An evaluation of a low-density DNA microarray using cytochrome P450 inducers.
The aim of this study was to validate a low-density DNA microarray "Rat HepatoChip", which contains 59 genes from a range of potential toxic markers and drug metabolism-related genes. Liver mRNA was isolated from rats dosed with six different chemicals, dexamethasone, troleandomycin, miconazole, clotrimazole, and methylclofanapate, which are all known to induce different cytochrome P450 genes, and isoniazid, which does not cause histopathological changes. Replicate microarrays were used to measure the variability in the chips and in the process. The average variability in signal between different chips observed in triplicate experiments was 33% ranging from 21 to 39% depending on genes. We also demonstrated a strong correlation between the liver histopathology and the gene expression profiles indicating that the gene expression profile reflects histopathological changes. These results suggest that the Rat HepatoChip microarray may provide a fast and effective tool for assessing the toxicity profile of developmental drug candidates during the drug discovery process.
Meneses-Lorente
Georgina
G
Merck Sharp & Dohme Neuroscience Research Center, Terling Park, Harlow, Essex, CM20 2QR, United Kingdom. georgina_meneseslorente@merck.com
de Longueville
Françoise
F
Dos Santos-Mendes
Sofia
S
Bonnert
Timothy P
TP
Jack
Andrew
A
Evrard
Stéphanie
S
Bertholet
Vincent
V
Pike
Andrew
A
Scott-Stevens
Paul
P
Remacle
José
J
Sohal
Bindi
B
D000284:Administration, Oral; D000818:Animals; D002992:Clofenapate / Q000008:administration & dosage / Q000493:pharmacokinetics; D003022:Clotrimazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005544:Forecasting / Q000379:methods; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D005819:Genetic Markers; D006824:Hybridization, Genetic / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D008825:Miconazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014217:Troleandomycin / Q000008:administration & dosage / Q000493:pharmacokinetics
D005819:Genetic Markers; D002992:Clofenapate; D008825:Miconazole; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D003022:Clotrimazole