The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

Zazuli, Zulfan; Duin, Naut J. C. B.; Jansen, Katja; Vijverberg, Susanne; Zee, Anke‐Hilse Maitland‐van der; Masereeuw, Rosalinde

doi:10.3390/ijms21186627

Cited by 25 publications

(19 citation statements)

References 114 publications

(177 reference statements)

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“…Serum creatinine is not an ideal biomarker for drug-induced kidney injury because it is influenced by renal and non-renal factors independent of kidney function [54]. In addition, creatinine (to a small extent) competes with cisplatin for excretion as both are substrates of the organic cation transporter 2 (OCT2) [55]. Third, dehydration and chemotherapy-induced nausea and vomiting cases were difficult to detect due to the retrospective nature of the discovery cohort.…”

Section: Strengths and Limitationsmentioning

confidence: 99%

Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

Zazuli

Jong

et al. 2021

JPM

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This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10−8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10−7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

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Section: Strengths and Limitationsmentioning

confidence: 99%

Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

Zazuli

Jong

et al. 2021

JPM

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“…The SNPs of SLC22A1 have been shown to influence hOCT1 transport characteristics (affinity K m and maximal velocity V max ) and the pharmacokinetics of drugs, which are substrates of hOCT1. This aspect of hOCT1 regulation has been already summarized in other excellent reviews (Yee et al, 2018;Zazuli et al, 2020) and will be further discussed in detail in other contributions to this special issue.…”

Section: Long-term Regulation Of Oct1 Factors Determining Oct1 Expresmentioning

confidence: 82%

Regulation Mechanisms of Expression and Function of Organic Cation Transporter 1

Ciarimboli¹

2021

Front. Pharmacol.

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The organic cation transporter 1 (OCT1) belongs together with OCT2 and OCT3 to the solute carrier family 22 (SLC22). OCTs are involved in the movement of organic cations through the plasma membrane. In humans, OCT1 is mainly expressed in the sinusoidal membrane of hepatocytes, while in rodents, OCT1 is strongly represented also in the basolateral membrane of renal proximal tubule cells. Considering that organic cations of endogenous origin are important neurotransmitters and that those of exogenous origin are important drugs, these transporters have significant physiological and pharmacological implications. Because of the high expression of OCTs in excretory organs, their activity has the potential to significantly impact not only local but also systemic concentration of their substrates. Even though many aspects governing OCT function, interaction with substrates, and pharmacological role have been extensively investigated, less is known about regulation of OCTs. Possible mechanisms of regulation include genetic and epigenetic modifications, rapid regulation processes induced by kinases, regulation caused by protein–protein interaction, and long-term regulation induced by specific metabolic and pathological situations. In this mini-review, the known regulatory processes of OCT1 expression and function obtained from in vitro and in vivo studies are summarized. Further research should be addressed to integrate this knowledge to known aspects of OCT1 physiology and pharmacology.

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“…Cellular metformin passage through the plasma membrane is mainly mediated by organic cation transporters (OCT) and multidrug and toxin extrusion proteins (MATEs) (Zhou et al, 2016). Polymorphisms of the genes encoding for these transporters may change cellular transport of metformin, despite that the question whether these mutations have a clinical significance is still debated (Zazuli et al, 2020). Interestingly, a mutation in the Solute Carrier 2A2 (SLC2A2) gene encoding for the glucose transporter 2 (GLUT2) has been demonstrated to have a clear clinical impact on metformin efficacy especially in obese patients (Zhou et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Expression and Function of Organic Cation Transporter 2 in Pancreas

Schorn

Dicke

Neugebauer

et al. 2021

Front. Cell Dev. Biol.

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Organic cation transporters (OCT) play an important role in mediating cellular uptake of several pharmaceuticals, such as the antidiabetic drug metformin and the platinum-derived chemotherapeutics. Since these drugs can also affect the pancreas, here it was investigated whether these transporters are expressed in this organ. An interaction between OCT2 and the glucose transporter 2 (GLUT2), which is expressed with important functional consequences in the kidneys and in the pancreas, has already been demonstrated elsewhere. Therefore, here it was further investigated whether the two proteins have a functional relationship. It was demonstrated that OCT2 is expressed in pancreas, probably in β cells of Langerhans islets, together with GLUT2. However, a co-localization was only evident in a cell-line model of rat pancreatic β cells under incubation with high glucose concentration. High glucose stimulated OCT2 expression and activity. On the other side, studies conducted in human embryonic kidney cells stably expressing OCT2, showed that overexpression of GLUT2 decreased OCT2 activity. Unfortunately, pull-down experiments aimed to confirm a physical OCT2/GLUT2 interaction were not successful. Renal glucose excretion was reduced in mice with genetic deletion of OCT2. Nonetheless, in these mice no regulation of known kidney glucose transporters was measured. Therefore, it may be speculated that OCT2 may influence cellular trafficking of GLUT2, without changing its amount. OCT2 may play a role in drug uptake of the pancreas, and its activity may be regulated by glucose and GLUT2. Vice versa, GLUT2 activity may be regulated through an interaction with OCT2.

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The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

Cited by 25 publications

References 114 publications

Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

Regulation Mechanisms of Expression and Function of Organic Cation Transporter 1

Expression and Function of Organic Cation Transporter 2 in Pancreas

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