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Topic: RSS FeedDevelopment of a DNA microarray for toxicology based on hepatotoxin-regulated sequences - Article
Environmental Health Perspectives, May 15, 2003 by Jeffrey F. Waring, Guy Cavet, Robert A. Jolly, Jeff McDowell, Hongye Dai, Rita Ciurlionis, Chunsheng Zhang, Roland Stoughton, Pek Lum, Allan Ferguson, Christopher J. Roberts, Roger G. Ulrich
Table 1. Hepatotoxins and dose levels used in the subtractive
hybridization study.
Low dose High dose
Compound (mg/kg/day) (mg/kg/day) Vehicle
3-Methylcholanthrene 10 100 Corn oil
Acetominophen 70 700 Saline
Actinomycin D 0.04 0.4 Saline
Adriamycin 1 10 Saline
Aflatoxin B1 0.05 0.5 Saline
Allopurinol 10 100 Saline
Allyl alcohol 10 40 Corn oil
Amiodarone 10 100 Saline
ANIT 10 40 Saline
Aroclor 1254 100 400 Corn oil
Arsenic 2 20 Saline
Aspirin 15 150 Saline
Bezafibrate 20 200 Saline
Carbamazepine 50 250 Saline
Carbon tetrachloride 100 1,000 Corn oil
Chlorpromazine 25 100 Saline
Cycloheximide 0.1 1.0 Saline
Cyclophosphamide 10 100 Saline
Dexamethasone 1 10 Saline
Diclofenac 10 40 Saline
Diethylnitrosamine 10 100 Saline
Diethylstilbestrol 2.5 25 Corn oil
Dimethyl formamide 100 1,000 Saline
Dinitrophenol 5 25 Saline
Diquat 17.2 68.8 (a) Saline
Erythromycin 80 800 Saline
Estradiol glucuronide 1 10 Saline
Ethanol ND 3,000 Saline
Etoposide 5 50 Saline
Galactosamine 50 500 Saline
Ibuprofen 20 200 Saline
Indomethacin 2 20 Saline
Iodoacetic acid 5 50 Saline
Iron dextran 50 500 Saline
Ketoconazole 30 120 Saline
L-Ethionine 5 50 Saline
Methapyrilene 5 50 Saline
Methotrexate 50 250 Saline
Microcystin 0.005 0.05 Saline
Monocrotaline 5 50 Saline
Nicotinic acid 200 2,000 Saline
Oligomycin 0.1 1.0 Saline
Perhexilene 32 320 Saline
Phenytoin 45 450 Saline
Quinidine 7.5 75 Saline
Retinol 50 500 Saline
Tamoxifen 5 50 Saline
Tetracycline 50 500 Saline
Tumor necrosis factor-[alpha] 0.001 0.010 Saline
Trovafloxacin 150 400 Saline
Valproic acid 50 500 Saline
Verapamil 40 200 Saline
Method
Compound of delivery Reference for dose
3-Methylcholanthrene ip Kleeberg et al. 1975
Acetominophen Oral Smith et al. 1998
Actinomycin D iv Bader et al. 1974
Adriamycin iv
Aflatoxin B1 Oral Root et al. 1997
Allopurinol Oral
Allyl alcohol ip Ganey and Schultze
1995
Amiodarone ip Reasor et al. 1996
ANIT Oral Chisholm and
Dolphin 1996
Aroclor 1254 ip Wolfgang et al. 1990
Arsenic ip Mahaffey et al. 1981
Aspirin Oral
Bezafibrate Oral Beier et al. 1988
Carbamazepine ip Regnaud et al. 1988
Carbon tetrachloride ip Wolfgang et al. 1990
Chlorpromazine Oral
Cycloheximide iv
Cyclophosphamide ip Brown et al. 1985
Dexamethasone iv
Diclofenac Oral
Diethylnitrosamine ip Williams et al. 1996
Diethylstilbestrol ip
Dimethyl formamide ip Mathew et al. 1980
Dinitrophenol Oral
Diquat ip Wolfgang et al. 1991
Erythromycin Oral Kaltiala et al. 1967
Estradiol glucuronide iv
Ethanol Oral Speisky et al. 1985
Etoposide ip Linden 1989
Galactosamine iv
Ibuprofen Oral Adams et al. 1969
Indomethacin ip Fracasso et al. 1987
Iodoacetic acid iv
Iron dextran ip Younes et al. 1989
Ketoconazole Oral Heel et al. 1982
L-Ethionine ip
Methapyrilene ip Graichen et al. 1985
Methotrexate ip Custer et al. 1977
Microcystin iv
Monocrotaline ip Perazzo et al. 1999
Nicotinic acid Oral
Oligomycin iv Kramar et al. 1984
Perhexilene Oral
Phenytoin Oral Garzon De la Mora
et al. 1990
Quinidine iv
Retinol Oral Lettinga et al. 1996
Tamoxifen Oral Wogan 1997
Tetracycline Oral
Tumor necrosis factor-[alpha] iv
Trovafloxacin Oral
Valproic acid Oral Kesterson et al. 1984
Verapamil Oral Landon et al. 1986
Compound Type of lesion
3-Methylcholanthrene Hypertrophy
Acetominophen Necrosis
Actinomycin D Necrosis
Adriamycin Necrosis
Aflatoxin B1 Necrosis
Allopurinol Phospholipidosis
Allyl alcohol Necrosis
Amiodarone Phospholipidosis
ANIT Cholestasis
Aroclor 1254 Hypertrophy
Arsenic Cirrhosis
Aspirin Steatosis
Bezafibrate Cholestasis
Carbamazepine Necrosis
Carbon tetrachloride Necrosis
Chlorpromazine Cholestasis
Cycloheximide Steatosis
Cyclophosphamide Necrosis
Dexamethasone Varying
Diclofenac Cirrhosis
Diethylnitrosamine Necrosis
Diethylstilbestrol Tumor formation
Dimethyl formamide Necrosis
Dinitrophenol Steatosis
Diquat Necrosis
Erythromycin Cholestasis
Estradiol glucuronide Cholestasis
Ethanol Steatosis
Etoposide Necrosis
Galactosamine Steatosis
Ibuprofen Cholestasis
Indomethacin Cholestasis
Iodoacetic acid Varying
Iron dextran Necrosis
Ketoconazole Hepititis
L-Ethionine Steatosis
Methapyrilene Steatosis
Methotrexate Steatosis
Microcystin Necrosis
Monocrotaline Necrosis
Nicotinic acid Cholestasis
Oligomycin Steatosis
Perhexilene Phospholipidosis
Phenytoin Cholestasis
Quinidine Varying
Retinol Steatosis
Tamoxifen Cholestasis
Tetracycline Steatosis
Tumor necrosis factor-[alpha] Hepititis
Trovafloxacin Necrosis
Valproic acid Steatosis
Verapamil Cholestasis
Abbreviations: ip, intraperitoneal; iv, intravenous; ND, not
done. (a) All animals in this treatment group died before
day 3 and were not used. Where no reference is provided,
dose levels were selected from unpublished results.
Table 2. Breakdown of probe selection for 25K
chip.
Subtractive hybridization
Unoriented 927
Oriented 1,548
CYP gene sequences 60
RefSeq sequences (a) 55
Sequences with human orthologs 1,144
Sequences selected by regulation
and/or kinetics 14,216
Sequences selected by intensity 6,449
Total 24,399
(a) Used in training set for sequence orientation.
Table 3. Some of the genes regulated by Aroclor 1254, 3-MC, or CPCA.
Accession number (a) Gene
E00717 CYP1A1
NM_012940 CYP1B1
NM_012600 Malic enzyme
NM_017014 Glutathione-S-transferase
D83796 UDP-Glucuronosyltransferase 1
U36482 Erp29
AA964229 Tricarboxylate carrier
J05030 Acyl-CoA dehydrogenase
D16478 Enoyl-CoA hydratase
K03249 Peroxisomal bifunctional enzyme
J02749 Acetyl-CoA acyltransferase,
3-Oxo-acyl-CoA thiolase A, peroxisomal
AI105060 Adipocyte lipid binding protein
D37920 Squalene epoxidase
AB016800 7-Dehydrocholesterol reductase
J05509 Cholesterol hydroxylase 7 [alpha]
NM_017024 Lecithin-cholesterol acyltransferase
AB021980 Fatty acid desaturase
NM_024132 Fatty acid amide hydrolase
NM_012556 Fatty acid binding protein 1
NM_030832 Fatty acid binding protein 7
AW534367 Prohepcidin
Cluster
Accession number (a) Aroclor 1254 3-MC CPCA (Fig. 3)
E00717 30.06 36.65 NC 1
NM_012940 63.13 100 NC 1
NM_012600 5.16 3.45 1.61 1
NM_017014 5.91 5.72 2.06 3
D83796 2.88 2.95 NC 3
U36482 1.6 1.67 NC 3
AA964229 -2.14 -2.68 NC 6
J05030 NC NC -1.94 NS
D16478 NC NC -1.35 NS
K03249 -1.84 -1.97 -5.41 7
J02749 4.23 2.93 -1.82 1
AI105060 NC NC 4.66 2
D37920 NC NC 10.21 2
AB016800 NC NC 1.83 NS
J05509 -7.81 -1.87 -5.52 7
NM_017024 NC NC -2.45 5
AB021980 1.22 2.11 -3.40 5
NM_024132 NC NC -2.11 5
NM_012556 NC NC -3.92 7
NM_030832 NC NC -3.79 7
AW534367 -7.57 -3.42 10.00 2
Abbreviations: NC, no change in expression; NS, gene was not shown
in Figure 3 cluster.
(a) Accession numbers are from GenBank (http://www.ncbi.nlm.nih.gov).
Table 4. Summary of regulated genes for Aroclor 1254, 3-MC, and CPCA.
Identified in Previously unknown
Compound Regulated genes Sub. hyb. sequences
Aroclor 1254 4,266 817 252
3-MC 5,005 892 251
CPCA 5,471 953 253
Sub. hyb., subtractive hybridization library.
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