Toxicological Sciences 63, 196-207 (2001)
Copyright © 2001 by the Society of Toxicology
MOLECULAR AND GENETIC TOXICOLOGY |
Assessment of Cisplatin-Induced Nephrotoxicity by Microarray Technology
* Department of Toxicology, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368;
Phase-1 Molecular Toxicology, Inc., Santa Fe, New Mexico 87505
Microarrays are a new technology used to study global gene expression and to decipher biological pathways. In the current study, microarrays were used to examine gene expression patterns associated with cisplatin-mediated nephrotoxicity. Sprague-Dawley rats received either single or seven daily ip doses of cisplatin (0.5 or 1 mg/kg/day) or the inactive isomer transplatin (1 or 3 mg/kg/day). Histopathological evaluation revealed renal proximal tubular necrosis in animals that received cisplatin for 7 days, but no hepatotoxic findings. Microarray analyses were performed using rat specific arrays containing 250 toxicity-related genes. Prominent gene expression changes were observed only in the kidneys of rats that received cisplatin for 7 days. Mechanistically, the gene expression pattern elicited by cisplatin (e.g., Bax
and SMP-30
) suggested the occurrence of apoptosis and the perturbation of intracellular calcium homeostasis. The induction of multidrug resistance genes (MDR1, P-gp) and tissue remodeling proteins (clusterin, IGFBP-1, and TIMP-1) indicated the development of cisplatin resistance and tissue regeneration. Select gene expression changes were further confirmed by TaqMan® analyses. Gene expression changes were not observed in the liver following cisplatin administration. In contrast to these in vivofindings, studies using NRK-52E kidney epithelial cells and clone-9 liver cells suggested that liver cells were more sensitive to cisplatin treatment. The discrepancies between thein vivoandin vitroresults suggest that caution should be taken when extrapolating data fromin vivotoin vitrosystems. Nonetheless, the current study elucidates the biochemical pathways involved in cisplatin toxicity and demonstrates the utility of microarrays in toxicological studies.
Key Words: microarray; toxicogenomics; cisplatin; nephrotoxicity; apoptosis; real-time PCR.
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