Functional consequences of polyamine synthesis inhibition by L-α-difluoromethylornithine (DFMO)

Cellular mechanisms for DFMO-mediated ototoxicity

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

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

L-α-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.

Original languageEnglish (US)
Pages (from-to)15097-15102
Number of pages6
JournalJournal of Biological Chemistry
Volume280
Issue number15
DOIs
StatePublished - Apr 15 2005

Fingerprint

Eflornithine
Polyamines
Stria Vascularis
Cochlear Duct
Electromotive force
Cochlea
Audition
Pharmaceutical Preparations
Ducts
Colonic Neoplasms
Hearing
Cells
Throughput
Inhibition (Psychology)
Clinical Trials
Acoustic waves

ASJC Scopus subject areas

  • Biochemistry

Cite this

Functional consequences of polyamine synthesis inhibition by L-α-difluoromethylornithine (DFMO) : Cellular mechanisms for DFMO-mediated ototoxicity. / Nie, Liping; Feng, Weihong; Diaz, Rodney C; Gratton, Michael A.; Doyle, Karen Jo; Yamoah, Ebenezer N.

In: Journal of Biological Chemistry, Vol. 280, No. 15, 15.04.2005, p. 15097-15102.

Research output: Contribution to journalArticle

Nie, Liping ; Feng, Weihong ; Diaz, Rodney C ; Gratton, Michael A. ; Doyle, Karen Jo ; Yamoah, Ebenezer N. / Functional consequences of polyamine synthesis inhibition by L-α-difluoromethylornithine (DFMO) : Cellular mechanisms for DFMO-mediated ototoxicity. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 15. pp. 15097-15102.
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