Selective inhibition of human heteromeric alpha9alpha10 nicotinic acetylcholine receptors at a low agonist concentration by low concentrations of ototoxic organic solvents.
Ethylbenzene and para-xylene (p-xylene), but not the chemically closely related organic solvents ortho-xylene (o-xylene) and meta-xylene (m-xylene), are known to cause ototoxicity and irreversible hearing loss, though the underlying mechanisms are still unknown. In this study, effects of ethylbenzene and of p-, o-, and m-xylene on human heteromeric alpha9alpha10 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes were investigated using the two-electrode voltage clamp technique. ACh dose-dependently evoked an alpha9alpha10 nAChR-mediated ion current with an EC(50) of 137 microM. When ACh is applied at a low concentration (10 microM), the nAChR-mediated ion current is inhibited by a low concentration (10 microM) of ethylbenzene and p-xylene, but not by the same concentration of the non-ototoxic solvents. At a high solvent concentration (300 microM), all solvents cause inhibition of the ion currents evoked by 10 microM ACh. Ion currents evoked by a near maximum-effective concentration ACh (1mM) are inhibited by the selected organic solvents only at 300 microM. These results demonstrate that low concentrations of the known ototoxic solvents ethylbenzene and p-xylene inhibit alpha9alpha10 nAChR-mediated ion currents, whereas the structurally related, non-ototoxic solvents m-xylene and o-xylene do not, indicating that the alpha9alpha10 nAChR is a potential target for solvent-induced ototoxicity.
van Kleef
Regina G D M
RG
Cellular and Molecular Toxicology, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands.
Vijverberg
Henk P M
HP
Westerink
Remco H S
RH
D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001555:Benzene Derivatives / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D006311:Hearing Disorders / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*; D014982:Xenopus laevis; D014992:Xylenes / Q000008:administration & dosage / Q000633:toxicity
D001555:Benzene Derivatives; C493739:CHRNA10 protein, human; D011978:Receptors, Nicotinic; D012997:Solvents; D014992:Xylenes; C443079:nAChR alpha9; C031286:4-xylene; C004912:ethylbenzene; D000109:Acetylcholine; C031285:3-xylene; C026114:2-xylene