Immunohistochemical localization of OCT2 in the cochlea of various species

Abstract

ObjectiveTo locate the organic cation transporter 2 (OCT2) in the cochlea of three different species and to modulate the ototoxicity of cisplatin in the guinea pig by pretreatment with phenformin, having a known affinity for OCT2.Study DesignImmunohistochemical and in vivo study.MethodsSections from the auditory end organs were subjected to immunohistochemical staining in order to identify OCT2 in cochlea from untreated rats, guinea pigs, and a pig. In the in vivo study, guinea pigs were given phenformin intravenously 30 minutes before cisplatin administration. Electrophysiological hearing thresholds were determined, and hair cells loss was assessed 96 hours later. The total amount of platinum in cochlear tissue was determined using mass spectrometry.ResultsOrganic cation transporter 2 was found in the supporting cells and in type I spiral ganglion cells in the cochlea of all species studied. Pretreatment with phenformin did not reduce the ototoxic side effect of cisplatin. Furthermore, the concentration of platinum in the cochlea was not affected by phenformin.ConclusionsThe localization of OCT2 in the supporting cells and type I spiral ganglion cells suggests that this transport protein is not primarily involved in cisplatin uptake from the systemic circulation. We hypothesize that OCT2 transport intensifies cisplatin ototoxicity via transport mechanisms in alternate compartments of the cochlea.Level of EvidenceN/A. Laryngoscope, 125:E320–E325, 2015

An integrated view of cisplatin-induced nephrotoxicity and ototoxicity

“…3B) and taken up by a variety of cochlear cells. Although it is unclear how transporters like OCT2 and CTR1 facilitate cisplatin trafficking through the cochlea, competitive inhibition of CTR1 and genetic loss of function in the OCT2 gene offer protection from cisplatin-induced ototoxicity (Ciarimboli et al, 2010; Hellberg et al, 2015; Lanvers-Kaminsky et al, 2015; More et al, 2010). Unlike most cells, sensory hair cells have mechano-electrical transduction (MET) channels that are uniquely gated by tip links between individual stereocilia in their apically-located hair bundle (Assad et al, 1991; Hudspeth, 1986; Hudspeth and Corey, 1977; Pickles et al, 1984).…”

The Role of Transporters in the Toxicity of Chemotherapeutic Drugs: Focus on Transporters for Organic Cations

“…79 However, the antibody used in that study is probably nonspecific because control labeling of rat kidneys showed that OCT2 is localized in the apical membrane of renal tubules. 79 This localization is evidently false because OCT2 is well known to be expressed in the basolateral membrane domain. 80 Outer and inner hair cells, the stria vascularis, the spiral ganglia, and the surrounding nerves of the cochlea also express the CTR1.…”

“…Recently, an immunohistological study of OCT2 expression in the rat cochlea failed to detect any expression of the transporter in hair cells or in the stria vascularis . However, the antibody used in that study is probably nonspecific because control labeling of rat kidneys showed that OCT2 is localized in the apical membrane of renal tubules . This localization is evidently false because OCT2 is well known to be expressed in the basolateral membrane domain .…”

“…In mice, expression of OCT2 has been demonstrated in cochlea outer and inner hair cells and cells of the stria vascularis, and the presence of OCT2 has been associated with acute cisplatin‐induced ototoxicity . Recently, an immunohistological study of OCT2 expression in the rat cochlea failed to detect any expression of the transporter in hair cells or in the stria vascularis . However, the antibody used in that study is probably nonspecific because control labeling of rat kidneys showed that OCT2 is localized in the apical membrane of renal tubules .…”

In reference to Immunohistochemical localization ofOCT2 in the cochlea of various species

“…In the article "Immunohistochemical localization of OCT2 in the cochlea of various species," which appeared in the September 2015 Issue of Laryngoscope, 1 Hellberg et al investigated the expression of the organic cation transporter 2 (Oct2) in the cochlea of different animals by immunohistochemical analysis. The issue is of importance because of the role of Oct2 as an uptake transporter for ototoxic and nephrotoxic drugs such as cisplatin, 2,3 and such an analysis has the potential to predict which cells are particularly sensitive to cisplatin toxicity.…”