Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells.
Studying peripheral blood transcriptome in the quest for translational markers of toxicity is considered to be an attractive offshoot in the field of toxicogenomics. Moreover, it is acknowledged that, xenobiotics which cause a toxic response through similar mechanisms lead to distinctive gene expression patterns. The current study was undertaken to gauge the response of an accessible surrogate tissue, such as blood, to drug-induced perturbations aimed at deriving gene expression patterns. Human peripheral blood mononuclear cells (hPBMC) were exposed to conventional drugs, with reported kidney and/or liver injury, in order to determine their transcriptomic response. Test drugs were divided into two classes viz., drugs affecting kidney (cyclophosphamide, amphotericin B, gentamicin and cisplatin) and liver (acetaminophen, rosiglitazone, fluconazole and isoniazid). After performing gene expression analysis and hierarchical clustering, signature patterns for the two classes were obtained, with a set of 365 genes that can discriminate the two classes of drugs. Our results imply that transcriptional profile of hPBMC get altered as a consequence of drug exposure and unique patterns indicative of specific organ toxicity can hence be deduced. These signature patterns obtained for drugs could be studied for their qualification to identify drug-induced toxicity.
Dadarkar
Shruta S
SS
The Department of Pharmacology, Piramal Life Sciences Limited, Mumbai 400063, Maharashtra, India. shruta.dadarkar@piramal.com
Fonseca
Lyle C
LC
Thakkar
Arvind D
AD
Mishra
Prabha B
PB
Rangasamy
Ashok K
AK
Padigaru
Muralidhara
M
D002478:Cells, Cultured; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008099:Liver / Q000187:drug effects*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis