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

Autor: Nickie Mercke, Madeleine Gomez, Cindy L. O'Bryant, Blessy George, Yichun Hu, Xia Wen, Lauren M. Aleksunes, Daniel W. Bowles, Cara Chang, Melanie S. Joy, Susan L. Hogan
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
Pharmacogenomic Variants
cisplatin
Pharmacology
Kidney
OCT2
lcsh:Chemistry
Prospective Studies
Cation Transport Proteins
lcsh:QH301-705.5
Spectroscopy
Copper Transporter 1
biology
Multidrug resistance-associated protein 2
nephrotoxicity
MRP2
Acute kidney injury
Organic Cation Transporter 2
CTR1
MATE1
General Medicine
Middle Aged
Multidrug Resistance-Associated Protein 2
3. Good health
Computer Science Applications
medicine.anatomical_structure
acute kidney injury
GGT1
Female
Multidrug Resistance-Associated Proteins
medicine.drug
Glomerular Filtration Rate
Adult
SLC47A1
Organic Cation Transport Proteins
Antineoplastic Agents
Catalysis
Article
Nephrotoxicity
NRF2
Inorganic Chemistry
03 medical and health sciences
medicine
Humans
Physical and Theoretical Chemistry
GST
Molecular Biology
Aged
Retrospective Studies
Cisplatin
pharmacogenomics
Clusterin
KEAP1
Organic Chemistry
medicine.disease
030104 developmental biology
Glutathione S-Transferase pi
lcsh:Biology (General)
lcsh:QD1-999
biology.protein
Biomarkers
Zdroj: International Journal of Molecular Sciences, Vol 18, Iss 7, p 1333 (2017)
International Journal of Molecular Sciences
International Journal of Molecular Sciences; Volume 18; Issue 7; Pages: 1333
ISSN: 1422-0067
Popis: 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.
Databáze: OpenAIRE
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