 776 780 this this DT 781 783 is be VBZ 784 786 an an DT 787 796 important important JJ 797 800 and and CC 801 811 ubiquitous ubiquitous JJ 812 827 bioinactivation bioinactivation NN 828 837 mechanism mechanism NN 837 838 . . . 839 840 4 4 LS 840 841 . . . 842 854 Fluorescence Fluorescence NNP 855 859 HPLC HPLC NNP 860 866 showed show VBD 867 871 that that IN 872 880 SMX-NHOH SMX-NHOH NNP 881 884 and and CC 885 891 SMX-NO SMX-NO NNP 892 900 depleted deplete VBD 901 904 CYS cys NN 905 908 and and CC 909 912 GSH gsh NN 913 915 in in IN 916 922 buffer buffer NN 922 923 , , , 924 927 and and CC 928 930 to to TO 931 932 a a DT 933 939 lesser less JJR 940 946 extent extent NN 946 947 , , , 948 950 in in IN 951 956 cells cell NNS 957 960 and and CC 961 967 plasma plasma NN 967 968 . . . 969 970 5 5 LS 970 971 . . . 972 982 Neutrophil Neutrophil NNP 983 992 apoptosis apoptosis NN 993 996 and and CC 997 1007 inhibition inhibition NN 1008 1010 of of IN 1011 1021 neutrophil neutrophil NN 1022 1030 function function NN 1031 1035 were be VBD 1036 1043 induced induce VBN 1044 1046 at at IN 1047 1052 lower low JJR 1053 1067 concentrations concentration NNS 1068 1070 of of IN 1071 1079 SMX-NHOH SMX-NHOH NNP 1080 1083 and and CC 1084 1090 SMX-NO SMX-NO NNP 1091 1095 than than IN 1096 1101 those those DT 1102 1110 inducing induce VBG 1111 1115 loss loss NN 1116 1118 of of IN 1119 1127 membrane membrane NN 1128 1137 viability viability NN 1137 1138 , , , 1139 1143 with with IN 1144 1147 SMX SMX NNP 1148 1154 having have VBG 1155 1157 no no DT 1158 1164 effect effect NN 1164 1165 . . . 1166 1177 Lymphocytes Lymphocyte NNP 1178 1182 were be VBD 1183 1196 significantly significantly RB 1197 1198 ( ( ( 1198 1204 P<0.05 p<0.05 NN 1204 1205 ) ) ) 1206 1210 more more RBR 1211 1220 sensitive sensitive JJ 1221 1223 to to TO 1224 1227 the the DT 1228 1234 direct direct JJ 1235 1244 cytotoxic cytotoxic JJ 1245 1252 effects effect NNS 1253 1255 of of IN 1256 1262 SMX-NO SMX-NO NNP 1263 1267 than than IN 1268 1279 neutrophils neutrophil NNS 1279 1280 . . . 1281 1282 6 6 CD 1282 1283 . . . 1284 1296 Partitioning partitioning NN 1297 1299 of of IN 1300 1308 SMX-NHOH SMX-NHOH NNP 1309 1313 into into IN 1314 1317 red red JJ 1318 1323 blood blood NN 1324 1329 cells cell NNS 1330 1333 was be VBD 1334 1347 significantly significantly RB 1348 1349 ( ( ( 1349 1355 P<0.05 p<0.05 NN 1355 1356 ) ) ) 1357 1362 lower low JJR 1363 1367 than than IN 1368 1372 with with IN 1373 1376 the the DT 1377 1390 hydroxylamine hydroxylamine NN 1391 1393 of of IN 1394 1401 dapsone dapsone NN 1401 1402 . . . 1403 1404 7 7 CD 1404 1405 . . . 1406 1409 Our our PRP$ 1410 1417 results result NNS 1418 1425 suggest suggest VBP 1426 1430 that that IN 1431 1434 the the DT 1435 1442 balance balance NN 1443 1450 between between IN 1451 1460 oxidation oxidation NN 1461 1463 of of IN 1464 1467 SMX SMX NNP 1468 1470 to to TO 1471 1474 its its PRP$ 1475 1480 toxic toxic JJ 1481 1492 metabolites metabolite NNS 1493 1496 and and CC 1497 1502 their their PRP$ 1503 1512 reduction reduction NN 1513 1515 is be VBZ 1516 1518 an an DT 1519 1528 important important JJ 1529 1539 protective protective JJ 1540 1548 cellular cellular JJ 1549 1558 mechanism mechanism NN 1558 1559 . . . 1560 1562 If if IN 1563 1565 an an DT 1566 1575 imbalance imbalance NN 1576 1582 exists exist VBZ 1582 1583 , , , 1584 1595 haptenation haptenation NN 1596 1598 of of IN 1599 1602 the the DT 1603 1608 toxic toxic JJ 1609 1620 metabolites metabolite NNS 1621 1623 to to TO 1624 1630 bodily bodily VB 1631 1639 proteins protein NNS 1640 1649 including include VBG 1650 1653 the the DT 1654 1661 surface surface NN 1662 1664 of of IN 1665 1671 viable viable JJ 1672 1677 cells cell NNS 1678 1681 can can MD 1682 1687 occur occur VB 1687 1688 , , , 1689 1692 and and CC 1693 1696 may may MD 1697 1703 result result VB 1704 1706 in in IN 1707 1711 drug drug NN 1712 1728 hypersensitivity hypersensitivity NN 1728 1729 . . .