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Int. J. Mol. Sci. 2017, 18(7), 1333; doi:10.3390/ijms18071333

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin

1
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO 80045, USA
2
Kidney Center, University of North Carolina School of Medicine, Division of Nephrology and Hypertension, Chapel Hill, NC 27599, USA
3
Cancer Center, University of Colorado, Aurora, CO 80045, USA
4
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA
5
Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, CO 80045, USA
*
Author to whom correspondence should be addressed.
Received: 28 April 2017 / Revised: 6 June 2017 / Accepted: 8 June 2017 / Published: 22 June 2017
(This article belongs to the Special Issue Nephrotoxicity)
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Abstract

Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI. View Full-Text
Keywords: cisplatin; nephrotoxicity; acute kidney injury; pharmacogenomics; CTR1; GGT1; GST; KEAP1; MATE1; MRP2; NRF2; OCT2 cisplatin; nephrotoxicity; acute kidney injury; pharmacogenomics; CTR1; GGT1; GST; KEAP1; MATE1; MRP2; NRF2; OCT2
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MDPI and ACS Style

Chang, C.; Hu, Y.; Hogan, S.L.; Mercke, N.; Gomez, M.; O’Bryant, C.; Bowles, D.W.; George, B.; Wen, X.; Aleksunes, L.M.; Joy, M.S. Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin. Int. J. Mol. Sci. 2017, 18, 1333.

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