Functional Consequences of Polyamine Synthesis Inhibition by l-α-Difluoromethylornithine (DFMO): CELLULAR MECHANISMS FOR DFMO-MEDIATED OTOTOXICITY

Liping Nie,Weihong Feng,Rodney Diaz,Michael A Gratton,Karen Jo Doyle,Ebenezer N Yamoah

doi:10.1074/jbc.m409856200

Abstract

L-Alpha-difluoromethylornithine (DFMO) is a chemopreventive agent for colon cancer in clinical trials. Yet, the drug produces an across-frequency elevation of the hearing threshold, suggesting that DFMO may affect a common trait along the cochlear spiral. The mechanism for the ototoxic effects of DFMO remains uncertain. The cochlear duct is exclusively endowed with endocochlear potential (EP). EP is a requisite for normal sound transduction, as it provides the electromotive force that determines the magnitude of the receptor potential of hair cells. EP is generated by the high throughput of K(+) across cells of the stria vascularis, conferred partly by the activity of Kir4.1 channels. Here, we show that the ototoxicity of DFMO may be mediated by alteration of the inward rectification of Kir4.1 channels, resulting in a marked reduction in EP. These findings are surprising given that the present model for EP generation asserts that Kir4.1 confers the outflow of K(+) in the stria vascularis. We have proposed an alternative model. These findings should also enable the rational design of new pharmaceuticals devoid of the untoward effect of DFMO.

Highlights

L-␣-Difluoromethylornithine (DFMO) is a chemopreventive agent for colon cancer in clinical trials
The analysis of the amino acid sequences of putative proteins from Kir4.1 cDNAs revealed high similarities between stria vascularis (StV)-specific and other cloned Kir4.1 channels [15, 32,33,34,35] and bore the signature of an intermediate inward rectifier (Fig. 1), which gave the assurance that the channel is likely to be subjected to partial polyamine block and to be influenced by ornithine decarboxylase (ODC) (Fig. 1)
We have identified, cloned (GenBankTM accession number AY374423), and functionally expressed an inner ear lateral wall Kir4.1 channel that may serve as a target for the underlying mechanism for DFMO-induced ototoxicity

Summary

Introduction

L-␣-Difluoromethylornithine (DFMO) is a chemopreventive agent for colon cancer in clinical trials. We show that the ototoxicity of DFMO may be mediated by alteration of the inward rectification of Kir4.1 channels, resulting in a marked reduction in EP These findings are surprising given that the present model for EP generation asserts that Kir4.1 confers the outflow of K؉ in the stria vascularis. A congenital deficiency in intermediate cells (IC(s)), melanocytes forming the middle cellular layer of the StV, results in a reduction in EP and an increase in the hearing threshold [13, 14] For this reason, as well as the fact that ICs express Kir4.1, it has been asserted that the Kir4.1 channel is responsible for the high throughput of outward Kϩ movement across the IC membrane that leads to generation of EP [15,16,17]. The underlying cellular mechanisms for the contribution of Kir4.1 to EP generation are reevaluated, and the possible mechanism of DFMO-mediated ototoxicity is outlined

Methods

Results

Conclusion