429

Jean-Charles Gautier (ed.), Drug Safety Evaluation: Methods and Protocols, Methods in Molecular Biology, vol. 691DOI 10.1007/978-1-60761-849-2, © Springer Science+Business Media, LLC 2011

Index

A

Absolute quantification .................. 227, 369, 394, 417–427Amplification efficiency .........................231, 232, 234–236Aneugens ........................................................123, 124, 129Antigen retrieval .....................................84–88, 92–95, 105Arrhythmia .................................................................... 152ATP content .................................................................. 208

B

Benzoquinone ................................. 304, 307, 318, 324, 327Bias investigation ................................................... 354, 361Bioactivation .......................................................... 284, 291Biomarkers ...................24, 25, 99, 104, 116, 120–124, 133,

187, 206, 351–367, 369–383, 385–410, 417–427Biomonitoring ........................................116, 120, 132, 133

C

Carbon 13NMR .................................................... 205–223Catalase ..........................................................418, 420–422Cation exchange fractionation ........................371, 374–377Cell culture ............................ 137, 143, 153–155, 168, 171,

245, 247, 248, 271, 286, 402Cell preparation ......................................153–155, 245–247Cellular metabolomics ........................................... 205–223Centromeres .......................................................... 115–133Clark electrode ...................................................... 245, 249Clastogens ..............................................123, 124, 130, 131Combination drugs ...................................................... 3–15Comet assay ....................................................129, 137–146Covalent binding ....................................283–300, 303, 305Cytochrome c ......................... 306, 309, 310, 312, 318–320,

322, 323, 325Cytochrome P450 ................................................. 283, 378Cytotoxicity study ...................................245, 247–248, 251

D

Developmental toxicity .................. 15, 24, 29, 33, 257–269, 271–278

Digital image analysis .............................................. 97–1113-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium

bromide (MTT) test ...........................245, 247, 251DNA damage ................................. 130, 137, 138, 143, 144

Dose selection ........................................................ 5, 11–12Drug development ....................... 4–10, 12, 14–15, 21, 151,

152, 187, 257, 284, 305, 369, 386Drug metabolism ............................................8, 10, 11, 206

E

Egg culture .....................................................260–263, 267Egg fertilization ..................................................... 258–260Electrophoresis ...................... 137–142, 144, 173, 187–203,

328–333, 337, 381Electrophysiology ...................................152–154, 156–159Embedding .......................44, 70, 71, 73–76, 80, 81, 91, 99,

104, 139, 141, 145Embryos ...................31, 260, 263, 265, 267–269, 272–275,

277, 278Embryotoxicity ................................................ 25, 271–278

F

Fixation ..............................................60, 70, 72–73, 84–85Fluorescence in situ hybridisation (FISH) ............... 97, 98,

106, 115–133Frog embryo teratogenesis assay Xenopus

(FETAX) ................................................... 257–269

G

Gas chromatography-mass spectrometry (GC-MS) ................... 387–388, 401–405, 410, 411

GeneChip hybridisation .........................170–171, 176–177Genetic polymorphisms ........................................ 131–132Genetic toxicology ..............................6, 115–133, 137–146Genomics .............................................................. 106, 386

H

High pressure liquid chromatography (HPLC) ........... 285, 287, 294–296, 298, 300, 305–310, 319, 321, 324, 336, 340, 341, 344, 370, 371, 373–375, 377, 387, 400, 401, 419, 422

Histological slides ...................................................... 40, 72Histology .................................40, 44, 69–71, 73, 81, 83, 84Histopathological procedures ........................31, 33, 39–43,

53, 69–81Human ether-a-go-go (HERG) ............................. 151–162

430 Drug Safety evaluation

Index

I

Idiosyncratic toxicity...................................................... 284Image analysis

2D-DIGE ....................................................... 199, 202tissue microarrays............................................... 97–111

Immunohistochemistry (IHC) ....... 70, 72, 83–95, 104–106In vitro transcription (IVT) ............................170, 175, 185Isobaric tag for relative and absolute quantitation

(iTRAQ) .................................................... 369–383Isoelectric focusing (IEF) ......................188–190, 194–195,

197, 198, 202, 381

J

Juvenile toxicity ......................................................... 17–33

K

Kidney ..............................18, 40, 44–46, 50, 51, 54–56, 99, 102, 108, 188, 191, 203, 206, 207, 210–215, 219, 223, 244, 339, 340

Kinetochores ...................................................116–118, 124

L

Lactate dehydrogenase (LDH) release ...........208–210, 219Liquid chromatography-mass spectrometry

(LC-MS) ........................... 339–346, 371, 372, 374, 377–379, 381, 386–389, 399–401, 403–405, 407, 410, 411, 418, 419, 427

Liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) ..................... 317–325, 327–338

Liver ........................... 18, 33, 40, 44–46, 51, 53–54, 62, 63, 99, 102, 188, 191–192, 203, 206–208, 210–220, 223, 243–247, 283–300, 327, 370–372, 376, 381, 418, 421

M

Macroscopy ....................................................39, 44, 45, 53Malformations .......................................259, 262–265, 269,

272, 276Mass spectrometry (MS) ....................... 193, 200, 201, 206,

298, 300, 305, 322, 329, 330, 336, 340, 342, 344, 345, 351, 371, 377–379, 378, 382, 385–411, 417, 419–422, 426

Matrix assisted laser desorption ionization-time of flight (MALDI-TOF) ....................303–314, 319

Mechanisms of toxicity .................................... 99, 187–203Metabolic profiling ..........385, 386, 390, 392, 400, 405, 406Metabolomics ................... 99, 205–223, 385, 401, 404–406Metabonomics ....................................................... 385–411Microarray ................................ 97–111, 166, 168, 176, 227Micronuclei (MN) .......................... 115, 117, 121, 123–132Micronucleus assay ................................................ 115–133

Microsomes ............................................284, 285, 288, 298Microtome ........................................ 71, 75–77, 85, 99, 103Mitochondrial respiration ...................................... 243–252Mouse ...............................12, 24, 25, 44, 49, 54, 55, 61–63,

92, 106, 168, 179, 180, 258Multi-dimensional protein identification technology

(MuDPIT) ................................................ 339–346Multiple reaction monitoring (MRM) ..................401, 410,

417–427

N

Necropsy .......................................................31, 39–64, 366Neutral red uptake test .................................................. 248Normalization ............................... 188, 192, 228–230, 367,

397–399, 410Nuclear magnetic resonance (NMR) ......205–223, 385–411

O

Oxygen consumption .....................................249, 251, 252

P

Patch-clamp .......................................................... 151–162Pathology ..........................29, 30, 33, 39–64, 69–81, 83–95,

97–111, 258, 267, 389Pediatric ............................................................... 17–23, 32Post-translational modifications .....................188, 303, 329Potassium channels ........................................................ 154Precision-cut tissue slices ....................................... 205–223Preclinical studies ...................................3–15, 20, 188, 351Predictive toxicology .........................................99, 187, 188Protein adducts ....................... 283–300, 317–325, 327–338Protein extraction .......................... 188–189, 191–192, 201,

370–373, 381, 418Proteomics ........................................ 99, 187, 369–383, 386

Q

QT interval .........................................................5, 151, 152Quality control .............................. 143, 180, 181, 193, 199,

352–354, 360–365, 426Quinones ................................ 304–307, 318, 319, 323, 325Quinone-thioethers ................ 304, 305, 307, 319, 323, 325

R

Radiolabeled compound .................................284, 285, 297Rat .............................. 12, 23–25, 27, 44, 45, 49, 52–55, 58,

61–63, 92, 99, 102, 167, 210, 211, 215–220, 243–252, 272, 284–287, 291, 294, 299, 325, 327–338, 354, 357, 366, 370, 393, 418

Rat hepatocytes ..................................................... 243–252Reactive intermediate ............................ 284, 288, 300, 304,

305, 317, 318Regulatory guidelines ...................................................... 26

Drug Safety evaluation

431

Index

Relative quantification ...........................227, 228, 230–234, 238–239, 422, 424–426

Repair endonucleases ............................................. 137–146Respirometer ..................................................245, 251, 252Reverse transcription-polymerase chain

reaction (RT-PCR) .............................182, 227–240RNA extraction ..............................................168, 171–172RNA quantification ........................................169, 172–173Rodents ......................................... 5, 12, 22, 23, 25–31, 33,

39–64, 354, 389

S

Safety biomarkers ..................................351–367, 369–383, 385–411, 417–427

Safety pharmacology ................................5, 6, 11, 151–162Safety testing ............................................................. 22, 25Sampling

blood .............................................29, 62, 366, 389–390GC-MS ........................................................... 387–388LC-MS.............................................319, 387, 389, 400NMR ................................................387, 389, 391, 392urine ................................................................ 389, 390

Sampling procedures ................................................. 39–64Screening assays ......................................257–269, 271–278Sectioning .................................................70–73, 75–78, 80Staining ............................................. 70, 72, 78–79, 81, 87,

88, 90–93, 95, 97, 102, 103, 105, 108, 109, 111, 125, 138, 141, 142, 171, 177, 178, 201, 328, 330, 332, 333

Standardization ......................................................... 83, 91Statistical analysis .................. 108, 128, 131, 200, 209–300,

227–240, 264–265, 379, 403Strand breaks ..........................................116, 137, 142, 145Study design .............................................21, 23, 26–28, 31Surface enhanced laser desorption ionisation

(SELDI) .................................................... 351–367

T

Teratogen........................................................257, 264, 267Teratogenesis ................................................................. 257Teratogenic index ...........................................263, 265, 266Tissue microarrays (TMA) ...................................... 97–111Tissue sampling ......................................................... 69–81Torsades de pointes ............................................................152Toxicology .................................................3–15, 17–33, 44,

73, 99, 115–133, 137–146, 187–203, 206, 369, 418Transcriptomics .....................................167–185, 187–203,

205–223, 227–240, 243–252, 258Transcript profiling ................................................ 167, 180Trimming .................................................40, 55, 70–71, 73Trypsinization................................. 245, 248–249, 251, 252Trypsin solution digest ..........................320–321, 324, 325,

342, 343Two-dimensional difference gel electrophoresis

(2D-DIGE) ............................................... 187–203

U

Ultra performance liquid chromatography-mass spectrometry (UPLC-MS) .................386, 400, 408

V

Volcano plot ........................................................... 182, 184

W

Western blot .............................................91, 103, 327–338

X

Xenopus laevis ..................................................................258

Z

Zebrafish ............................................................... 271–278