Phenotypic and genotypic assessment of concomitant drug-induced toxic effects in liver, kidney and blood

• Published in: Journal of applied toxicology Vol. 31; no. 2; pp. 117 - 130
• Main Authors: Dadarkar, Shruta S., Fonseca, Lyle C., Mishra, Prabha B., Lobo, Aurelio S., Doshi, Lalit S., Dagia, Nilesh M., Rangasamy, Ashok K., Padigaru, Muralidhara
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.03.2011; Wiley; Wiley Subscription Services, Inc
• Subjects: Animals; Biological and medical sciences; biomarkers; Biomarkers - blood; Biomarkers - metabolism; Blood; Blood Cells - drug effects; Blood Cells - metabolism; Blood Cells - pathology; Chemical and Drug Induced Liver Injury - blood; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Drug-Related Side Effects and Adverse Reactions - blood; Drug-Related Side Effects and Adverse Reactions - metabolism; Drug-Related Side Effects and Adverse Reactions - pathology; Drugs; Female; Gene Expression Profiling - methods; Gene Expression Regulation - drug effects; Genes; hepatotoxicity; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidneys; Liver; Medical sciences; nephrotoxicity; Organ Specificity; Organs; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; surrogate; Toxicity; Toxicity Tests, Acute - methods; toxicogenomics; Toxicology; Drug; Kidney disease; Evaluation; Biological fluid; Urinary system disease; Digestive system; Toxicity; Liver; biomarkers; Biological marker; Genotype; Hepatic disease; Toxicogenomics; Kidney; Blood; Phenotype; Urinary system; nephrotoxicity; hepatotoxicity; Digestive diseases; surrogate
• DOI: 10.1002/jat.1562
• ISSN: 0260-437X; 1099-1263

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. Copyright © 2010 John Wiley & Sons, Ltd. Little is known about blood as a surrogate tissue in drug‐induced toxicity. Rats treated with therapeutics were assessed for multi‐organ toxicity. Phenotypic parameters confirmed hepatoxicity/nephrotoxicity. Test drugs generated specific gene expression patterns for each organ. Hierarchical clustering led to ‘fingerprints’ indicative of toxicity. In blood, a set of genes was derived which closely correlated with individual drug‐induced concomitant changes in liver/kidney. Our findings underscore the importance of transcriptional profiling and recommend judicious use of blood as a surrogate for toxicity.