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

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Pharmacogenomic Variants*; Acute Kidney Injury/*chemically induced ; Acute Kidney Injury/*genetics ; Antineoplastic Agents/*adverse effects ; Cisplatin/*adverse effects ; Kidney/*drug effects; Acute Kidney Injury/physiopathology ; Acute Kidney Injury/urine ; Adult ; Aged ; Biomarkers/urine ; Cation Transport Proteins/genetics ; Copper Transporter 1 ; Female ; Glomerular Filtration Rate ; Glutathione S-Transferase pi/genetics ; Humans ; Kidney/physiopathology ; Male ; Middle Aged ; Multidrug Resistance-Associated Protein 2 ; Multidrug Resistance-Associated Proteins/genetics ; Organic Cation Transport Proteins/genetics ; Organic Cation Transporter 2/genetics ; Prospective Studies ; Retrospective Studies

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.
Competing Interests: The authors declared no conflict of interest.

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R01 GM107122 United States GM NIGMS NIH HHS; R21 DK093903 United States DK NIDDK NIH HHS; T32 ES007148 United States ES NIEHS NIH HHS

Keywords: CTR1; GGT1; GST; KEAP1; MATE1; MRP2; NRF2; OCT2; acute kidney injury; cisplatin; nephrotoxicity; pharmacogenomics

0 (ABCC2 protein, human)
0 (Antineoplastic Agents)
0 (Biomarkers)
0 (Cation Transport Proteins)
0 (Copper Transporter 1)
0 (Multidrug Resistance-Associated Protein 2)
0 (Multidrug Resistance-Associated Proteins)
0 (Organic Cation Transport Proteins)
0 (Organic Cation Transporter 2)
0 (SLC22A2 protein, human)
0 (SLC31A1 protein, human)
0 (SLC47A1 protein, human)
EC 2.5.1.18 (GSTP1 protein, human)
EC 2.5.1.18 (Glutathione S-Transferase pi)
Q20Q21Q62J (Cisplatin)

Date Created: 20170623 Date Completed: 20180322 Latest Revision: 20211204

20231215

PMC5535826

10.3390/ijms18071333

28640195