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Vol 1 | Issue 1 | Apr – Jun 2022                                                                                       Indian J Pharm Drug Studies | 5 

Review Article  

Role of membrane transporters in Cisplatin induced nephrotoxicity 

Sakshi1, Gaaminepreet Singh1 

From, 1Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab. 

Correspondence to: Gaaminepreet Singh, ISF College of Pharmacy, Moga, Punjab, India. Tel.: +91 7696579358; Email: 

gpsinghcologist@hotmail.com. 

ABSTRACT 

Transporters are important mediators of specific cellular uptake and thus, not only for effects, but also for side effects, metabolism, and 

excretion of many drugs such as cisplatin. Cisplatin is a potent cytostatic drug, whose use is limited by its severe acute and chronic nephro-, 

oto-, and peripheral neurotoxicity. For this reason, other platinum derivatives, such as carboplatin and oxaliplatin, with less toxicity but still 

with antitumoral action have been developed. Several transporters, which are expressed on the cell membranes, have been associated with 

cisplatin transport across the plasma membrane and across the cell: the copper transporter 1 (CTR1), the copper transporter 2 (CTR2), the P-

type copper-transporting ATPases ATP7A and ATP7B, the organic cation transporter 2 (OCT2), and the multidrug extrusion transporter 1 

(MATE1). Some of these transporters are also able to accept other platinum derivatives as substrate. Since membrane transporters display a 

specific tissue distribution, they can be important molecules that mediate the entry of platinum derivatives in target and also non-target cells 

possibly mediating specific effects and side effects of the chemotherapeutic drug. This paper summarizes the literature on toxicities of cisplatin 

compared to that of carboplatin and oxaliplatin and the interaction of these platinum derivatives with membrane transporters. 

Keywords: Nephrotoxicity, Ototoxicity, Neurotoxicity, MATE1, OCT2, CTR2. 

n the last several decades, novel cancer drugs have been 

developed and used in clinical practice, being more specific 

against cancer cells and extremely effective against several 

previously untreatable malignancies, the so-called molecularly 

targeted agents, but also suffer from nephrotoxicity which limits 

the efficacy of the treatment and impact their quality of life and 

overall survival [1]. Most of the chemotherapeutic agents 

developed so far exert their action in the cell and therefore have 

to cross the cell membrane to reach their targets [2]. However, 

they are often poorly lipophilic compounds, which cannot easily 

pass the cell membrane and thus need to be transported into the 

cell by specific systems of protein nature called transporters [3]. 

General concept of drug movement across biological 

membranes is that they can pass cell membranes via passive 

diffusion at a rate related to their lipophilicity. However, it is 

becoming evident that membrane transporters are also 

important determinants of in vivo drug disposition, therapeutic 

efficacy, and adverse drug reactions [3].  

In epithelial tissues, which are constituted by polarized cells, 

transporters are even specifically expressed on the apical or 

baso-lateral cell  membrane [4]. In this way, a specific drug-

transporter interaction can be exploited to target drugs to 

selected cells and tissues, but of course can also explain specific 

undesired adverse effects [5]. Membrane transporters such as 

the copper transporter-1 (CTR1), the copper transporter-2 

(CTR2), the p-type copper transporting ATPases atp7a and 

atp7b, the organic cation transporter-2 (OCT2), and the 

multidrug extrusion transporter-1 (MATE1) mediate cellular 

transport of cisplatin [6]. Transporter mediated uptake has been 

shown to be an important process mediating cellular 

accumulation of cisplatin. Cisplatin is one of the most widely 

utilized antitumor drugs in the world [7].  

Cisplatin was the first platinum-based drug that 

revolutionized the treatment of neoplastic diseases. For 

example, before the introduction of cisplatin as 

chemotherapeutic agent, testicular cancer was associated with a 

survival rate of only 5% [8]. Today, treatment of this cancer 

with a combination of new surgical techniques and cisplatin 

chemotherapy allows to achieve a cure rate of over 90%. 

Currently, cisplatin is widely used for the therapy of solid 

tumors [9]. However, its use is limited by severe side effects 

such as nephro- and ototoxicity and peripheral neurotoxicity. 

Therefore, there is a need to put an effort in developing less 

toxic platinum derivatives [10]. 

Action of cisplatin on cell growth was unexpectedly 

discovered by rosenberg in 1965 by investigating the effects of 

an electric field on the growth of escherichia coli bacteria [11]. 

When placed in an electric field using platinum-conducting 

plates, bacteria ceased to divide. Rosenberg hypothesized that 

if cisplatin could inhibit bacterial cell division it could also 

suppress tumor cell growth. Cisplatin was approved by the FDA 

I 

mailto:gpsinghcologist@hotmail.com


Sakshi and Singh                                                                                                              Cisplatin induced nephrotoxicity  

Vol 1 | Issue 1 | Apr – Jun 2022                                                                                       Indian J Pharm Drug Studies | 6 

in 1978 for the treatment of metastatic testicular or ovarian 

cancer and is also administered for many other types of solid 

tumors [12]. 

A common event happening when platinating agents enter a 

cell is their aquation that is losing of chloride or oxalate ions 

and gaining two water molecules to form aquaions. The low 

intracellular concentration of chloride ions facilitates this 

process [13]. Positively charged aquated form is more reactive 

to the cellular targets, such as nucleophilic molecules within the 

cell, including DNA, RNA, and proteins [14]. It is generally 

accepted that DNA is the preferential cytotoxic target for 

cisplatin and other platinating agents: these substances bind 

preferentially the imidazole ring of the purines guanosine and 

adenosine forming monoadducts, intrastrand crosslinks, and 

interstrand crosslinks [15]. All crosslinks distort the structure of 

the DNA duplex and begin the DNA damage response 

signaling, resulting in cell cycle arrest and apoptosis [16]. 

Cisplatin Toxicity 

Cisplatin treatment, even though effective against tumors, has 

severe side-effects such as nephrotoxicity, which is often dose-

limiting, ototoxicity, and peripheral neurotoxicity [5]. 

Nephrotoxicity 

In patients cisplatin-induced nephrotoxicity manifests acutely 

and/or chronically. Clinically, cisplatin nephrotoxicity develops 

after 10 days of cisplatin administration and is manifested as 

lower glomerular filtration rate, higher serum creatinine, and 

reduced serum magnesium and potassium levels Interestingly, 

striking differences between patients in susceptibility to 

progressive nephrotoxicity are Even though nephrotoxicity can 

be controlled by diuretics and prehydration of patients [17]. It 

is recognized that the prevalence of cisplatin nephrotoxicity is 

high, occurring in about one third of patients undergoing 

cisplatin treatment In animal studies it has been shown that the 

kidney accumulates more cisplatin than other organs and that 

the proximal tubules are principally damaged by cisplatin [18]. 

Ototoxicity 

Ototoxicity is an9 untypical side effect for a chemotherapeutic 

drug. Cisplatin treatment causes a hearing loss, which can also 

lead to deafness [19]. Ototoxicity remains an unresolved 

clinical problem especially in infants and younger children, 

where it leads to a considerable risk of delayed language 

development due to impaired perception of higher frequency 

consonant sounds that is of great importance in the presence of 

background noise [20]. Incidence of ototoxicity is reported to 

be between 23 and 50% in adults and greater than 50% in 

children, clinical symptoms of toxicity consist of bilateral 

symmetrical high-frequency sensori-neural hearing loss, ear 

pain, or tinnitus [21]. Damage induced by cisplatin begins at the 

cochlea base, where high-frequency sounds are processed, and 

proceeds towards the apex, affecting also hearing at lower 

frequencies as the cumulative dose increases [21]. In the 

cochlea, cisplatin seems to induce the generation of reactive 

oxygen species and/or the depletion of scavenging enzymes 

causing cell apoptosis [22]. 

Neurotoxicity 

Most patients treated with cisplatin develop a symptomatic and 

clinically detectable sensory neuropathy, caused by its 

preferential uptake in the dorsal root ganglia, which produces a 

dose-related large fibre sensory neuropathy [5]. Symptoms 

include unpleasant distal paresthesias (tingling in the 

extremities) and numbness, associated with large fibre sensory 

-loss (reduced vibration and joint position sensations) and 

diminished or absent muscle stretch reflexes [23]. Sensory 

ataxia (incoordination) may be disabling in those patients who 

have severe neuropathy. these symptoms may appear as soon as 

one month after initiating treatment [24]. The neuropathy may 

only partially recover or not recover at all. In rodents, cisplatin 

affects sensory nerve structure and function, showing 

preferential toxicity to large diameter neurons and 

proprioceptive sensory modalities, while motor nerves are 

spared from toxicity. The mechanism of platinum neurotoxicity 

remains in completely understood although it may involve 

platinum accumulation within the dorsal root ganglia (DRG) 

leading to atrophy or loss of peripheral sensory neurons [25]. 

Cellular Transport of Cisplatin 

Several different transporters seem to be involved in the cellular 

transport of cisplatin: CTR1, CTR2the P-type copper-

transporting ATPases ATP7A and ATP7B, OCT2 and MATE1 

[5]. 

Copper Transporter 1 (CTR1) 

Copper transporter 1 (Ctr1, Solute Carrier 31A1-SLC31A1) is 

a membrane protein that plays a significant role in the cellular 

cisplatin uptake. Down-regulation of Ctr1 extensively reduced 

cisplatin uptake in yeast and inmouse embryonic fibroblasts 

[26]. The natural substrate of Ctr1 is monovalent copper (Cu+). 

Cu+ uptake by Ctr1 triggers transporter internalization [27]. 

However, whether this phenomenon also happens upon 

cisplatin transport is debated. As observed for Cu+, cisplatin 

binds to Methionine-rich motifs of the extracellular domain of 

Ctr1. Ctr1 carries out vital physiological function supplying the 

cell with copper, which is an essential cellular nutrient used in 

a broad range of enzymatic reactions. Because of its important 

biological role, Ctr1 is almost ubiquitously expressed and 

perhaps may not be the decisive transporter for specific 

cisplatin toxicities. Since several cell lines from human tumor 

samples express Ctr1- mRNA, this transporter could represent 

the uptake route of cisplatin in cancer cells. Indeed, high 



Sakshi and Singh                                                                                                              Cisplatin induced nephrotoxicity  

Vol 1 | Issue 1 | Apr – Jun 2022                                                                                       Indian J Pharm Drug Studies | 7 

expression levels of Ctr1 have been associated with cisplatin 

therapeutic success whereas Ctr1 mutations are associated with 

cisplatin resistance. Ctr1 has been also associated with the 

cellular transport of carboplatin and oxaliplatin [28]. 

Copper Transporter 2 (CTR2) 

Copper transporter 2 (Ctr2, SLC31A2) is a copper transport 

protein  with substantia structural homology to Ctr1. Ctr2 is 

mainly expressed in late endosomes and lysosomes , where it 

probably mediates the efflux of copper under conditions of low 

environmental copper concentration [12]. A similar function of 

Ctr2 was proposed for cisplatin. Studies in Ctr2-deficientmice 

suggested that Ctr2 functions as an indirect regulator of Cu+-

uptake and intracellular flux by stabilizing the biosynthesis of 

cleaved Ctr1. The cleaved Ctr1 is a transporter form which 

lacks metal binding Methionine- and Histidine-rich motifs and 

of consequence has decreased Cu+ and also cisplatin uptake 

function [29]. Therefore, high expression of Ctr2 seems to be 

associated with resistance to the cytotoxic effect of cisplatin and 

knockdown of Ctr2 was associated with an increased cisplatin 

accumulation and cytotoxicity [30]. 

Copper-Transporting (ATP7A and ATP7B)  

The P-type copper-transporting ATPases ATP7A and ATP7B 

are also involved in cellular cisplatin handling [31]. These 

transporters play an important role in regulating the cellular 

copper levels, because too high intracellular copper 

concentrations are toxic for the cell [32]. Inactivation of these 

transporters, as present for example in Menkes’ disease 

(inactivation of ATP7A) and in Wilson’s disease (inactivation 

of ATP7B), is associated with copper deficiency because of 

impaired copper efflux from enterocytes into the blood or 

massive cellular copper overload, respectively [26].  

While ATP7A is mainly expressed in intestine, choroid 

plexus, vascular smooth muscle and endothelial cells, as well as 

in cerebrovascular endothelial cells, ATP7B is principally 

expressed in the liver and the brain [33]. Regarding the 

transport of cisplatin, ATP7A and ATP7B mediate its efflux 

from the cell or its distribution to specific sub-cellular 

compartments [34]. For this reason, the expression of these 

transporters is correlated with cisplatin cellular sensitivity and 

resistance ATP7B is stronger associated with the acquisition of 

resistance than Ctr1 or ATP7A. Besides cisplatin, ATP7A and 

B transporters also interact with carboplatin and oxaliplatin 

[35].  

Even though the effects of ATP7A and B transporters on 

cisplatin cellular distribution are very similar to those observed 

for copper, platinum drugs are not readily exported after 

vesicular sequestration [35]. Interestingly, copper transport 

systems are expressed and active in DRG, which are sensitive 

to toxicity from platinum derivatives. Here, Ctr1 is expressed in 

large-sized neurons and ATP7A in small DRG neurons, 

suggesting that large neurons are especially sensitive and small 

neurons are protected from toxic effects of platinum derivatives 

[36]. 

Organic Cation Transporters (OCT1-3, SLC22A1-3)  

A specific interaction of cisplatin with OCTs has also been 

demonstrated. Since OCTs have a specific organ distribution, 

with high renal expression, the cisplatin-OCT interaction is of 

pecial interest to explain selective organ toxicity of cisplatin 

[26]. OCTs are highly expressed in excretory organs such as the 

liver and the kidneys, where they mediate the electrogenic 

uptake of heir substrates in hepatocytes and proximal tubule 

cells. OCTs are defined as polyspecific transporters, because 

they can transport several unrelated substances. The driving 

force for the cellular transport by OCTs is the electrochemical 

gradient of the substrate [37]. In excretory organs, OCTs 

mediate the first step of secretion process, consisting of 

substrate uptake through the baso-lateral plasma membrane (the 

blood-faced part of plasma membrane). The subsequent 

substrate efflux through the luminal membrane (the bile- or 

urine-faced part of plasma membrane) is the final secretion step, 

resulting in a vectorial substrate movement from the blood to 

the bile or urine in the liver or kidneys, respectively. In humans 

the paralogs hOCT1 and hOCT2 are specifically expressed in 

the basolateral membrane of hepatocytes and renal proximal 

tubule cells, respectively [38]. Cisplatin seems to interact 

preferentially with hOCT2, suggesting that hOCT2 is the 

critical transporter for renal cisplatin uptake in humans. Also 

the second- and third generation platinum derivatives 

oxaliplatin are substrates of OCTs [38].  

For the interpretation of translational studies, it is important 

to underline that the rodent OCT orthologs have a different 

organ distribution and kinetic properties compared with human 

OCTs: for example, in mice OCT1 is expressed in renal 

proximal tubules at higher level than OCT2. Competition of 

OCT-mediated cisplatin transport is able to reduce cisplatin 

uptake and toxicity in vitro and in vivo. OCT2 has been 

demonstrated to be expressed in the mouse cochlea in hair cells 

of organ of corti and in the cells of the stria vascularis and in 

mouse and human DRG), structures that are specially sensitive 

to toxicity by platinum-derivatives. In animal models it has 

been demonstrated that OCTs are critical mediators of cisplatin 

ototoxicity and oxaliplatin peripheral neurotoxicity [5]. 

Multidrug and Toxin Extrusion Protein 1 (MATE1, 

SLC47A1) 

Several evidences indicate that MATE1 mediates secretion of 

cisplatin into the urine. Mice with genetic deletion of MATE1 

are more sensitive to cisplatin nephrotoxicity [39]. 

Furthermore, cell transfected with MATE1 displayed a higher 

cisplatin uptake than control cells. Interestingly, MATE1 and 



Sakshi and Singh                                                                                                              Cisplatin induced nephrotoxicity  

Vol 1 | Issue 1 | Apr – Jun 2022                                                                                       Indian J Pharm Drug Studies | 8 

MATE2-K, another member of MATE family which is solely 

expressed in human kidneys, seem to transport oxaliplatin with 

higher affinity than cisplatin, offering a possible explanation of 

the low oxaliplatin nephrotoxicity. As outlined above, 

inhibition of OCT2 may be a protective strategy against 

cisplatin nephrotoxicity [40].  

However, some inhibitors of OCT2 such as cimetidine and 

ondansetron interact with higher potency with MATE1, 

blocking cisplatin efflux from the cells and potentially 

increasing cisplatin renal toxicity [41]. Indeed, co-treatment of 

mice with cisplatin and cimetidine was effective in protecting 

the animals from ototoxicity but not from nephrotoxicity [42]. 

There are some investigations suggesting a role of novel 

organic cation transporters (OCTNs) for oxaliplatin transport. 

These transporters are expressed on the apical membrane of 

renal proximal tubule cells and in rat DRGs. When transfected 

in human embryonic kidney cells, rat and human OCTN1 and 

OCTN2 mediate significant oxaliplatin uptake, suggesting that 

OCTNs are involved in oxaliplatin neurotoxicity [26]. Apart 

from these not directly ATP-dependent transporters, multidrug 

resistance-associated protein 2 (Mrp2) transporter seems to be 

involved in the efflux of cisplatin and its conjugates from 

kidney cells, and for this reason to play an important role for 

control of cisplatin renal toxicity [43]. 

CONCLUSION 

Cellular transport of platinum derivatives is mediated by several 

transport systems. Some transporters, such as OCTs, are 

specifically expressed in organs, which are damaged by 

antitumor therapy with platinum derivatives. For this reason, 

they may be a target for protective intervention. However, an 

efficient protection can be only reached by specific inhibition 

of OCTs. 

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How to cite this article: Sakshi, Gaaminepreet Singh. 

Role of membrane proteins in cisplatin induced 

nephrotoxicity. Indian J Pharm Drug Studies. 2022: 1(1); 

5-9. 

Funding: None                Conflict of Interest: None Stated 

 


