Overview of the application of transcription profiling using selected nephrotoxicants for toxicology assessment

被引:36
作者
Kramer, JA
Pettit, SD
Amin, RP
Bertram, TA
Car, B
Cunningham, M
Curtiss, SW
Davis, JW
Kind, C
Lawton, M
Naciff, JM
Oreffo, V
Roman, RJ
Sistare, FD
Stevens, J
Thompson, K
Vickers, AE
Wild, S
Afsharif, CA
机构
[1] ILSI Hlth & Environm Sci Inst, Washington, DC 20005 USA
[2] Pfizer Inc, St Louis, MO USA
[3] Pfizer Inc, Groton, CT 06340 USA
[4] NIEHS, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC USA
[5] Bristol Myers Squibb Co, Wilmington, DE USA
[6] Schering Plough Res Inst, Lafayette, NJ USA
[7] AstraZeneca, Charnwood, Leics, England
[8] Procter & Gamble Co, Miami Valley Labs, Cincinnati, OH USA
[9] Med Coll Wisconsin, Milwaukee, WI 53226 USA
[10] US FDA, Ctr Drug Evaluat & Res, Laurel, MD USA
[11] Eli Lilly & Co, Greenfield, IN 46140 USA
[12] Novartis Pharmaceut, E Hanover, NJ USA
[13] Amgen Inc, Thousand Oaks, CA 91320 USA
关键词
cisplatin; gentamicin; nephrotoxicity; puromycin; risk assessment;
D O I
10.1289/ehp.6673
中图分类号
X [环境科学、安全科学];
学科分类号
08 ; 0830 ;
摘要
Microarrays allow for the simultaneous measurement of changes in the levels of thousands of messenger RNAs within a single experiment. As such, the potential for the application of transcription profiling to preclinical safety assessment and mechanism-based risk assessment is profound. However, several practical and technical challenges remain. Among these are nomenclature issues, platform-specific data formats, and the lack of uniform analysis methods and tools. Experiments were designed to address biological, technical, and methodological variability, to evaluate different approaches to data analysis, and to understand the application of the technology to other profiling methodologies and to mechanism-based risk assessment. These goals were addressed using experimental information derived from analysis of the biological response to three mechanistically distinct nephrotoxins: cisplatin, gentamicin, and puromycin aminonucleoside. In spite of the technical challenges, the transcription profiling data yielded mechanistically and topographically valuable information. The analyses detailed in the articles from the Nephrotoxicity Working Group of the International Life Sciences Institute Health and Environmental Sciences Institute suggest at least equal sensitivity of microarray technology compared to traditional end points. Additionally, microarray analysis of these prototypical nephrotoxicants provided an opportunity for the development of candidate bridging biomarkers of nephrotoxicity. The potential future extension of these applications for risk assessment is also discussed.
引用
收藏
页码:460 / 464
页数:5
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