Phenotypic and genotypic assessment of concomitant drug-induced toxic effects in liver, kidney and blood.
Several studies have characterized drug-induced toxicity in liver and kidney. However, the majority of these studies have been performed with 'individual' organs in isolation. Separately, little is known about the role of whole blood as a surrogate tissue in drug-induced toxicity. Accordingly, we investigated the 'concurrent' response of liver, kidney and whole blood during a toxic assault. Rats were acutely treated with therapeutics (acetaminophen, rosiglitazone, fluconazole, isoniazid, cyclophosphamide, amphotericin B, gentamicin and cisplatin) reported for their liver and/or kidney toxicity. Changes in clinical chemistry parameters (e.g. AST, urea) and/or observed microscopic tissue damage confirmed induced hepatotoxicity and/or nephrotoxicity by all drugs. Drug-induced toxicity was not confined to an 'individual' organ. Not all drugs elicited significant alterations in phenotypic parameters of toxicity (e.g. ALT, creatinine). Accordingly, the transcriptional profile of the organs was studied using a toxicity panel of 30 genes derived from literature. Each of the test drugs generated specific gene expression patterns which were unique for all three organs. Hierarchical cluster analyses of purported hepatotoxicants and nephrotoxicants each led to characteristic 'fingerprints' (e.g. decrease in Cyp3a1 indicative of hepatotoxicity; increase in Spp1 and decrease in Gstp1 indicative of nephrotoxicity). In whole blood cells, a set of genes was derived which closely correlated with individual drug-induced concomitant changes in liver or kidney. Collectively, these data demonstrate drug-induced multi-organ toxicity. Furthermore, our findings underscore the importance of transcriptional profiling during inadequate phenotypic anchorage and suggest that whole blood may be judiciously used as a surrogate for drug-induced extra-hematological organ toxicity.
Dadarkar
Shruta S
SS
Department of Pharmacology, Piramal Life Sciences Limited, Mumbai, Maharashtra, India. shruta.dadarkar@piramal.com
Fonseca
Lyle C
LC
Mishra
Prabha B
PB
Lobo
Aurelio S
AS
Doshi
Lalit S
LS
Dagia
Nilesh M
NM
Rangasamy
Ashok K
AK
Padigaru
Muralidhara
M
D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001773:Blood Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism / Q000473:pathology; D064420:Drug-Related Side Effects and Adverse Reactions / Q000097:blood / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023382:Toxicity Tests, Acute / Q000379:methods
D015415:Biomarkers; D012333:RNA, Messenger