Functional consequences of polyamine synthesis inhibition by L-alpha-difluoromethylornithine (DFMO): cellular mechanisms for DFMO-mediated ototoxicity.
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.
Nie
Liping
L
Center for Neuroscience, Department of Otolaryngology, University of California, Davis 95616, USA.
Feng
Weihong
W
Diaz
Rodney
R
Gratton
Michael A
MA
Doyle
Karen Jo
KJ
Yamoah
Ebenezer N
EN
D000595:Amino Acid Sequence; D000818:Animals; D003053:Cochlear Duct / Q000187:drug effects; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000518:Eflornithine / Q000494:pharmacology*; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006309:Hearing; D051379:Mice; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009865:Oocytes / Q000378:metabolism; D010641:Phenotype; D011073:Polyamines / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011188:Potassium / Q000737:chemistry; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013016:Sound; D013316:Stria Vascularis / Q000378:metabolism; D013997:Time Factors; D014981:Xenopus; D000098854:Kcnj10 Channel
D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D000098854:Kcnj10 Channel; D011073:Polyamines; D024661:Potassium Channels, Inwardly Rectifying; D011188:Potassium; D000518:Eflornithine