Ortiz de Montellano Paul R.(Ed.) Cytochrome P450. Structure, Mechanism, and Biochemistry
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678
Index
Ligand, axial
contd.
imidazole, 51
protein environment effects, 52
and spin state, 48, 157
thiolate ligand, 48, 49
effect of structure on, 60, 61
effect on iron, 48, 52, 61, 183, 190, 248
thiolate ligand equivalents
methoxide, 62
methyl mercaptide,
49-51, 59-61,
69, 70
thiolate (SH-), 50, 60, 70
thiophenoxide, 51
water as 6th ligand, 48, 65, 192
Ligand binding domain, 323
Limonene, 9, 569
Linamarin, 564
Lindane, 210
Linear free energy relationships
inactivation by cyclopropylamines, 273
substrate oxidation, 427
Linker domain, P450 reductase, 120, 121
Linoleic acid
oxidation of, 187,409,423
as PPAR ligand, 332
Linum usitatissium (flaxseed), 555
Linuron, 566
Lipase, 117
Lipid peroxidation, 403, 422
Lipoxins,, 436, 531, 535
Lipoxygenases, 531, 536
Liquiritigenin, 571
Lithocolic acid, 327, 440
LKMl, see Antibodies
Loganin, 224, 571
Losartan, 409, 411
Lotaustralin, 564
Lotus japonicus, 571
Lovastatin, 425
desaturation of, 210
LRH-1,451
LTB4, see Leukotriene B4
Lupinus sp., 671
Luteinizing hormone, 363
LXRa,440,461
LXRP,440,461
Lycopersicon esculentum (tomato), 555
Lysine acylation, 254
Macarpine, 572
Magnetic circular dichroism, 156
Major histocompatibility locus, 453
Malondialdehyde, 439
Manganese porphyrin, 8, 19-22, 51, 62
as haloperoxidase, 22, 23
oxygen exchange in reaction, 19,20, 22
peroxynitrite reaction, 23, 24
Manganese porphyrin
contd.
stereoselective oxidation by, 25, 26
Manihot esculenta (cassava), 557, 561
Marmesin, 186,223
MDL 19347, 292
Meander region, 95
Mechanism-based inhibitors, see Inhibition
Medicago
5fl?/vfl (alfalfa), 555,571
truncatula, 575
Medicarpin, 571
Meloxicam, 428
Membrane
binding of P450 to, 92, 93, 442
heme relative to, 93, 95
insertion sequence, 92, 93
model phospholipid depth, 95, 129
permeability to calcium, 542
phospholipid monolayers, 95, 129
targeting to membrane, 92
targeting to in mitochondria, 92
topology, 129
Mentha sp., 569
Menthofuran,
261,
404, 621, 624
Menthol, formation of, 569
Mephenytoin, 378, 386, 406-408, 412, 621, 625, 626
19-Mercapto-androst-4-ene-3,17-dione, 289
10-P-Mercaptoestr-4-ene-3,17-dione, 290
Metabolic intermediate complexes
properties, 262, 263, 264, 265, 425
spectra, 645
Metabolon, 563, 574
Metallocorroles, 19
Metalloenzymes, 150
Metalloporphyrin, 62
activation of dioxygen, 6-10, 155, 157, 159
amphiphilic, 24
chiral oxidations by, 25, 26
hydroxylation, 17
see Manganese porphyrin
olefin epoxidation, 17,
18-21,
26, 535
radical cations, 17, 18, 207
Methane, 11, 68, 69, 71, 72, 590
Methane monooxygenase, 15, 164
Methanosarcinia barkeri, 589
Methemoglobin reduction, 134
Methemoglobinemia, 134, 394, 400
Methimazole, 362
Methionine N-hydroxylation, 555
Methionine synthase, 134
reductase, 118, 120, 124, 125, 132
Methoxsalen, 250, 261, 386
2'Methoxyacetophenone, 405
3-Methoxy-4-aminoazobenzene,
401,
436
Methoxychlor, 330
18-Methoxycoronaridine, 412
Index
679
S-Methoxy-A'^TV-dimethyltryptamine,
416
Methoxylamine,
261
3-Methoxyphenethylamine,
416
4-Methoxyphenethylamine,
416
8-Methoxypsoralen,
250, 404, 621, 642
Methoxyresorufin,
633
8-Methoxypsoralen,
263
5-Methoxytryptamine,
416
9-Methylanthracene,
207, 208
14a-Methyl-15-aza-D-homosterols,
291
N-Methylcoclaurine
3'-hydroxylation,
557, 571, 572
3-Methylcholanthrene,
335, 336, 363, 398
Methylcyclohexane,
31
6-Methyleneandrosta-1,4-diene-3,17-dione,
289
4,4'-Methylene-bis(2-chloroaniline),
384, 428
Methylenedioxy carbene
complex,
264, 645
Methylene
chloride, 420
Methylenedioxy
compounds, 263, 571
Methylenedioxy
bridge,
formation
of,
571-573
14-Methylergosta-8,24(28)-dien-3,6-diol,
604, 608
14-Methylfecosterol,
604, 608
2-Methyl-l-heptene,
267
3-Methylindole
desaturation
of,
211,
422, 436
P450 inactivation
by, 280, 378
4-Methyl-N-methyl-N-(2-phenyl-2H-
pyrazol-3-yl)benzenesulfonamide
(DMZ), 101
4-(Methylnitrosamino)-1
-(3-pyridyl)-1
-butanol, 3 84
4-(Methylnitrosamino)-1
-(3-pyridyl)-1
-butanone, 378,
384,
403
Methylococcus
capsulatus, 588, 590, 591, 594
fusion protein with
ferredoxin,
592, 594
4-Methylpentanal,
211, 212, 445
4-Methylpyrazole
as
inhibitor,
421, 621, 627
0-Methylsterigmatocystin,
224
N-Methylsulfonyl-12,12-dibromododec-11
-enamide,
293
N-Methylsulfonyl-6-(2-
propargyloxyphenyl)hexanamide,
293, 294
Methyl
thieno[3.2.d][1.2.3]-thiadiazole-6-carboxylate,
283
Methyltrienolone,
351
Methylvinylmaleimide,
282
Methymycin,
600
Metyrapone, 249, 250, 642
Mice
C57B1/6, 335
129SvJ,
538
Transgenic, 395, 416, 433, 435, 440, 455
see
Null mice
Miconazole, 250, 290, 291, 293, 592, 593
Microperoxidase,
154, 160
Microsporum
spp., 603
Midazolam,
386, 425, 426, 622, 629
cooperativity
in
metabolism
of, 429
Mifepristone, 250, 259, 271, 622
Mitogen,
541
Mitomycin
c, 120
MKP-1,449
Molecular
dynamics, see
Computation
Monosodium
glutamate, 353, 355
Morpholine, 598
Morphine
biosynthesis, 463, 554, 572, 573
Mortierella
isabellina,
198
Mossbauer,
17, 156,
158,267
computed
parameters, 45, 54
MSPPOH,
293, 294
Musca
domestica,
222
Mycobacterium
avium,
591
CYPome
of, 594, 598
bovis, 589, 592, 593
CYPome
of, 594, 598
chelonei,
592, 593
fortuitum, 592, 593
leprae, 589, 592, 594, 596
CYPome
of, 594, 598
marinum,
591
smegmatis, 589, 591-593, 596
CYPome
of, 594, 596, 598
phylogenetic
tree, 596, 597
tuberculosis, 125, 127, 135, 589, 590-593, 596, 609
CYPome
of, 594, 596
phylogenetic
tree, 596, 597
Mycosphearella
graminicola,
591
Mycotoxin
biosynthesis, 603
Myeloperoxidase,
1
Myoglobin
engineering
of, 169
heme modification
of, 281
hydroperoxo
complex,
158, 159
iron-aryl
complex,
274, 275
oxygen
complexes, 156, 157
reaction with
peroxides, 281, 154
Myristic
acid,
434
Myzus
nicotiana,
554
NADP Sepharose
chromatography,
227
Naphthalene,
210,422
dihydro-, 210
tetrahydro-, 33
a-Naphthoflavone,
389, 398, 399, 402, 408, 409, 538
as
allosteric
effector,
427, 428
as
inhibitor,
428
2-Naphthylamine,
384
2-Naphthylhydrazine,
274
Narbomycin,
600
Naringenin,408,430,
571
NcoR,
324,424
Nectria
haematococca,
603
Nematode,
sterol from
diet,
590, 592
Neomethycin,
600
680
Index
NF-IC,
449
Neopinone, 573
Neurospora crassa, 589, 591, 602, 603
NF-1,328
NFKB,
442
Nicotiana tabacum, 554
Nicotine
binding to P450
oxidation of, 396, 403
Nifedipine, 134, 386, 423,425, 426,
621,
628, 637
NIH shift, 75, 202, 204
Nikkomycin, 599
Nitrene, 267
Nitric oxide, 2
as ligand, 51
P450 inhibition by, 248
as product, 16, 571
Nitric oxide reductase , see CYP55A1
Nitric oxide synthase, 1, 2
alternative electron acceptors, 120
and calmodulin, 16, 118, 120
domains, 118
structure, 16, 17,89
mechanism, 16, 127, 150, 159
reactions, 16, 124
redox properties, 125, 132
spectroscopic properties, 156
and tetrahydrobiopterin, 16
Nitrite, 21
/7-Nitroanisole, 194, 640
6-Nitrobenzo[a]pyrene, 401
4-Nitrocatechol, 420
6-Nitrochrysene, 401
2-Nitrofluoranthene, 401
3-Nitrofluoranthene, 401
Nitrogen oxidation
N-dealkylation, 193, 194
methyl vs ethyl, 195
electron transfer in, 193
N-oxidation, 194
/7-Nitrophenol, 420, 621
1-Nitropyrene,
401
2-Nitropyrene, 401
Nitroso complex, 266
N-Nitrosobenzylmethylamine, 403
N-Nitrosobutylamine, 403
N-Nitrosodimethylamine, 403, 621, 627, 636
N-Nitrosomethylphenylamine, 405
N-Nitrosophenylmethylamine, 403
N-Nitrosodipropylamine, 403
N-Nitrosodiethylamine, 403, 405, 420
N-Nitrosonornicotine, 403
Nitrous oxide, 30
NMR
of adrenodoxin, 136
ofcytochromeP450 reductase, 120, 122
NMR
contd.
i^F,
203
ligand binding, 25, 27, 64
of metalloporphyrins, 17, 157, 267
of Pd/PdX complex, 136
Nomenclature, See P450
NonO,
449
Norbomane, 3, 4, 8
exo-tetradeuterio-, 4
Norbornene
epoxidation, 17,26,269
metalloporphyrin adduct, 269
Norcarane, 11, 12,15,188
Norepinephrine signaling, 538
Nomitrosonicotine, 384
Novobiocin, 599, 600
NRl, 118, 120, 124, 125
Nuclear receptors, 323, 325
enhancer, 328
phosphorylation, 324
Null mice, 380, 395, 396
acetyl CoA, 332, 334
AHR, 338
CAR, 330, 331
CYP1B1,395,396,400,401
CYP2E1,395,419,420,422
cyp4al4, 543, 544
CYP7A1,439,440
CYP11A1,446
CYP19A 1,452
CYP27A1,458
CYP27B 1,460
P450 reductase, 119, 120. 605
PPAR, 334, 335, 531, 539
PXR, 326, 327
Nystatin, 598, 599
Obtusifoliol 14a-demethylation, 555, 558, 590
17-Octadecynoic acid, 294, 621, 630, 637
1-Octene,
33,268
/ra/25-[l-2H]-,
198,268
«-Octylamine, 646
0-dealkylation,
193, 194
17-ODYA, see 17-octadecynoic acid
Okadaic acid, 329
Olanexidine, 214
Olanzapine, 399
Oleandomycin, 599
Oleic acid, 198
Olefin oxidation, see Epoxidation
Oligomycin biosynthesis, 601
Oltipraz, 254
Omeprazole, 386, 394, 397, 399, 412, 621
Ondansetron, 399
Orbital
a2„,
50,
59,
62,
66,
77,
189
Index
681
Orbital
contd.
d,
48,
50
0RCA3,
569, 574
Org-30365,
289
Org-30958, 289
Organic anion transporter, 327
Oryza sativa, 554
Orphenadine, 406
Oryza sativa, 591
Osmaronin, 565
Osmotic stress, 165, 586, 591
Ostrinia nubilatis, 568
Ovariectomy, 351
Oxidase, 151-153, 156, 158
Oxidation potential, see Redox potentials
Oxidative stress, 422
N-Oxides, see Oxygen donors
reduction of, 120
2,3-Oxidosqualene cyclase, 590, 592
Oximes, dehydration to nitriles, 228, 564
(19R)-10-oxiranylestr-4-ene-3,17-dione, 290
7-Oxocholesterol, 439, 441
3-Oxodecalin-4-ene-10-carboxaldehyde, 222
7-Oxo-24,25-dihydrolanosterol, 291
2-Oxoglutarate dioxygenase, 567, 568
Oxonium ion, 265
Oxygen, activation of
mechanism of, 149, 150
oxygen-oxygen bond cleavage, 58, 59, 150, 154, 170
homo-vs heterolytic, 151, 154, 155, 160, 439, 533
Oxygen donors
acyl peroxide, 3, 23, 161
alkyl peroxides, 3, 154, 185, 254, 263
unsuitability of, 221
hydrogen peroxide, 3, 5, 152,
221,
222
hypochlorite, 23, 28
iodosobenzene, 3, 18, 28, 185, 194, 207, 221, 254,
439
reversibility of reaction, 17
N-oxides,
30-33,
197
Oxone®, 32
periodate, 3, 32
persulfide, 23
product differences vs native system, 416
Oxysterols, 458
Ozone layer, 30
P420
formation, 285
ligand in, 265
quantitation, 645, 646
spectrum, 645
P450
active site
conserved residues, 598, 601
electrostatic potential, 89
P450
contd.
ordered solvent, 89
water content, 65
branchpoints in catalysis, 156
see Catalytic cycle
conformational dynamics, 102, 106, 428, 429, 435
cooperativity in, 394, 427-^29
distance from iron of oxidized atom, 100
entry channel, 47, 65, 105, 108
expression of isoforms, 336, 392
heme binding to protein, 435, 436
human
identities, 378, 379
classification, 380
diseases, mutation based, 383
inducers, major, 387
liver content, 380-382, 385
relative importance of isoforms, 383, 386
hydrogen bond network, 57, 63, 152, 164
isomerase of hydroperoxides, 5
levels of, 381
sex differences, 347
mitochondrial, 379, 380, 419, 443, 444, 454, 456
nomenclature, 414, 554, 555, 586
phylogenetic trees, 555. 591
proteosomal degradation, 282
proton delivery, 63, 152, 154, 155, 161, 162, 165,
167,
169
see Cysteine ligand
quantitation, 644
rate limiting steps, 154, 427
reduction potentials, 54, 134
resting state, calculations on, 51
RZ values, 645
spectroscopic maxima, 644
stoichiometry, P450 catalysis, 184
structure fold, overall, 87
see Substrate access channel
topography, control of reaction, 73
P450Bi„j (CYP107H1), 135, 212, 213, 589
P450^^
(CYPlOl), 585, 586, 595
active site, 46, 64
alternate oxygen donors, 3
Asp251,
48, 63, 152, 164, 165, 167
Ala252, 163
autooxidation, 183
C357H, 183
computational studies of mechanism, 69-71
D251N, 158
entry channel, 65, 136
See Ferrous dioxygen complex
ferryl species, 3, 46, 59, 60, 167
fusion protein of, 138
Gin
360,
48,
60, 61
Gly248,
162
Gly359, 48, 60
682 Index
P450cam (CYPlOl)
contd.
hydrogen bonding network, 57, 90, 152, 162, 167
See Ferric hydroperoxo
I-helix,
90
iron-aryl complex, 274
Leu358,
48, 60
ligand binding, 108, 109, 167
oxy-complex, 55, 89, 160, 167
oxygen activation, 55, 56
potassium binding site, 168
protein radical of, 3
proton delivery, 48, 57, 152, 162, 165-169
putidaredoxin interaction with, 100, 135, 136
rate limiting step, 136
reaction catalyzed, 65, 103
spin state, 155
solvent isotope effect, 56
substrate binding, 63, 64, 155
structure, 87-89, 101, 104, 108-110
Thr252, 6, 48, 55, 57, 152, 162-168, 185
Tyr96,
64, 65, 167, 168
see Uncoupling
water content of active site, 65, 71
P450BJ^.3
(CYP102), 585-587, 594, 601
active site, 537
aldehyde oxidation, 222, 283
domains, 118,596
electron transfer, internal, 132, 133
hydride transfer, 132
reaction catalyzed, 11, 103
redox properties, 125, 133
reductase domain interaction, 95, 96, 98, 115, 120,
130
regulation of, 131
salt bridges in, 92
structure, 87, 88, 106
substrate
access channel, 65, 537
specificity, 537, 540, 595, 596
structure with, 100, 101, 105, 109, 131
turnover number, 131
P450BSP
peroxide dependence, 99
fatty acid oxidation, 99
structure, 99, 102
P450^^JCYP176A1)
redox partners, 588
cineol metabolism, 595
P450j^jj^,
See Nitric oxide reductase
P450EP„K
function, 99
reaction catalyzed, 103, 595
structure, 99, 100, 101, 104, 106
P450eryF(CYP107)
binding two substrates, 428
cooperativity, 428
P450eryF (CYP107)
contd.
computational studies, 55, 65
distal hydrogen donor, 89, 90
reaction catalyzed, 103
structure, 87-89, 101,428
substrate-assisted mechanism, 90,
91,
163
P450^^^(CYP55A1), 587
ligand complexes, 169
NADH binding to, 105
proton delivery, 169
reduction of
NO,
105, 169, 603
structure of, 169, 183
P450o,y3
vancomycin biosynthesis, 105
X-ray structure, 206
P450p^,^,599
P450j^P, 116
P450^^^,5eeCYPllAl
P450^oy(SoyC), 135
P450^^^p(CYP108),598
structure, 183
substrate, 595
P450™c. 599
Paclitaxel 6a-hydroxylation, 621, 625
Palmitic acid, 332, 434
Palmitoleic acid, 100, 105
Papaver somniferum, 554
Paraciticein, 569
Parathion,250,251,395
Parathyroid hormone, 454, 459, 538
Parkinson's disease, 418
Paroxetine, 264, 265, 621, 627
Paxillin biosynthesis, 603
Pbx 1,449
PAR, see Pregnane X receptor
PAS superfamily, 323, 324, 336
PBREM, 405, 407
Penicillin biosynthesis, 585, 586, 587
Penicillium
chrysogenum, 586, 587
digitanum, 607
italicum, 591
paxilli, 603
Pentafluorochlorobenzene, 203
Pentalenolacton biosynthesis, 601
Pentobarbital metabohsm, 119
7-Pentoxyresorufin, 422, 634
Perhexihne, 394
Peroxidase
axial ligand, 52, 89
catalytic cycle, 151
Compound I, 17, 150, 154
dioxygen bond cleavage, 154
distal histidine, 154
electronic state, 52
engineering of, 169
Index
683
Peroxidase
contd.
pKaofFe-OOH, 154
reduction potentials, 89
spin state, 52
Peroxide shunt, 153, 156, 160, 184
Peroxisome proliferator activated receptor (PPAR), 323,
331,545
binding protein, 333
coregulators, 333, 335
interaction with genes, 119
ligands for, 332, 533
null mice, 334, 335
PPARa, 119,332,440,539
PPARP, 332
PPAR7, 332,451
species difference, 334
structure, 333
Peroxisome proliferation, 331, 332, 396, 434, 621
hormonal effects on, 354
regulation of P450 reductase, 119
Peroxygenase
activated species, 150
catal)^ic cycle, 151
Peroxynitrite, 23, 24, 442
Persea americana (avocado), 556, 566
Petroselium crispum (parsley), 555
PGE2,
437, 534
PGD2,
427
PGE 1,427
PGH synthase, see Prostaglandin H synthase
PGG2,
439
PGHj,
439
PGH2,441,442,531
P450 role in isomerization, 532
hydroxylation of, 434, 534
PGJ2,
452
PGI2,
533
Phanerochaete chrysosporium, 589, 591, 598, 602, 610
Pharmacogenetics, 387
Pharmacogenomics, 387
Pharmacokinetics, 347, 387, 393, 394, 409, 419, 424
Pharmacophore models, 397, 399, 414-416, 455
Phaseolus aureus (mung bean), 555
Phenacetin, 204, 205, 394, 398^00, 621, 624, 633, 646
Phencyclidine, 259, 260
Phenelzine, 273, 274
Phenformin, 418
Phenobarbital
in arachidonate epoxidation, 539
as inducer, 402, 408, 412, 539, 621
hormonal effects on, 354
induction of P450 reductase, 119
negative regulation of, 363
receptor, 325
responsive enhancer module, 328
Phenol, substituted, 185, 204
Phenylacetaldehyde, 28, 200
Phenylacetaldoxime, 555
Phenylacetate
growth on, 586
2-hydroxylation, 586
Phenylacetylene, 257, 263, 269, 270, 271
Phenylalanine
in biosynthesis, 561, 569
N-hydroxylation of, 555
1
-Phenyl-1 -butanone, 200
Phenylbutazone, 442
^ra«5-l-Phenylbutene, 200
4-Phenyl-l-butyne, 271
Phenylcyclohexylamine, 260
1 -(1 -Phenylcyclohexyl)-2,3-dihydro-4-pyridone, 259
Phenylethyldiazene, 277
Phenethylisothiocyanate, 404
6-Phenyl-l-hexyne, 271
6-Phenyl-2-hexyne, 271
Phenylhydrazine, 273, 274
N-Phenylhydrazone, 273
Phenylimidazole
P450 inhibition by, 249
structure of P450 complex, 100, 104
Phenylketene, 257
5-Phenyl-l-pentyne, 271
2-Phenylphenanthridinone, 250
3-Phenylpropionaldehyde, 282, 283
1-Phenyl-1-propyne,
271
Phenylpropanoid pathway, 570, 574
Phenytoin, 252, 386, 409, 443, 621
Phlobaphenes, 570
Phorbol esters, 438, 440
Phosphatidylcholine, 117, 541
Phosphatidylethanolamine, 541
Phosphatidylinositol, 541
Phospholipases, 402, 535
Photoacoustic calorimetry, 165
Photochemical reduction, 157
Photosystem I, 135
Phthalate dioxygenase reductase, 138, 589
Phylogenetic relationships, 555, 591
Phyllotreta nemorum, 562
Phytoalexins, 553, 566, 568, 571, 603
Phytoanticipins, 553, 560
Phytoattractants, 553
Phytohormones, 554, 556, 558, 569, 574
Piceatannol, 402
Picia anomola, 591
Pikromycin, 599, 600
Pimelic acid, 213
Pinoline, 416
Piperonyl butoxide, 278, 642
Pisatin, 603
Pisum sativum (snow pea), 571
Pituitary, 350, 351
684
Index
Plasmalogens, 133
Pneumocystis carinii, 603
Polychlorinated biphenyls, 336, 397, 399
Polycistric ovary syndrome, 450
Polycyclic aromatic hydrocarbons
binding to DNA, 207
fungal hydroxylation of, 602
induction of
P450,
335
ionization potentials, 207
negative regulation of
P450,
363
oxidation of, 384,401
Polyglandular syndrome, 446
Polymorphisms, human, 383, 387
see individual P450 isoforms
influence on drug development, 389, 392, 394, 413
interindividual variation, 392
single nucleotide (SNP), 387, 395, 402, 406, 409,
419,
423,
424,
433,
435,
442,
449, 461
toxicities due to, 394, 396
ultrarapid metabolizers, 387, 414, 418
Polymorphonuclear leukocytes, 535
Popupus tremuloides (querken aspen), 555
Porphyria, 278
Porphyrin
binaphthyl, 9, 10,25,26
biosynthesis, 278
see Metalloporphyrin
octamethyl, 62
"picnic-basket", 25, 26
polyfluorinated, 28, 29
see Protoporphyrin IX
saddling, 62
me50-tetraaryl, 17, 18, 20, 29, 195
me^o-tetramethyl, 62
"twin-coronet", 26, 27
Posaconazole, 605, 607
Potential energy surfaces, 47
Potentiometry, 127, 128
PPAR, See Peroxisome proliferator activated receptor
^^P phosphate source, 157
Prandiol, 223
Pregnancy, P450 induction in, 534
Pregnane X receptor (PXR), 323, 325
in CYP3A induction, 324, 424, 425, 431, 433
in CYP2B induction, 330, 405, 406
in CYP2C induction, 408
in CYP7A inducction, 440
null mice, 326, 327
Pregn-4,20-diene-3-one, 634
5p-Pregnane-3,20-dione, CAR ligand, 329
Pregnenolone
21-chloro-,255
21,21-dichloro-,255
17a-hydroxy-, 449
hydroxylation, 441, 449
Pregnenolone
contd.
oxidation of, mechanism, 216, 217
^^O studies in oxidation of, 215
Pregnenolone
16a-carbonitrile, 324-327
6,16a-dimethyl, 325
Premarin®, 402
Proanthocyanidins, 570
Prodrugs, 394
Progesterone, 415
binding to CYP2C5, 108
and CAR activity, 329
21,21-dichloro-,255
17a-hydroxy-, 449
17-hydroxylation, 449
2a-hydroxylation, 640
6p-hydroxylation, 637, 640
15a-hydroxylation, 640
16a-hydroxylation, 635, 640
21-hydroxylation, 413, 453, 634, 637, 640
e«r-Progesterone, 450, 453
9'-Propargyl
abscisic acid, 259
Propargylamine
N-(2-heptyl)-, 259
7V-(2-heptyl)-A^-methyl-, 259
Propene
computational studies of oxidation, 68, 70, 71, 74,
77-79
in heme N-alkylation, 74, 268
Propentdyopents, 282
Propionaldehyde, 221
2-phenyl-, 221
Propofol, 406
7-Propoxycoumarin, 422
2-«-Propyl-4-pentenoic acid, 208
2-n-Propyl-2(£)-pentenoic acid, 209
4-(l-Propynyl)biphenyl, 271
10-(2-Propynyl)estr-4-ene-3,17-dione, 290
2-(l-Propynyl)naphthalene, 271
2-(l-Propynyl)phenanthrene, 271, 398
3-(l-Propynyl)phenanthrene, 271
9-Propynylphenanthrene, 271
l-(l'-Propynyl)pyrene, 271, 398
Prostacyclin, 438,
441,
531
Prostacyclin synthase, see CYP8A1
Prostaglandin H synthase, 531
EET oxidation, 533
model of, 26, 27
N-dealkylation by, 195
reaction catalyzed, 540
Prostaglandins
biosynthesis, 1, 119
in inflammation, 332
metabolism of, 294, 378, 437
Prostanoids, metabolism of, 532, 533
Index 685
Protein kinase A, 445, 449, 453
Protein kinase C, 425, 453
Proteosomal degradation, 282
Proton inventory, 165
Protoporphyrin IX
meso-Si\ky\-,
283
N-alkyl-, 278
N-(2-hydroxyalkyl)-, 277
N-(2-phenylethenyl)-, 277
N-(2-phenylethyl)-, 277
N-vinyl-, 277
4-(l-Propynyl)biphenyl, 199
Pseudohermaphroditism, 450
Pseudomona aeruginosa, 589
Pseudomonasputida, 3, 15, 87, 134, 585, 595
Psoralen, 187,223
Psoriasis, 460
Puberty, 348, 349
Putidaredoxin, 134, 595
fusion protein of, 138
interaction with
P450^^j^,
135, 136
interaction with putidaredoxin reductase, 98, 116
mechanism, 136
structure of, 97, 99, 135
Putidaredoxin reductase, 134, 595
dithiol/disulfide oxidoreductase activity, 138
fusion protein of, 137
structure of, 97, 99, 116
Pyrene, 428
Pyridine, 249
1 -methyl-4-phenyl-1,2,3,4-tetrahydro-, 196
4-aryl(alkyl)-l,4-dihydro-, 211
4-phenyl-^ra«5-1 -(2-phenylcyclopropyl)-1,2,3,6-
tetrahydro-, 197
17-(5-pyrimidyl)androsta-5,16-dien-3P-ol, 292
17-(3-pyridyl)androsta-5,16-dien-3(3-ol, 292
PXR, See Pregnane receptor
Quadricyclane, 192
Quercitin, 408
Quinidine
as allosteric effector, 428, 429
as inhibitor, 254, 386, 389, 394, 417, 621, 626
as substrate, 423
Quinine, 426
Quinone methide, 253
R-76713,250,287,288
Radiation, 556
Radical
alkoxy, 70,215,217
alkyl, 11, 12, 14, 189, 265, 272, 273, 275, 277, 280
aryloxy, 26, 206, 207
rer^butoxy, 8, 70, 189, 196
caged substrate radical, 8, 9, 14
Radical
contd.
lifetime, 9, 68, 187, 188
probes, 9, 11,68-70
properties of in transition state, 72
rearrangement, 11, 15, 189
recombination, 5, 11, 12, 188
spin trapping of, 194, 272, 273
trimethylsilyl, 286
tyrosine, 185, 186
Radical cation
aromatic ring, 203, 207
porphyrin, 2, 3, 6, 11, 67, 153
protein, 3
sulfur, 253
Radical clock, 9,
11,
68-70, 186-188
effects of metals on, 14
Radiolysis,5, 157, 158, 167, 191
Raloxifene, 253, 254
Ralston metallidurans, 589
Random mutagenesis, 399
Rapamycin, 599
Rat
Dahl Salt Resistant (DR), 543
Dahl Salt Sensitive (DS), 543
dwarf,
355
Fischer 344, 363
Nude, 459
Spontaneously Hypertensive (SHR), 543
Sprague-Dawley, 363, 544
Ravuconazole, 605, 607
Reaction barriers, 47
Rearrangements, oxidative
see Acetylenes
see Aryl migration
see Epoxidation
see NIH shift
see Radical clock
Receptor
see
Aryl hydrocarbon receptor
see Androstane receptor
see BRII receptor
see Famesoid receptor
see Glucocorticoid receptor
see Growth hormone receptor
see Nuclear receptors
see Peroxisome proliferator activated receptor
see Phenobarbital receptor
see Pregnane X receptor
see Retinoid X receptor
see Vitamin D receptor
Redox potentials
P450 control of, 89, 131, 132
Reductase partners, classification, 587-589
Regulation
see Diet, effects on P450
686
Index
Regulation
contd.
downregulation by cytokines, 388
endocrine, 347, 541
see Fasting
see Induction
Renex 690
Repeats, 323, 324, 336
Resonance Raman, 27, 156, 167
Response elements, 324, 326, 328, 337, 338, 397
Resveratrol, 283, 402
Reticuline, 205, 206, 571-573
Retinoic acid, 119
4-hydroxylation, 349, 379, 407, 409, 433, 455, 456
in P450 regulation, 440
Retinoid X receptor (RXR), 324, 328,
451,
454
Rheumatoid arthritis, 450
Rhizopus
niger,
586, 587
Rhodococcus sp., 588, 595, 596
Rhodotorula minuta, 226
Rhophalosiphum maydis, 568
Rhapontigenin, 283, 284, 402, 632
Rickets, 459, 460
Rifampicin, 386, 402, 407, 408, 412, 424, 433
Rifampin, 621
Ritonavir, 254, 415
Rosiglitazone, 407
RU486, 325
Ruthenium
P450gj^.3 modification, 96
porphyrin, 8, 12, 26,
28-33,
62, 73
RZ values, 645
Saccharomyces cerevisiae, 585
azole binding to, 605
in azole resistance, 608, 603, 605
14a-demethylase, 558
A^2-desaturation in, 210
P450 enzymes, 589, 591, 601
P450 reduction in, 120, 605. 606
Saccharum sp. (sugar cane) 560
Salen metal complexes, 19
Salt, 541, 543
Salt-inducible kinase (SIK), 445
Salt wasting syndrome, 453
Salutaridine, 205, 206, 572, 573
Saperconazole, 250
SCH66712, 283, 284, 417, 621, 627
Schizosacchawmyces pombe, 447, 589, 591, 601
Scoulerine, 571,572
Screening, high throughput, 133, 426
Secobarbital, 250, 256, 263, 267, 285, 634
Secologanin, 224, 568, 569
Sedormid, 256
Seminal vesicles, 534
Senecionine, 384
Senescence, 349
Sequence
homology model difficulties, 109
structure models
CYP1A1,397
CYP1A2, 399
CYP1B1,402
CYP2A6, 404
CYP2B6, 406
CYP2C9,410
CYP2C18,411
CYP2C19,413
CYP2D6,416
CYP2E 1,420
CYP3A4, 427
CYP4A11,434
CYP11B1,434
CYP11B2,448
CYP17A 1,450
CYP19A 1,452
CYP21A2,453
SET mechanism, 195, 196, 226
Sex hormone deficiencies, 383
Sex-linked differences
androgenic imprinting, 350
in eicosanoid metabolism, 536
and growth hormone, 350-352
in hepatic metabolism, 348
P450 levels in rat, 347, 353, 388, 537, 543, 544
specific forms, 348
Shear stress response element, 442
Sildenafil, 425
Simvastatin, desaturation of, 210
Sinapoyl malate, 556
Sinorhizobium meliloti, 589
SKF525-A, 278, 643
Smoking, 395-397, 399, 400, 403, 404, 418
SMRT, 324, 330, 333, 424
Na+-K+-ATPase, 536, 538
SOCS proteins, 361
Sodium transport, 541, 543
Solarium
lycopersicon (potato), 560
Solvents
see Ethanol
induction by, 419
inhibition of P450 activity, 389, 409
Soret maximum
alkyl or aryl-iron complex, 273, 275
carbene-iron complex, 264, 285
fifth iron ligand effect, 158, 248
MI complex, 265
red shift, 157
reverse Type I, 248, 646
split, 54, 156
Type I, 646
Type II, 248, 249, 291, 292, 605, 646
Sorghum
bicolor,
557, 558, 561, 573, 591
Index
687
SoyB,
135
Spl,
433,
442,
445,
449, 459,
461
Sp3,433,
445, 499
Sparteine, 383, 386,414
Spin densities, 61
Spin echo envelope modulation (ESEEM), 51
Spin state
computation of, 47, 50, 51, 80
doublet, 51, 189,201
quartet, 11, 12, 21, 49, 189, 190, 201
high, 48, 136
ligand effect on, 51, 61, 131
low,
48,
136
relation to electron transfer, 131, 248
sextet, 11,51
spectra associated with, 644
spin-orbit coupling, 9
substrate binding effect on, 3
Spiro[2,4]octane, 188
Spiro[2,5]octane, 12
Spiromethylsulfone, 415
Spironolactone, 253, 280, 281, 453
7a-thio-, 450
Spirosulfonamide, 415
Spontaneously hypertensive rat, 543
Squalene,
1,590,592
SR12813,
325
SRC-1,324,330,333
SREBP,461
Starvation, 331,537
Stat-3,451
Stat-5a, 360
Stat-5b,
356-361,
364
Sterigmatocystin,
211,
384
Steroid
22-desaturation, 586, 592, 601-604
6p-hydroxylation, 349, 555
7a-hydroxylation, 349
I la-hydroxylation, 586, 587
II (3-hydroxylation, 586
12-hydroxylase, 443
17a-hydroxylation, 379
23-hydroxylation, 555
27-hydroxylation, 379
C4-methyl oxidase, 605
5a-reductase, 349, 351, 364
Steroidogenesis pathway, 444
Steroidogenic factor
1
(SFl), 445^47, 449,
415,453
Sterol 11(3-/18-hydroxylase, see CYPl IB
Sterol 17a-hydroxylase/C 17-20 lyase, see CYPl7
Sterol 21-hydroxylase, see CYP21
Stigmasterol, 592
Stilbene, 33, 198, 570
St. John's wort, 394, 430
Stopped flow studies, 20, 124, 126, 127, 132, 157
Streptomyces
avermitilis, 589, 596, 598
CYPome, 600, 601
genome, 599
coelicolor, 99, 589, 590, 594, 596, 600, 601
CYP51 knockout of, 592
genome, 599
griseus, 135, 599
Streptomycete P450s, 599
Strictosidine, 569
Styrene epoxidation, 185, 384, 420, 422
p-chloro-,
25, 28
electronic effects on, 28
heme alkylation during, 267
isotope effects on, 198
/?-methoxy-, 28
/7-methyl-, 198
cw-|3-methyl, 25, 26
/7-nitro-, 28
/7-phenyl, 198
rearrangement during, 30, 200
stereochemistry of, 27, 33, 65
Substrate
access channel, 47, 65, 102, 105, 108, 410, 537, 609
exit channel, 47
Substrate binding, 183
channeling, in plant pathways, 563
contacting residues, 63
control of redox/spin states, 3
determinants of, 63
location, 47
mobility in relation to, 5, 64
of multiple substrates, 428
spectroscopic changes upon, 556, 646
water expulsion by, 71, 72
Substrates, functional markers, 621
Sulfaphenazole, 386, 407^10, 621, 626, 635
Sulfenic acid, 253
Sulfinic acid, 253
Sulfite reductase, 96, 118
Sulfolobus
solfataricus, 91, 100, 596, 601
tokodaii, 589
Sulfonic acid, 253
Sulforaphane, 254
Sulfur oxidation
S-dealkylation,
193
S-oxidation,
76, 197
sulfur radical cation, 77, 197, 198
Superoxide
dismutase, 197,258,282
reaction with P450, 157
uncoupling product, 134
Supersomes®, 252
Surfactant, 285
Sus scrofa, 591