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J. Biol. Chem., Vol. 280, Issue 15, 15097-15102, April 15, 2005

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Functional Consequences of Polyamine Synthesis Inhibition by L--Difluoromethylornithine (DFMO)

CELLULAR MECHANISMS FOR DFMO-MEDIATED OTOTOXICITY^*

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

From the Center for Neuroscience, Department of Otolaryngology, University of California, Davis, Davis, California 95616 and the Department of Otorhinolaryngology, University of Pennsylvania, Philadelphia, Pennsylvania 19014

L--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.

Received for publication, August 26, 2004 , and in revised form, January 21, 2005.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY374423.

^* This work was supported in part by a grant from the Deafness Research Foundation (to L. N.) and by Grants DC007592 and DC004523 from the National Institutes of Health (to E. N. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by Grant DC006442 from the National Institutes of Health.

^|| To whom correspondence should be addressed: Center for Neuroscience, Dept. of Otolaryngology, University of California, Davis, 1544 Newton Ct., Davis, CA 95616. Tel.: 530-754-6630; Fax: 530-754-7183; E-mail: enyamoah{at}ucdavis.edu.

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